WO2012106584A2 - Pitavastatin salts - Google Patents

Abstract

The present disclosure includes salt of pitavastatin, and processes for their preparation and isolation. It further relates to crystalline forms of pitavastatin salts and hydrates thereof, and process for preparing an amorphous form of pitavastatin

Description

PITAVASTATIN SALTS

INTRODUCTION

Aspects of the present application relate to salts of pitavastatin, and to processes for their preparation and isolation. Aspects also relate to crystalline forms of pitavastatin salts and hydrates or solvates thereof, and processes for preparing an amorphous form of pitavastatin calcium. Aspects of the application relate to pharmaceutical compositions comprising salts of the present application, or hydrates or solvates thereof, and their uses to treat hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

The drug having the adopted name "pitavastatin" has a chemical name (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy-6- heptenoic acid, and has structural formula (1 ).

(1 )

Pitavastatin is used as a cholesterol lowering agent (HMG-CoA reductase inhibitor). The HMG-CoA reductase enzyme catalyzes the conversions of HMG- CoA to mevalonate. Inhibitors of HMG-CoA reductase are commonly referred to as "statins." Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. The pitavastatin calcium salt is the active ingredient in products sold as LIVALO®, for the treatment of hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type Ha and lib).

Pitavastatin and its pharmaceutically acceptable salts are described in U.S.

Patent Nos. 5,753,675 and 5,856,336, respectively. International Patent Application Publication No. WO 2005/06371 1 A1 describes crystalline Form A of pitavastatin calcium that contains 5 to 15% of water. International Patent Application Publication No. WO 2004072/040 A1 discloses crystalline Forms A, B, C, D, E, F, and an amorphous form of pitavastatin calcium, and processes for their preparation.

Polymorphism is common among drug compounds. Pharmaceutical stability is believed to depend on simultaneous influences 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 processes of the polymorphic forms of pitavastatin calcium. Therefore, it would be desirable to prepare and characterize new polymorphic forms of pitavastatin calcium. Further, it would be desirable to have reliable processes for producing these forms.

U.S. Patent No. 5,856,336 describes pitavastatin sodium, but there is no specific disclosure for other salts of pitavastatin. Chinese Patent Application No. 101 195603 A discloses the lithium and ammonium salts of pitavastatin.

The literature has reports of organic amine salts of pitavastatin. International Patent Application Publication No. WO 2007/132482 discloses organic amine salts of pitavastatin, such as salts of pitavastatin with methylamine, n-butylamine, sec-butylamine, and L-arginine. International Patent Application Publication No. WO 2002/092570 A1 , discloses benzylamine and dicyclohexylamine salts of pitavastatin. International Patent Application Publication No. WO 2010/027060 A1 discloses a purification process for pitavastatin, involving forming chiral amine salts of pitavastatin with (S)- - aminobenzenepropanol, (R)-p-aminobenzenepropanol, (R)-a-methyl-l - naphthalenemethanamine, (S)-a-aminobenzeneacetic acid methyl ester, and (R)- a-ethylbenzenemethanamine, and crystallizing the salts.

Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, chemical reactivity, etc. These properties may appreciably influence pharmaceutical properties such as dissolution rates and bioavailability.

In addition, polymorphism is common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice. Different polymorphic forms of the same pharmaceutically active moiety also differ in their physical properties such as melting point, solubility, chemical reactivity, etc. These properties may also appreciably influence pharmaceutical properties such as dissolution rate and bioavailability.

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.

Although the known salts of pitavastatin 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. Further, the discovery of new salts and polymorphic forms of a drug enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional pitavastatin salts and polymorphs of pitavastatin salts.

Pharmaceutical stability is believed to depend on simultaneous influence of various factors, of which some important factors are the size of crystals, shape of crystals, solvent content, residual solvents, and impurities. One or more of these factors may be uniquely addressed by the isolation process of the crystalline forms of salts of pitavastatin.

Therefore, it would be desirable to prepare and characterize new pitavastatin salts and their polymorphs. Further, it would be desirable to have reliable processes for producing these pitavastatin salts and forms. Additionally, it has been the endeavor of pharmaceutical scientists to provide stable amorphous forms of drug substances that would have rapid onset of action and an enhanced bioavailability. SUMMARY

Embodiments of the present application relate to salts of pitavastatin with barium, magnesium, potassium, meglumine, diethanolamine, piperidine, phenylethylamine, piperazine, n-propylamine, and diisopropylamine. Further, the application relates to crystalline forms and hydrates of these salts, and to processes for their preparation.

In an aspect, there are provided processes for preparing salts of pitavastatin, embodiments comprising:

a) providing a solution of pitavastatin or a salt thereof; and

b) combining a cation source or organic base with the solution.

An aspect of the present application relates to processes for preparing an amorphous form of pitavastatin calcium, embodiments comprising removing the solvent from a solution of pitavastatin calcium.

In an aspect of the application, there are provided processes for preparing an amorphous form of pitavastatin calcium, embodiments comprising combining a solution of pitavastatin calcium with a suitable anti-solvent.

Aspects of the application provide pharmaceutical compositions comprising therapeutically effective amount of salts of pitavastatin with barium, magnesium, potassium, meglumine, diethanolamine, piperidine, phenylethylamine, piperazine, n-propylamine, and diisopropylamine, together with one or more pharmaceutically acceptable excipients.

An aspect of the application provides pharmaceutical compositions comprising therapeutically effective amount of amorphous pitavastatin calcium, together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an illustration of a powder X-ray diffraction ("PXRD") pattern of pitavastatin barium, prepared according to Example 2.

FIG. 2 is an illustration of a differential scanning calorimetry ("DSC") curve of pitavastatin barium, prepared according to Example 2.

FIG. 3 is an illustration of a thermogravimetric analysis ("TGA") curve of pitavastatin barium, prepared according to Example 2. FIG. 4 is an illustration of a PXRD pattern of pitavastatin potassium, prepared according to Example 3.

FIG. 5 is an illustration of a PXRD pattern of pitavastatin magnesium, prepared according to Example 4.

FIG. 6 is an illustration of a DSC curve of pitavastatin magnesium, prepared according to Example 4.

