DESC:Field of the invention
The present invention relates to novel polymorphic forms of Pitavastatin tert-butyl amine salt and its hydrates and/or solvates thereof and processes for preparation of the same.

Background and the prior art
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 and mixed dyslipidemia. Pitavastatin calcium is chemically known as monocalcium salt of bis {(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxy-6-heptenoate} represented by structural formula (1).

Pitavastatin and its pharmaceutically acceptable salts are described in US 5,753,675 patent and US 5,856,336 patent, respectively.

Processes for the preparation of Pitavastatin are well documented in the literature. European patents, EP 0304063 and EP 1099694 and Miyachi et al [Tetrahedron Letters (1993) vol. 34, pages 8267-8270] and Takahashi et al [Bull. Chem. Soc. Japan (1995) Vol. 68, 2649-2656] describe processes for preparation of Pitavastatin. A complete procedure for the preparation of Pitavastatin calcium is described in EP 0520406.

The literature also reports organic amine salts of Pitavastatin.

WO 2007132482 discloses a process for the preparation of pitavastatin calcium salt via formation of pitavastatin organic amine salt, such as methyl amine, ethyl amine, tertiary-butyl amine, diisopropyl amine, dicyclohexyl amine, isobutyl amine, n-butylamine, 2-butyl amine, phenyl ethyl amine, morpholine and pyrrolidine.

WO 2007132482 discloses organic amine salts of Pitavastatin, such as methyl amine salt, n-butyl amine salt, sec-butyl amine salt, tertiary-butyl amine salt and dicyclohexyl amine salt.

WO 2002092570 discloses benzylamine and dicyclohexylamine salts of Pitavastatin.

WO 2010027060 discloses a purification process for Pitavastatin, involving forming chiral amine salts of Pitavastatin with (S)-2-amino-3-phenyl-1-propanol, (R)-2-amino-3-methyl-1-butanol, (R)-2-amino-3-phenyl-1-propanol, (R)-1-(phenyl) propyl-amine, (R)-1-(1-naphthyl) ethylamine, (S)-phenyl-glycine methyl ester.

WO 2012106584 discloses meglumine, diethanolamine, piperidine, phenyl ethylamine, piperazine, n-propylamine, and diisopropylamine salts of Pitavastatin.

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.

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 novel polymorphic forms of Pitavastatin tert-butyl amine salt and their hydrates and/or solvates.

Object of the invention
It is an object of the present invention to provide novel polymorphic forms of Pitavastatin tert-butyl amine salt and their hydrates and/or solvates.

It is another object of the present invention to provide a process for preparation of novel polymorphic forms of Pitavastatin tert-butyl amine salt and their hydrates and/or solvates.

It is yet another object of the present invention to provide a pharmaceutical composition comprising an effective amount of novel polymorphic forms of Pitavastatin tert-butyl amine salt and their hydrates and/or solvates.

Brief Description of accompanying figures
Figure 1a illustrates the XRPD of the polymorphic form L of Pitavastatin tert-butyl amine salt
Figure 1b illustrates the IR spectra of the polymorphic form L of Pitavastatin tert-butyl amine salt
Figure 2a illustrates the XRPD of the polymorphic form L1 of Pitavastatin tert-butyl amine salt
Figure 2b illustrates the IR spectra of the polymorphic form L1 of Pitavastatin tert-butyl amine salt

Description of the invention
Accordingly, the present invention relates to novel polymorphic forms of Pitavastatin tert-butyl amine salt represented by structural formula (2).

In an embodiment the present invention provides novel crystalline polymorphic Form-L of Pitavastatin tert-butyl amine salt characterized by XRPD and IR spectra.

Another embodiment of the present invention provides crystalline polymorphic Form-L of Pitavastatin tert-butyl amine salt characterized by XRPD having characteristic peaks at 10.38, 12.17, 15.82, 19.40 19.81, 21.43 and 22.38 ± 0.2 degree 2?.

The XRPD of the polymorphic form L of Pitavastatin tert-butyl amine salt is as shown in figure 1a and IR spectra is as shown in figure 1b.

In yet another embodiment of the present invention provides novel crystalline polymorphic Form-L1 of Pitavastatin tert-butyl amine salt characterized by XRPD and IR spectra.