FIG. 7 is an illustration of a TGA curve of pitavastatin magnesium, prepared according to Example 4.

FIG. 8 is an illustration of a PXRD pattern of pitavastatin meglumine salt, prepared according to Example 5.

FIG. 9 is an illustration of a DSC curve of pitavastatin meglumine salt, prepared according to Example 5.

FIG. 10 is an illustration of a TGA curve of pitavastatin meglumine salt, prepared according to Example 5.

FIG. 1 1 is an illustration of a PXRD pattern of pitavastatin diethanolamine salt, prepared according to Example 6.

FIG. 12 is an illustration of a DSC curve of pitavastatin diethanolamine salt, prepared according to Example 6.

FIG. 13 is an illustration of a TGA curve of pitavastatin diethanolamine salt, prepared according to Example 6.

FIG. 14 is an illustration of a PXRD pattern of pitavastatin piperidine salt, prepared according to Example 7.

FIG. 15 is an illustration of a DSC curve of pitavastatin piperidine salt, prepared according to Example 7.

FIG. 16 is an illustration of a TGA curve of pitavastatin piperidine salt, prepared according to Example 7.

FIG. 17 is an illustration of a PXRD pattern of pitavastatin phenylethylannine salt, prepared according to Example 8.

FIG. 18 is an illustration of a DSC curve of pitavastatin phenylethylannine salt, prepared according to Example 8.

FIG. 19 is an illustration of a TGA curve of pitavastatin phenylethylannine salt, prepared according to Example 8.

FIG. 20 is an illustration of a PXRD pattern of pitavastatin piperazine salt, prepared according to example 9. FIG. 21 is an illustration of a DSC curve of pitavastatin piperazine salt, prepared according to example 9.

FIG. 22 is an illustration of a TGA curve of pitavastatin piperazine salt, prepared according to example 9.

FIG. 23 is an illustration of a PXRD pattern of pitavastatin n-propylamine salt, prepared according to example 10.

FIG. 24 is an illustration of a DSC curve of pitavastatin n-propylamine salt, prepared according to example 10.

FIG. 25 is an illustration of TGA curve of pitavastatin n-propylamine salt prepared according to example 10.

FIG. 26 is an illustration of PXRD pattern of pitavastatin diisopropylamine salt prepared according to example 1 1 .

FIG. 27 is an illustration of a DSC curve of pitavastatin diisopropylamine salt, prepared according to example 1 1 .

FIG. 28 is an illustration of a TGA curve of pitavastatin diisopropylamine salt, prepared according to example 1 1 .

FIG. 29 is an illustration of a PXRD pattern of pitavastatin calcium, prepared according to example 12.

FIG. 30 is an illustration of a DSC curve of pitavastatin calcium, prepared according to example 12.

FIG. 31 is an illustration of a TGA curve of pitavastatin calcium, prepared according to example 12.

FIG. 32 is an illustration of a PXRD pattern of pitavastatin barium, prepared according to example 13.

FIG. 33 is an illustration of a DSC curve of pitavastatin barium, prepared according to example 13.

FIG. 34 is an illustration of a TGA curve of pitavastatin barium, prepared according to example 13.

FIG. 35 is an illustration of a PXRD pattern of pitavastatin calcium, prepared according to example 14.

FIG. 36 is an illustration of a modulated DSC curve of pitavastatin calcium, prepared according to example 14.

FIG. 37 is an illustration of a PXRD pattern of pitavastatin calcium, prepared according to example 18. FIG. 38 is an illustration of a modulated DSC curve of pitavastatin calcium, prepared according to example 18.

DETAILED DESCRIPTION

Embodiments of the present application relate to salts of pitavastatin with barium, magnesium, potassium, meglumine, diethanol amine, piperidine, n- propylamine, diisopropylamine and piperazine. Further, relates to crystalline forms and hydrates of these salts and processes for their preparation.

In an aspect, there are provided processes for preparing salts of pitavastatin, embodiments comprising combining a suspension or solution of pitavastatin free acid, or a salt thereof, with a source of a cation or an organic base to the solution.

A suspension or a solution may be obtained, for example, by providing pitavastatin free acid or a salt of pitavastatin of any form in a suitable liquid. The salt may be obtained by treating pitavastatin free acid or an ester thereof with a base in a solvent, wherein the base can be inorganic or organic. If it is intended to obtain a solution of pitavastatin free acid or its salt, the mixture can be heated to dissolution temperatures that can be any temperatures, as long as the stability of the pitavastatin free acid or its salt is not compromised and a substantially clear solution is obtained. For example, the dissolution temperatures may range from about 20°C to about the reflux temperature of the solvent.

Amounts of solvent per gram of pitavastatin free acid or its salt typically vary from about 5 ml_ to about 200 ml_. Undissolved particles from a mixture comprising pitavastatin salts can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material.

Solvents employed for preparation of salts of pitavastatin include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as, for example, dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as, for example, toluene, xylene, and cyclohexane; nitriles such as acetonitrile; dipolar aprotic solvents such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide, and the like; water; and any mixtures of two or more thereof.

The solution or suspension is combined with a source of a cation or a base, to form the desired salt. The source of a cation employed in step b) could be an inorganic salt or an organic salt. Examples of such salts include, but are not limited to, barium chloride, magnesium chloride, ammonium chloride, ammonium acetate, calcium acetate, and the like. The bases employed can be inorganic or organic. Inorganic bases include, but are not limited to, alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates, and ammonium hydroxide. Examples of organic bases include, but are not limited to, triethylamine, meglumine, diethanolamine, piperidine, morpholine, and the like. The source of cation or a base can be combined in solid or liquid forms, such as in mixtures with a solvent. Suitable solvents are similar to those of the list above.

The mole ratio of a source of cation to pitavastatin free acid or its salt can be in the range of about 0.4-1 .5:1 . The reaction can be efficiently completed at ambient temperatures or, if desired the mass can be heated to elevated temperatures up to about the solvent reflux temperatures, and maintained for a time required for the desired extent of reaction, such as from about 10 minutes to about 5 hours, or longer.

To produce crystalline products, suitable temperatures for crystallization are from about 0°C to about 50°C, about 0°C to about 30°C, about 10°C to about 30°C, about 10°C to about 20°C, or any other temperatures may be used. Suitable times for crystallization will vary, and can be from about 10 minutes to about 10 hours, or longer.

The formed salts of pitavastatin may be isolated using conventional techniques that are known in the art. For example, useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.

Evaporation as used herein refers to distilling of solvent completely or almost completely, at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling solvent using a technique including, but not limited to, tray drying, spray drying, fluidized bed drying, thin-film drying under reduced pressure, or thin-film drying at atmospheric pressure.

The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. 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 1 hour to about 24 hours, or longer.

Once obtained, crystals of pitavastatin salts may be used as the nucleating agent or "seed" crystals for subsequent crystallizations of salts of pitavastatin from solutions. The isolated pitavastatin salts can be present in any forms which include, but are not limited to, crystalline or amorphous which may further be anhydrates, solvates, or hydrates. Certain salt forms of pitavastatin have been prepared and structurally characterized as described herein, and are referred to herein as pitavastatin barium, pitavastatin potassium, pitavastatin magnesium, pitavastatin meglumine salt, pitavastatin diethanolamine salt, pitavastatin piperidine salt, pitavastatin n-propylamine salt, pitavastatin diisopropylamine salt, and pitavastatin piperazine salt.

Solid form salts of pitavastatin salts of the present application have been characterized by means of their PXRD patterns and Fourier-transform infrared (FTIR) absorption spectra. Further, the described salt forms of pitavastatin of the present application exhibit a high solubility in water, i.e. greater than 50 mg/mL, and hence may also show enhanced pharmaceutical properties such as dissolution profiles and bioavailability. Additionally, the formation of the described pitavastatin salts of the application can be used to efficiently purify pitavastatin free acid. According to the application the salts of pitavastatin can be mono-salts, di-salts, or mixtures of mono-salts and di-salts.

The crystalline salts of the present application exhibit pharmaceutical advantages over pitavastatin free acid in the preparation of pharmaceutical dosage forms containing the pharmacologically active ingredient. In particular, the enhanced chemical and physical stability of the crystalline salts constitute advantageous properties in the preparation of solid pharmaceutical dosage forms containing the pharmacologically active ingredient.

Embodiments of the present application provide certain salts of pitavastatin, for example, pitavastatin barium. In embodiments, there is provided a crystalline form of pitavastatin barium. In embodiments, there is provided essentially pure pitavastatin barium. In embodiments, there is provided substantially pure pitavastatin barium. In embodiments, there is provided pure pitavastatin barium.

In embodiments, there is provided a crystalline form of pitavastatin barium characterized by its PXRD pattern having peaks substantially in accordance with the pattern shown in Fig. 1 . In embodiments, there is provided a crystalline form of pitavastatin barium characterized by a PXRD pattern having peaks at about 13.9, 18.9, 22.8, 24.0, and 25.8, ±0.2 degrees 2Θ. The crystalline form of pitavastatin barium can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 2.

In embodiments, there is provided pitavastatin magnesium. In embodiments, there is provided a crystalline form of pitavastatin magnesium. In embodiments, there is provided essentially pure pitavastatin magnesium. In embodiments, there is provided substantially pure pitavastatin magnesium. In embodiments, there is provided pure pitavastatin magnesium.

In embodiments, there is provided a crystalline form of pitavastatin magnesium characterized by its PXRD pattern having peaks located substantially in accordance with the pattern shown in Fig. 5. In embodiments, there is provided a crystalline form of pitavastatin magnesium characterized by its PXRD pattern having peaks located at about 4.5, 9.1 , and 13.6, ±0.2 degrees 2Θ. The crystalline form of pitavastatin barium can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 6.

In embodiments, there is provided a salt of pitavastatin with meglumine. In embodiments, there is provided a crystalline form of pitavastatin meglumine. In embodiments, there is proved essentially pure pitavastatin meglumine. In embodiments, there is provided substantially pure pitavastatin meglumine. In embodiments, there is provided pure pitavastatin meglumine.

In embodiments, there is provided a crystalline form of pitavastatin meglumine salt characterized by its PXRD pattern having peaks located substantially in accordance with the pattern shown in Fig. 8. In embodiments, there is provided a crystalline form of pitavastatin meglumine salt characterized by its PXRD pattern having peaks located at about 3.7, 9.0, 19.6, 19.9, 21 .7, and 22.1 , ±0.2 degrees 2Θ. The crystalline form of pitavastatin meglumine salt can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 9.

In embodiments, there is provided a salt of pitavastatin with diethanolamine. In embodiments, there is provided a crystalline form of a salt of pitavastatin with diethanolamine. In embodiments, there is provided an essentially pure salt of pitavastatin with diethanolamine. In embodiments, there is provided a substantially pure salt of pitavastatin with diethanolamine. In embodiments, there is provided a pure salt of pitavastatin with diethanolamine.

In embodiments, there is provided a crystalline form of pitavastatin diethanolamine salt characterized by its PXRD pattern having peaks located substantially according to the pattern shown in Fig. 1 1 . In embodiments, there is provided a crystalline form of pitavastatin diethanolamine salt characterized by its PXRD pattern having peaks located at about 8.4, 12.6, 16.8, 18.4, 20.7, 20.9, 22.1 , and 22.3, ±0.2 degrees 2Θ. The crystalline form of pitavastatin diethanolamine salt can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 12.

In embodiments, there is provided a salt of pitavastatin with piperidine. In embodiments, there is provided a crystalline form of a salt of pitavastatin with piperidine. In embodiments, there is provided an essentially pure salt of pitavastatin with piperidine. In embodiments, there is provided a substantially pure salt of pitavastatin with piperidine. In embodiments, there is provided a pure salt of pitavastatin with piperidine.

In embodiments, there is provided a crystalline form of pitavastatin piperidine salt characterized by a PXRD pattern having peaks located substantially in accordance with the pattern shown in Fig. 14. In embodiments, there is provided a crystalline form of pitavastatin piperidine salt characterized by a PXRD pattern having peaks located at about 8.6, 10.1 , 15.7, 17.4, 20.0, 20.3, and 32.5, ±0.2 degrees 2Θ. The crystalline form of pitavastatin piperidine salt can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 15.