Another embodiment of the invention provides crystalline polymorphic Form-L1 of Pitavastatin tert-butyl amine salt characterized by XRPD having characteristic peaks at 10.36, 10.94, 12.15, 13.12, 14.17, 14.61, 15.72, 16.03, 16.45, 17.29, 19.30, 19.94, 20.63, 21.37, 21.99, 22.41, 23.52 and 24.00 ± 0.2 degree 2?.

The XRPD of the polymorphic form L1 of Pitavastatin tert-butyl amine salt is as shown in figure 2a and IR spectra is as shown in figure 2b.

In another aspect of the present invention provides a process for preparation of the polymorphic form L of Pitavastatin tert-butyl amine salt. The polymorphic form L of Pitavastatin tert-butyl amine salt is prepared from (4R, 6S)-(E)-6-[2-(2-cyclopropyl-4-(fluorophenyl) quinoline-3-yl)-vinyl]-2, 2-dimethyl-1, 3-dioxane-4-yl] acetic acid tertiary butyl ester of compound [PTV-III].

The compound PTV-III is first converted to the corresponding diol t-butyl ester of compound [PTV-IV] by reacting with acid such as hydrochloric acid, acetic acid, sulfuric acid; preferably, 5% aqueous hydrochloric acid in acetonitrile at not more than 10 oC temperatures, which is converted in situ to Pitavastatin acid of compound [PTV-V] by treatment with first aqueous sodium hydroxide solution and thereafter with 10% aqueous hydrochloric acid to adjust pH at 4.0. The Pitavastatin acid of compound [PTV-V] is extracted with ethyl acetate and treated with tert-butyl amine to afford the Pitavastatin tert-butyl amine salt of polymorphic form L.

In another aspect of the invention provides process for preparation of the polymorphic form L1 of Pitavastatin tert-butyl amine salt. The polymorphic form L1 of Pitavastatin tert-butyl amine salt is prepared from (4R, 6S)-(E)-6-[2-(2-cyclopropyl-4-(fluorophenyl) quinoline-3-yl)-vinyl]-2, 2-dimethyl-1, 3-dioxane-4-yl] acetic acid tertiary butyl ester of compound [PTV-III].

The compound PTV-III is first converted to the corresponding diol t-butyl ester of compound [PTV-IV] by reacting with acid such as hydrochloric acid, acetic acid, sulfuric acid, preferably, 5% dil. hydrochloric acid in acetonitrile at not more than 10 oC temperature, which is converted in situ to Pitavastatin acid of compound [PTV-V] by treatment with first aqueous sodium hydroxide solution and thereafter with 10% aqueous hydrochloric acid to adjust pH at 4.0. The Pitavastatin acid of compound [PTV-V] is extracted with ethyl acetate and concentrated under vacuum. The residue obtained is further treated with tert butyl amine in acetone to afford Pitavastatin tert-butyl amine salt of polymorphic form L1.

The form L and form L1 of Pitavastatin tert-butyl amine salt of the present invention can be used as HMG-CoA reductase inhibitors.

The polymorphic forms of Pitavastatin tert-butyl amine salt of the present invention can be used to prepare pharmaceutical composition for the reduction of elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C). Such pharmaceutical composition can be prepared by the methods known in the literature.

The reaction is schematically depicted in Scheme-1.

The present invention is further illustrated with the following non-limiting examples.

Example-1: Preparation of Pitavastatin tertiary butyl amine salt (Form L)
A mixture of 200.0 gm (4R, 6S)-(E)-6-[2-(2-cyclopropyl-4-(fluorophenyl) quinoline-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester compound [PTV-III] and 600 ml acetonitrile was cooled to 5-8 °C temperature. Added 5.0% aqueous hydrochloric acid solution (428 ml) to the reaction mixture. Stirred the reaction mixture for 2-3 hours at 25-30 °C temperature. Added solution of sodium hydroxide (48 gm) in DM water (232 ml) into the reaction mixture. Stirred the reaction mixture for 2-3 hours at 25-30 °C temperature. Quenched the reaction mixture with DM water and washed with ethyl acetate. Aqueous layer containing product cooled to 5-8 °C temperature. Adjusted the pH of the reaction mixture to 4.0 with 10% hydrochloric acid. Extracted the product in ethyl acetate and washed with 20% sodium chloride aqueous solution. Separated the ethyl acetate layer and added solution of 42.4 gm of tertiary butyl amine in ethylacetate to the mixture. Stirred the reaction mixture for 60-90 min at 25-30 °C temperature. Filtered the solid and washed with ethyl acetate to get the title compound (155.0 gm).