In embodiments, there is provided a salt of pitavastatin with phenylethylamine. In embodiments, there is provided a crystalline form of a salt of pitavastatin with phenylethylamine. In embodiments, there is provided an essentially pure salt of pitavastatin with phenylethylamine. In embodiments, there is provided a substantially pure salt of pitavastatin with phenylethylamine. In embodiments, there is provided a pure salt of pitavastatin with phenylethylamine.

In embodiments, there is provided a crystalline form of pitavastatin phenylethylamine salt characterized by a PXRD pattern having peaks located substantially in accordance with the pattern shown in Fig. 17. In embodiments, there is provided a crystalline form of pitavastatin phenylethylamine salt characterized by a PXRD pattern having peaks located at about 4.5, 8.9, 1 1 .7, 16.3, 20.6, and 23.4, ±0.2 degrees 2Θ. The crystalline form of pitavastatin phenylethylamine salt can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 18.

In embodiments, there is provided a salt of pitavastatin with piperazine. In embodiments, there is provided a crystalline form of a salt of pitavastatin with piperazine. In embodiments, there is provided an essentially pure salt of pitavastatin with piperazine. In embodiments, there is provided a substantially pure salt of pitavastatin with piperazine. In embodiments, there is provided a pure salt of pitavastatin with piperazine.

In embodiments, there is provided a crystalline form of pitavastatin piperazine salt characterized by a PXRD pattern having peaks located substantially in accordance with the pattern shown in Fig. 20. In embodiments, there is provided a crystalline form of pitavastatin piperazine salt characterized by a PXRD pattern having peaks located at about 5.7, 6.4, 8.7, 10.1 , 10.4, 16.8,

17.4, 17.9, 18.1 , 19.7, 20.0, 20.3, 21 .6, 22.0, 22.2, and 22.5, ±0.2 degrees 2Θ. The crystalline form of pitavastatin piperazine salt can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 21 .

In embodiments, there is provided a salt of pitavastatin with n-propylamine. In embodiments, there is provided a crystalline form of salt of pitavastatin with n- propylamine. In embodiments, there is provided an essentially pure salt of pitavastatin with n-propylamine. In embodiments, there is provided a substantially pure salt of pitavastatin with n-propylamine. In embodiments, there is provided a pure salt of pitavastatin with n-propylamine.

In embodiments, there is provided a crystalline form of pitavastatin n- propylamine salt characterized by a PXRD pattern having peaks located substantially in accordance with the pattern shown in Fig. 23. In embodiments, there is provided a crystalline form of pitavastatin n-propylamine salt characterized by a PXRD pattern having peaks located at about 9.4, 12.6, 18.0, 20.1 , 20.6, 22.2,

22.5, 23.4, and 25.0, ±0.2 degrees 2Θ. The crystalline form of pitavastatin n- propylamine salt can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 24.

In embodiments, there is provided a salt of pitavastatin with diisopropylamine. In embodiments, there is provided a crystalline form of a salt of pitavastatin with diisopropylamine. In embodiments, there is provided an essentially pure salt of pitavastatin with diisopropylamine. In embodiments, there is provided a substantially pure salt of pitavastatin with diisopropylamine. In embodiments, there is provided a pure salt of pitavastatin with diisopropylamine.

In embodiments, there is provided a crystalline form of pitavastatin diisopropylamine salt characterized by a PXRD pattern having peaks located substantially in accordance with the pattern shown in Fig. 26. In embodiments, there is provided a crystalline form of pitavastatin diisopropylamine salt characterized by a PXRD pattern having peaks located at about 4.1 , 9.4, 1 1 .8, 12.4, 15.1 , 18.2, 18.5, 18.8, 22.3, 23.6, 24.1 , and 25.0, ±0.2 degrees 2Θ. The crystalline form of pitavastatin diisopropylamine salt can also be characterized by its infrared absorption spectrum and/or DSC thermogram, such as the curve shown in Fig. 27. In embodiments, there is provided pitavastatin potassium salt.

In an aspect, there are provided processes for preparing an amorphous form of pitavastatin calcium, embodiments comprising removing the solvent from a solution of pitavastatin calcium.

Any liquid substance which has capacity to dissolve pitavastatin calcium at room temperature or higher temperatures can be used as a solvent to form the solution of pitavastatin calcium. For example, suitable solvents include, but are not limited to, alcohols, such as methanol, ethanol, and 2-propanol; ethers, such as diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, THF, and methyl THF; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles such as acetonitrile; dipolar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, and the like; water; and any mixtures of two or more thereof. The concentration of pitavastatin calcium in step a) can be, but is not limited to, 3 to 10% w/v.

The solvent can be removed using techniques known in the art, such as spray drying, thin-film drying, rotational evaporation, or distillation under vacuum. In embodiments, a 9% solution of pitavastatin calcium is spray dried.

Isolation and drying of a recovered form of pitavastatin calcium can be done by techniques known in the art.

In an aspect, there are provided processes for preparing an amorphous form of pitavastatin calcium, embodiments comprising combining a solution of pitavastatin calcium and an anti-solvent for pitavastatin calcium.

The solution of pitavastatin calcium can be obtained by dissolving any form of the compound in a suitable solvent. It also can be obtained by treating a reaction mixture from the synthesis of pitavastatin free acid or ester thereof with a suitable source of calcium in a solvent. To obtain a clear solution of pitavastatin calcium, the reaction mixture can be heated to dissolution temperatures that can be any temperatures, as long as the stability of the pitavastatin calcium is not compromised and a substantially clear solution is obtained. For example, the dissolution temperatures may range from about 20°C to about the reflux temperature of the solvent. Suitable solvents and anti-solvents include, but are not limited to, alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, THF, and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as, for example, dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as, for example, toluene, xylene, and cyclohexane; nitriles such as acetonitrile; dipolar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, and the like; water; and any mixtures of two or more thereof.

Optionally, if desired, the solution of pitavastatin calcium can be concentrated by removing a portion of the solvent, before combining with the anti- solvent. Typical solvents employed include a halogenated hydrocarbon, dioxane, THF, or methyl ethyl ketone. The anti-solvent used herein refers to a solvent in which pitavastatin calcium is less or poorly soluble and which includes, but is not limited to, cyclohexane, pentanes, hexanes, heptanes, and the like.

The pitavastatin calcium may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, etc. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.

The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. 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 1 hour to about 15 hours, or longer. The Dio, D₅o, and D₉₀ values are useful ways for indicating a particle size distribution. D₉₀ refers to at least 90 volume percent of the particles having a size smaller than the said value. Likewise, D₁₀ refers to 10 volume percent of the particles having a size smaller than the said value. D₅₀ refers to 50 volume percent of the particles having a size smaller than the said value. Methods for determining D10, D₅₀, and D₉₀ include laser light diffraction, such as using equipment from Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.

Unless indicated otherwise, the solid state forms of the present application can be dried. Drying may be carried out, for example, at elevated temperature under reduced pressure. The crystalline form can be dried at temperatures from about 40°C to about 60°C, or about 40°C and about 50°C, for example, about 40°C. The drying can be carried out under reduced pressures (i.e., less than 1 atmosphere, for example, from about 10 mbar to about 100 mbar, or about 10 mbar to about 25 mbar). The drying can take place over a period of about 8 hours to about 36 hours, or about 10 hours to about 24 hours, for example, about 16 hours. Drying can be carried out for longer times.

Also provided are pharmaceutical compositions containing a therapeutically effective amount of a salt of pitavastatin or amorphous form of pitavastatin as described herein, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions that include salts of pitavastatin or amorphous form 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 that 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 by direct blending, dry granulation, and wet granulation or by 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 may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that find use in making pharmaceutical dosage forms include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and 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, ethyl celluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and 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, and the like.

The processes of present application are simple, cost-effective, eco- friendly, reproducible, scalable, and robust to produce salts of pitavastatin 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 or International Application Publication No. WO 95/1 1898 A1 , which are incorporated herein by reference in their entireties, as well as by other processes known in the art.

The polymorphic forms described herein, unless stated otherwise, can be characterized by PXRD patterns, DSC curves, and TGA curves. PXRD data reported herein are obtained using copper Ka radiation, having the wavelength 1 .54A. The PXRD patterns of the drawings have a y-axis in intensity units and an x-axis that is the 2Θ angle, in degrees. DSC analysis can be carried out in a DSC Q1000 instrument from TA Instruments with a ramp of 10°C/ minute up to 250°C. The DSC curves of the drawings for crystalline forms have a y-axis that is heat flow in watts/gram and an x-axis that is the temperature in °C. TGA analysis can be carried out in a TGA Q500 instrument with a ramp of 10°C/minute up to 250°C. The TGA curves of the drawings have a y-axis that is weight percent and an x- axis that is the temperature in °C.

Amorphous pitavastatin calcium can be analyzed by modulated DSC (MDSC). MDSC analysis can be carried out in a DSC Q1000 instrument from TA Instruments with a ramp of 5°C/ minute up to 200°C with modulation rate of 0.8°C per 60 seconds after equilibrating at 0°C. The MDSC curves of the Figs. 36 and 38 show both heat flow (solid line) and reverse heat flow (dotted line) in watts/gram on the y-axis and temperature in °C on the x-axis.

Crystalline forms can be characterized by scattering techniques, e.g., x-ray diffraction powder patterns, by spectroscopic methods, e.g., infrared and/or ¹³C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. A polymorphic form typically is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblain, Journal of Pharmaceutical Sciences, 1975 64:1269-1288, and J. Haleblain and W. McCrone, Journal of Pharmaceutical Sciences, 1969 58:91 1 -929.

Generally, a diffraction angle (2Θ) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ±0.2°. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ±0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2Θ±0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (2Θ) of 7.7° to 8.1°". Although the intensities of peaks in the 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. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, 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 degrees. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the application in any manner.

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 formula, yet having distinct physical properties when compared to other polymorphs of the same formula.

All percentages and ratios used herein are by weight of a 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 normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements, whether or not described herein.

As used herein, the terms "salt(s) of pravastatin," "pitavastatin salt(s)" and other similar phrases encompass crystalline and amorphous forms, solvates, hydrates, stereoisomers, both individual and in mixtures thereof, racemates, enantiomers, or the like.

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, salts of pitavastatin, and the unique crystalline forms, solvates and/or optical isomers thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or as depicted in a Figure, 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 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, and the like. However, those of ordinary skill in the art should be able to compare the figures herein with a pattern generated of an unknown form of, in this case, salts of pitavastatin, and confirm its identity as one of the forms disclosed and claimed herein. The same holds true for other techniques which may be reported herein.

In addition, where a reference is made to a drawing figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that crystalline form, salt and/or optical isomer, within any associated and recited margin of error, for purposes of identification.

When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% purity or greater, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means

99% of one enantiomer or diastereomer, as appropriate. "Substantially" pure means, the same as "pure" except that the lower limit is about 98% purity or greater and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% purity.

Moisture content can be conveniently measured, such as by a Karl Fischer method or a drying procedure.

As used herein, the term "room temperature" refers to ambient temperatures from about 20°C to about 35°C, from about 25°C to about 35°C, from about 25°C to about 30°C, or for example, about 25°C.

As used herein, the term "overnight" refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.

An "alcohol solvent" is an organic solvent containing a carbon bound to a hydroxyl group. Alcohol solvents include, but are 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, and the like.

An "ether solvent" is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms. Ether solvents include, but are 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, C_2-6 ethers, and the like.

A "halogenated hydrocarbon solvent" is an organic solvent containing a carbon bound to a halogen. Halogenated hydrocarbon solvents include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 -trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, and the like. A "ketone solvent" is an organic solvent containing a carbonyl group - (C=O)- bonded to two other carbon atoms. Ketone solvents include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C_3- 6 ketones, and the like.

A "hydrocarbon solvent" refers to a liquid hydrocarbon, which may be linear, branched, cyclic, saturated, unsaturated, non-aromatic, or aromatic. It is capable of dissolving a solute to form a solution. Examples of hydrocarbon solvents 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, Cs-Cs aliphatic hydrocarbons, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, and mixtures thereof.