Yield (w/w): 0.77 (65.0%)
HPLC purity: 99.71 %

Example-2: Preparation of Pitavastatin tertiary butyl amine salt (Form L1)
A mixture of 25.0 gm (4R, 6S)-(E)-6-[2-(2-cyclopropyl -4-(fluorophenyl) quinoline-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester compound [PTV-III] and 75 ml acetonitrile was cooled to 5-8 °C temperature. Added 5.0% aqueous hydrochloric acid solution (54 ml) to the reaction mixture. Stirred the reaction mixture for 2-3 hours at 25-30 °C temperature. Added solution of sodium hydroxide (5.75 gm. 3.0 mole) in DM water (29 ml) into the reaction mixture. Stirred the reaction mixture for 2-3 hours at 25-30 °C temperature. Quenched the reaction mixture with DM water and washed with Ethylacetate. Aqueous layer containing product cooled to 5-8 °C temperature. Adjusted the pH of the reaction mixture to 4.0 with 10% hydrochloric acid. Extracted the product in ethylacetate and washed with 20% sodium chloride solution. Separated the ethylacetate layer containing product and distilled out under vacuum at 40-45 °C temperature. Added acetone (90 ml) to the residue followed by tertiary butyl amine (4.68 gm) under stirring. Stirred the reaction mixture for 60-90 min at 25-30 °C temperature. Filtered the solid and washed with acetone to get the title compound (16.0 gm).

Yield (w/w): 0.88 (75.0%)
,CLAIMS:1. A crystalline pitavastatin tert-butyl amine form-L or a hydrate thereof, wherein the crystalline pitavastatin tert-butyl amine form-L has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2O (±0.2o 2O) at 15.82o, 19.40o, 19.81o and 21.43o ±0.2o.

2. The compound as claimed in claim 1 having an x-ray powder diffraction pattern substantially same as that shown in FIG. 1a.

3. The compound as claimed in claim 1 having an IR substantially same as that shown in FIG. 1b.

4. A process for the preparation of polymorphic form-L of pitavastatin tert-butyl amine salt of formula (2),

which comprises the steps of:
(a) reacting (4R, 6S)-(E)-6-[2-(2-cyclopropyl -4-(fluorophenyl) quinoline-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester of compound [PTV-III],

with acid such as hydrochloric acid, acetic acid, sulfuric acid to remove the acetonide and form Diol t-butyl ester of compound [PTV-IV],

(b) reacting the Diol t-butyl ester of compound [PTV-IV] with an alkali base such as sodium hydroxide and further treating with acid such as hydrochloric acid to form Pitavastatin Acid of compound [PTV-V],

(c) reacting Pitavastatin Acid of compound [PTV-V] with tertiary-butyl amine in ethyl acetate to form polymorphic form-L of pitavastatin tert-butyl amine salt of formula (2); wherein the reaction is carried out in one pot without isolating of the compound [PTV-IV] and the compound [PTV-V].

5. A crystalline pitavastatin tert-butyl amine form-L1 or a hydrate thereof, wherein the crystalline pitavastatin tert-butyl amine form-L1 has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2O (±0.2o 2O) at 10.36o, 12.15o, 16.59o, 17.22o, 19.30o and 22.41o ±0.2o.

6. The compound as claimed in claim 5 having an x-ray powder diffraction pattern substantially same as that shown in FIG. 2a.

7. The compound as claimed in claim 5 having an IR substantially same as that shown in FIG. 2b.

8. A process for the preparation of polymorphic form-L1 of pitavastatin tert-butyl amine salt of formula (2),

which comprises the steps of:
(a) reacting (4R, 6S)-(E)-6-[2-(2-cyclopropyl -4-(fluorophenyl) quinoline-3-yl)-vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid tertiary butyl ester of compound [PTV-III],

with acid such as hydrochloric acid, acetic acid, sulfuric acid to remove the acetonide and form Diol t-Butyl ester of compound [PTV-IV],

(b) reacting the Diol t-butyl ester of compound [PTV-IV] with an alkali base such as sodium hydroxide and further treating with acid such as hydrochloric acid to form Pitavastatin Acid of compound [PTV-V],

(c) reacting Pitavastatin Acid of compound [PTV-V] with tertiary-butyl amine in acetone to form polymorphic form-L of pitavastatin tert-butyl amine salt of formula (2); wherein the reaction is carried out in one pot without isolating of the compound [PTV-IV] and the compound [PTV-V].