A "nitrile solvent" is an organic solvent containing a cyano -(C≡N) bonded to another carbon atom. Nitrile solvents include, but are not limited to, acetonitrile, propionitrile, C2-6 nitriles, and the like.

An "organic base" is an organic compound, which acts as a base.

Examples of such bases include, but are not limited to: aliphatic amines, e.g., triethylamine, tributylamine, diisopropylamine, Hunig's base, diethanolamine, dimethylethanolamine, triethanolamine dimethylamine, diethylamine, di-n- propylamine, diisopropylamine, N-ethylmethylamine, di-n-butylamine, diisobutylamine, di-sec-butylamine, di-tert-butylamine, diamylamine, di-n- octylamine, di-(2-ethylhexyl)-amine, di-iso-nonylamine, diallylamine, N- methylaniline, hexylamine, phenethylamine, and the like; alicyclic amines, e.g. DABCO, 4-methylmorpholine, piperazine, N-methyl-1 ,5,9- triazabicyclo[4.4.0]decene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, dicyclohexylamine, N-methylpyrrolidine, 1 -methylpiperidine, 1 ,5- diazabicyclo[4.3.0]non-5-ene, Ν,Ν-dimethylpiperazine, hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), 2,3,5,6-tetramethylpyridine (TEMP), aziridine, pyrrolidine, piperidine, 2,2,6,6-tetramethylpiperidine, dicyclohexylundecane (DCU), or the like; aromatic amines, e.g., pyridine, N,N- dimethylaminopyridine, lutidine, picoline, collidine, Ν,Ν-dimethylaniline, pyrrole, imidazole, indole, purine, and the like; and substances such as tetramethyl guanidine, tetramethylammonium hydroxide, tetraethylammonium hydroxide, and the like.

A "polar aprotic solvent" has a dielectric constant greater than 15.

Examples include: 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 γ-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. These organic solvents may be used individually or any two or more of these may be combined.

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 disclosure in any manner.

EXAMPLE 1 : PREPARATION OF PRAVASTATIN FREE ACID

Pitavastatin calcium (30 g) and ethyl acetate (150 ml_) are charged into a round bottom flask and the mixture is stirred at about 25-35°C for about 15 minutes. Then 10% hydrochloric acid (60 ml_) is added and the reaction mixture is stirred at 25-35°C for about 10-15 minutes. The layers are separated and organic layer is washed with water (2x90 ml_). The organic layer solvent is evaporated completely under vacuum at 25-35°C, to afford pitavastatin free acid in 95.9% yield. Moisture content: 0.32% w/w.

The pitavastatin is used to prepare salts in the following examples.

EXAMPLE 2: PREPARATION OF PITAVASTATIN BARIUM

Pitavastatin free acid (4 g) and isopropyl alcohol (20 mL) are charged into a round bottom flask. Barium hydroxide is added at 25-35°C and the mixture is maintained at this temperature for 5-6 hours. The formed solid is collected by filtration, washed with isopropyl alcohol (4 mL), and dried at about 50-55°C to afford the title compound. Yield: 2.1 g, Moisture content: 8.6 % w/w, HPLC purity: 98.0%. The product has a particle size distribution with D₉₀ = 63.04 μιτι, D₁₀ = 2.21 μιτι, and D₅o = 10.44 μιτι.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 1 -3.

EXAMPLE 3: PREPARATION OF PRAVASTATIN POTASSIUM

Pitavastatin free acid (8 g) and isopropyl alcohol (40 mL) are charged into a round bottom flask. Potassium hydroxide is added at 25-35°C and the mixture is maintained at this temperature overnight. The solvent is completely evaporated under vacuum and ethyl acetate is added to the residue. The mixture is stirred and the solvent is evaporated, to afford the title compound. Yield: 7.8 g; Moisture content: 3.2% w/w; HPLC purity: 98.42%.

The PXRD pattern of the product is shown in Fig. 4.

EXAMPLE 4: PREPARATION OF PITAVASTATIN MAGNESIUM

Pitavastatin free acid (10 g) and acetonitrile (50 mL) are charged into a round bottom flask, followed by addition of sodium hydroxide (1 .1 g) at 25-35°C. The mixture is maintained at this temperature for 2-3 hours, then solvent is evaporated completely under vacuum to afford a residue. Water (50 mL) is added to the residue and the mixture is stirred at room temperature, followed by addition of magnesium sulfate heptahydrate (7 g). The mixture is maintained at 25-35°C for 4-5 hours and the formed solid is collected by filtration and washed with water (20 mL), and subsequently dried at about 50-55°C to afford the title compound as a crystalline solid. Yield: 9.19 g; Moisture content: 7.66% w/w; HPLC purity:

98.84%.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 5-7.

EXAMPLE 5: PREPARATION OF PITAVASTATIN MEGLUMINE SALT

Pitavastatin free acid (4 g) and isopropyl alcohol (20 mL) are charged into a round bottom flask. Meglumine (2.2 g) is added at 25-35°C and the mixture is maintained at this temperature for 5-6 hours. The formed solid is collected by filtration, washed with isopropyl alcohol (4 mL), and dried at about 50-55°C to afford the title compound. Yield: 3 g; Moisture content: 2.2% w/w; HPLC purity: 98.68%. The product has a particle size distribution with D₉₀ = 327.40 μιτι, D₁₀ = 7.89 pm, and D₅₀ = 6.68 μηη.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 8-10.

EXAMPLE 6: PREPARATION OF PITAVASTATIN DIETHANOLAMINE SALT Pitavastatin free acid (4 g) and acetonitrile (20 mL) are charged into a round bottom flask. Diethanolamine (1 .1 mL) is added t at 25-35°C and the mixture is maintained at this temperature for 1 -2 hours. The formed solid is collected by filtration, washed with acetonitrile (8 mL), and dried at about 50-55°C to afford the title compound. Yield: 3.3 g; Moisture content: 1 .16% w/w; HPLC purity: 98.98%.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 1 1 -13.

EXAMPLE 7: PREPARATION OF PITAVASTATIN PIPERIDINE SALT

Pitavastatin free acid (6 g) and acetonitrile (30 mL) are charged into a round bottom flask. Piperidine (1 .7 mL) is added at 25-35°C and the mixture is maintained at this temperature for 1 -2 hours. The formed solid is collected by filtration, washed with acetonitrile (12 mL), and dried at about 50-55°C to afford the title compound. Yield: 4.8 g; Moisture content: 0.4% w/w; HPLC purity:

98.94%. The product has a particle size distribution with D₉₀ = 54.23 pm, D₁₀ = 2.59 μηη, and D₅₀ = 20.85 μηη.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 14-16.

EXAMPLE 8: PREPARATION OF PITAVASTATIN PHENYLETHYLAMINE SALT Pitavastatin free acid (4 g) and acetonitrile (20 mL) are charged into a round bottom flask. 1 -Phenylethylamine (1 .5 mL) is added at 25-35°C and the mixture is maintained at this temperature for 1 -2 hours. The formed solid is collected by filtration, washed with acetonitrile (8 mL), and dried at about 50-55°C to afford the title compound. Yield: 3.3 g; Moisture content: 0.4% w/w; HPLC purity: 98.61 %.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 17-19.

EXAMPLE 9: PREPARATION OF PRAVASTATIN PIPERAZINE SALT

Pitavastatin free acid (6 g) and acetonitrile (60 mL) are charged into a round bottom flask. Piperazine (670 mg) is added at 25-35°C and the mixture is maintained at this temperature for 1 -2 hours. The formed solid is collected by filtration, washed with acetonitrile (12 mL), and dried at about 50-55°C to afford the title compound. Yield: 5.5 g; Moisture content: 2.2% w/w; HPLC purity:

99.32%. The product has a particle size distribution with D₉₀ = 191 .65 μιτι, Dio = 1 .61 μιτι, and D₅o = 1 1 -61 μιτι.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 20-22.

EXAMPLE 10: PREPARATION OF PITAVASTATIN n-PROPYLAMINE SALT Pitavastatin free acid (3 g) and acetonitrile (18 mL) are charged into a round bottom flask. N-Propylamine (0.7 mL) is added at 25-35°C and the mixture is maintained at this temperature for 1 -2 hours. The formed solid is collected by filtration, washed with acetonitrile (6 mL), and dried at about 50-55°C to afford the title compound. Yield: 1 .8 g; Moisture content: 0.7% w/w.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 23-25.

EXAMPLE 1 1 : PREPARATION OF PITAVASTATIN DIISOPROPYLAMINE SALT

Pitavastatin free acid (3 g) and acetonitrile (18 mL) are charged into a round bottom flask. Diisopropylamine (1 .2 mL) is added at 25-35°C and the mixture is maintained at this temperature for 1 -2 hours. The formed solid is collected by filtration, washed with acetonitrile (6 mL), and dried at about 50-55°C to afford the title compound. Yield: 1 .8 g; Moisture content: 0.13% w/w; HPLC purity: 98.89%.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 26-28. EXAMPLE 12: PREPARATION OF PRAVASTATIN CALCIUM

Pitavastatin piperazine salt (3 g) and water (30 mL) are charged into a round bottom flask and stirred for 15-30 minutes. An aqueous solution of calcium chloride (394 mg in 1 .2 mL of water) is added t at 25-35°C and the mixture is maintained at this temperature for 1 -2 hours. The formed solid is collected by filtration, washed with water (6 mL), and dried at about 50-55°C to afford the title compound. Yield: 2.8 g; Moisture content: 2.8% w/w; HPLC purity: 98.44%.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 29-31 .

EXAMPLE 13: PREPARATION OF PITAVASTATIN BARIUM

Pitavastatin free acid (5 g) and methanol (25 mL) are charged into a round bottom flask and stirred for 15 minutes. An aqueous solution of barium hydroxide (2.2 g in 25 mL of water) is added at 25-35°C and the mixture is maintained at this temperature for 1 -2 hours. The formed solid is collected by filtration, washed with a mixture of methanol and water (1 :1 by volume, 20 mL), and dried at about 50- 55°C to afford the title compound. Yield: 4.3 g.

The PXRD pattern, DSC curve, and TGA curve of the product are shown, respectively, in Figs. 32-34.

EXAMPLE 14: PREPARATION OF AMORPHOUS PITAVASTATIN CALCIUM

Pitavastatin calcium (10 g) and dichloromethane (200 mL) are charged into a round bottom flask and the mixture is stirred at about 25-35°C for about 15 minutes. Then solution is filtered to make it particle free. The clear solution is subjected to spray drying at an inlet temperature of 45°C under a nitrogen pressure of 5 kgf/cm² and an outlet temperature of about 30-32°C. The solid is dried in a vacuum tray dryer at 55°C for 16 hours, to afford the title compound having HPLC purity of 99.57%. Moisture content: 3.4% (w/w). The PXRD pattern is depicted in Fig. 35. MDSC shows the sample to have a glass transition temperature of about 132°C, as depicted in Fig. 36. EXAMPLE 15: PREPARATION OF AMORPHOUS PRAVASTATIN CALCIUM

Pitavastatin calcium (2 g) and dichloromethane (24 mL) are charged into a flask and the mixture is stirred at about 25-35°C for about 10 minutes to obtain a clear solution. The solution is divided into four parts and two of the parts are subjected separately to procedures described below.

A) Pentane (25 mL) is charged into a vessel and cooled to 10°C. While maintaining the temperature at 10°C, one quarter of the above solution of pitavastatin calcium in dichloromethane is added and the mixture is stirred for about 10-15 minutes. The formed solid is collected by filtration under vacuum to afford the title compound.

B) Cyclohexane (25 mL) is charged into a vessel and cooled to 10°C. While maintaining the temperature at 10°C, one quarter of the above solution of pitavastatin calcium in dichloromethane is added and the mixture is stirred for about 10-15 minutes. The formed solid is collected by filtration under vacuum to afford the title compound.

EXAMPLE 16: PREPARATION OF AMORPHOUS PITAVASTATIN CALCIUM

Pitavastatin calcium (40 g) and dichloromethane (480 mL) are charged into a flask and the mixture is stirred at about 25-35°C for about 10 minutes to obtain a clear solution. The solution is filtered to make the solution particle free.

Cyclohexane (2 L) is charged into a separate flask and cooled to 5-10°C, and one quarter of the above solution of pitavastatin calcium in dichloromethane is added at about 5-10°C and maintained at this temperature for 2 hours. The formed solid is isolated by filtration and washed with cyclohexane (80 mL). The solid is dried under vacuum at room temperature in a vacuum tray dryer (VTD) for 2 hours and subsequently at 50°C for 3 hours in the VTD, and then at 65°C for 15 hours in the VTD, to afford the title compound in 96% yield.

EXAMPLE 17: PREPARATION OF AMORPHOUS PITAVASTATIN CALCIUM Pitavastatin calcium (5 g) and dichloromethane (120 mL) are charged into a flask and the mixture is stirred at about 25-35°C for about 40 minutes to obtain a clear solution. The solution is filtered to make the solution particle free. The clear solution is subjected to complete distillation under vacuum at about 35°C to afford a reside which is further dried in a VTD at 50°C for 24 hours, to afford the title compound.

EXAMPLE 18: PREPARATION OF AMORPHOUS PRAVASTATIN CALCIUM Pitavastatin calcium (30 g) and ethyl acetate (450 mL) are charged into a flask and the mixture is stirred at about 25-35°C for about 40 minutes to obtain a clear solution. The solution is filtered to make the solution particle free. The clear solution is subjected to spray drying at an inlet temperature of 80°C under a nitrogen pressure of 5 kgf/cm² and an outlet temperature of about 51 °C. The solid obtained is dried in a vacuum tray dryer at 40°C for 15 hours to afford the title compound, having HPLC purity of -99.71 %. Moisture content: 2.83% (w/w). The PXRD pattern is depicted in Fig. 37. MDSC shows the product to have a glass transition temperature of about 132°C as depicted in Fig. 38.

Claims

CLAIMS:

1 . A salt of pitavastatin with a cation or organic base, wherein a cation is barium, potassium, or magnesium, and an organic base is meglumine, diethanolamine, piperidine, phenylethylamine, piperazine, n-propylamine, or diisopropylamine.

2. A pitavastatin salt according to claim 1 , which is a pitavastatin barium salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

3. A pitavastatin barium salt according to claim 3, being in a crystalline form and having a powder X-ray diffraction pattern comprising peaks located substantially according to the pattern of Fig. 1 .

4. A pitavastatin salt according to claim 1 , which is a pitavastatin potassium salt, or a hydrate or solvate thereof.

5. A pitavastatin potassium salt of claim 4, having a powder X-ray diffraction pattern comprising peaks located substantially in accordance with the pattern of Fig. 4.

6. A pitavastatin salt according to claim 1 , which is a pitavastatin magnesium salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

7. A pitavastatin magnesium salt according to claim 6, being in crystalline form and having a powder X-ray diffraction pattern comprising peaks located substantially according to the pattern of Fig. 5.

8. A pitavastatin salt according to claim 1 , which is a pitavastatin meglumine, salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

9. A pitavastatin meglumine salt according to claim 8, being in crystalline form and having a powder X-ray diffraction pattern comprising peaks located substantially according to the pattern of Fig. 8.

10. A pitavastatin salt according to claim 1 , which is a pitavastatin

diethanolamine salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

1 1 . A pitavastatin diethanolamine salt according to claim 10, being in crystalline form and having a powder X-ray diffraction pattern comprising peaks located substantially according to the pattern of Fig. 1 1 .

12. A pitavastatin salt according to claim 1 , which is a pitavastatin piperidine salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

13. A pitavastatin piperidine salt according to claim 12, being in crystalline form and having a powder X-ray diffraction pattern comprising peaks located

substantially according to the pattern of Fig. 14.

14. A pitavastatin salt according to claim 1 , which is a pitavastatin

phenylethylamine salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

15. A pitavastatin phenylethylamine salt according to claim 14, being in crystalline form and having a powder X-ray diffraction pattern comprising peaks located substantially according to the pattern of Fig. 17.

16. A pitavastatin salt according to claim 1 , which is a pitavastatin piperazine salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

17. A pitavastatin piperazine salt according to claim 16, being in crystalline form and having a powder X-ray diffraction pattern comprising peaks located substantially according to the pattern of Fig. 20.

18. A pitavastatin salt according to claim 1 , which is a pitavastatin n- propylamine salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

19. A pitavastatin n-propylamine salt according to claim 18, being in crystalline form and having a powder X-ray diffraction pattern comprising peaks located substantially according to the pattern of Fig. 23.

20. A pitavastatin salt according to claim 1 , which is a pitavastatin

diisopropylamine salt, or a hydrate or solvate thereof, being in a crystalline form or in amorphous form.

21 . A pitavastatin diisopropylamine salt according to claim 20, being in crystalline form and having a powder X-ray diffraction pattern comprising peaks located substantially according to the pattern of Fig. 26.

22. A process for preparing a pitavastatin salt according to any of claims 1 -19, comprising:

a) providing a solution of pitavastatin free acid or a salt thereof in a solvent; and

b) combining a source of a cation or an organic base with the solution of step a).

23. A process according to claim 22 wherein a source of a cation or an organic base is barium hydroxide, potassium hydroxide, magnesium sulfate, meglumine, diethanolamine, piperazine, piperidine, n-propylamine, or diisopropylamine.

24. A process for preparing amorphous pitavastatin calcium, comprising removing solvent from a solution of pitavastatin calcium.

25. A process according to claim 24, wherein removing solvent is performed by spray drying, rotational evaporation, thin-film drying, or vacuum distillation.

26. A process for preparing an amorphous form of pitavastatin calcium, comprising combining a solution of pitavastatin calcium with an anti-solvent for pitavastatin calcium.

27. A process according to claim 26, wherein a solution has a solvent comprising a halogenated hydrocarbon, dioxane, tetrahydrofuran, or methyl ethyl ketone.

28. A process according to claims 26 or 27, wherein an anti-solvent comprises cyclohexane, a pentane, a hexane, or a heptane.