WO2006067795A2

WO2006067795A2 - Novel polymorphic forms of atorvastatin lactone and process for preparing the same

Info

Publication number: WO2006067795A2
Application number: PCT/IN2004/000401
Authority: WO
Inventors: Sreenivas Rao Bhatraju; Annu Dua; Geetesh Kaushik; Rajesh Kumar Thaper; Sushil Kumar Dubey
Original assignee: Jubilant Organosys Limited
Priority date: 2004-12-23
Filing date: 2004-12-23
Publication date: 2006-06-29
Also published as: WO2006067795A3

Abstract

The present invention provides novel crystalline polymorphic Forms and amorphous Form of atorvastatin lactone, characterized by powder X-ray diffraction pattern and Infrared absorption spectrum. The novel processes for their preparation are also disclosed.

Description

NOVEL POLYMORPHIC FORMS OF ATORVASTATIN LACTONE AND PROCESS FOR PREPARING THE SAME

FIELD OF THE INVENTION

This invention, in general relates to the novel crystalline polymorphic forms and amorphous form of atorvastatin lactone. More particularly, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, the present invention is directed to crystalline Form I, Form II and amorphous form of atorvastatin lactone and the process for preparing the same.

BACKGROUND OF THE INVENTION

Hypercholesterolemia and hyperlipidemia, conditions of excessively high levels of blood cholesterol and lipids, are well-recognized risk factors in the onset of atherosclerosis and coronary heart disease. The blood cholesterol pool is generally dependent on dietary uptake of cholesterol from the intestine and biosynthesis of cholesterol throughout the body, especially the liver. Cholesterol is an indispensable component of virtually all cell membrane systems as well as a precursor of a variety of steroid hormones and bile acids.

It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an important enzyme catalyzing the intracellular synthesis of cholesterol, will bring about reduced levels of blood cholesterol especially in terms of the low density lipoprotein form of cholesterol. Therefore, HMG-CoA reductase enzyme inhibitors are considered potentially useful as hypocholesterolemic or hypolipidemic agents.

One of the inhibitors of cholesterol biosynthesis i.e. Lipitor generically called Atorvastatin [trans(+)-5-(4-fluorophenyl)-2-(l-methylethyl)-N,4-diρhenyl-l-[(2- tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl] - 1 H-pyrrole-3 -carboxamide (I)] is first described among compounds of US Patent No. 4,681,893. The compounds therein broadly include 4-hydroxypyran-2-ones and the corresponding ring-open acids derived there from. US Patent No. 5,273,995 incorporated by reference, discloses the enantiomer having the R form of the ring open acid of trans (+)-5-(4-fiuorophenyi)-2- ( 1 -methylethyl)-N,4-diphenyl- 1 - [2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl] - lH-pyrrole-3-carboxamide i.e. [R(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(l - methylethyl)-3-phenyl-4- [(phenyl amino)carbonyl]-lH-pyrrole-l-heptanoic acid or their pharmaceutically acceptable salt like calcium salt (II).

I II

Crystalline atorvastatin calcium salt trihydrate (II), which is thermodynamically more stable and readily isolable, recommended as drug, is used in the treatmeni of hypercholesterolemia. However, in case of lovastatin and simvastatin the stable lactone form is recommended as drug, which is readily isolable in crystalline form. Lactone form is the prodrug and is converted into active metabolite, the hydroxy acid, inside the body after administration. In case of atorvastatin, difficulty in isolation of lactone in the manufacturing process is one of the reasons that lactone is not recommended as drug and thermodynamically more stable and readily isolable in crystalline form, calcium salt trihydrate is recommended as drug. Due to these reasons extensive studies have been done only on the polymorphic properties of atorvastatin calcium salt, leading to the discovery of a large number of new polymorphs.

US Patent No. 4,681,893 describes that atorvastatin lactone may exist in solvated or unsolvated form with pharmaceutically acceptable solvents such as water, ethanol and the like and compares its activity with prior art compound compactin.

The lactone form of atorvastatin has not been disclosed in the prior art with regard to the existence of polymorphism, except for its preparation by the innovator and use as intermediate in the manufacturing process of atorvastatin calcium to remove potential impurities, otherwise difficult to remove. The present invention provides the novel polymorphs of atorvastatin lactone designated as crystalline Form I, Form II and amorphous form in both solvated and hydrated states and novel processes for their preparation using different solvents and reaction conditions.

SUMMARY OF THE INVENTION

It is the principal aspect of the present invention to provide novel crystalline polymorph of the atorvastatin lactone, referred to hereinafter as Form I, Form II and amorphous form characterized by infrared absorption spectrum, X-ray powder diffraction pattern, thermo gravimetric analysis (TGA), gas chromatography (GC), differential scanning calorimetry (DSC), moisture content and/or melting point.

Furthermore, the present invention is also directed to the process for preparation of novel crystalline polymorph of the atorvastatin lactone by using different solvent system and conditions.

In accordance with one preferred embodiment of the present invention, there is provided a crystalline atorvastatin lactone Form I having a melting point 127-13O⁰C, moisture content 0.3-0.5% and DMSO content 17-22% supported by thermo gravimetric analysis (TGA).

In accordance with another preferred embodiment of the invention, there is provided a crystalline atorvastatin lactone Form II having melting point 97-99⁰C and moisture content 1-4%.

In accordance with still another preferred embodiment of the present invention, there is provided an amorphous form of atorvastatin lactone having melting point 108-110⁰C and moisture content 1.6-1.8%

Accordingly, the present invention also provides the process for the preparation of crystalline atorvastatin lactone Form I₅ which comprises dissolving atorvastatin lactone in an aromatic solvent like toluene, to get the clear solution followed by the slow addition of DMSO at ambient temperature, filtering the resulting solid under suction and drying the same under vacuum to obtain the final product.

Accordingly, the present invention also provides the process for the preparation of crystalline atorvastatin lactone Form II, which comprises crystallizing atorvastatin lactone in alcohol, ketone, non-polar hydrocarbons or water and mixture thereof, filtering the resulting solid under suction and drying the same under vacuum to get the form II.

According to the present invention there is also provided a process for preparation of an amorphous form of atorvastatin lactone, which comprises dissolving atorvastatin lactone in a solvent to get the clear solution followed by the slow addition of anti- solvent, stirring the resultant precipitated oily material for a period of time to get solid material, filtering the resultant and drying the same under vacuum to get final product.

The novel polymorphic forms of atorvastatin lactone described herein the present invention may be used as pharmaceutical agents as HMG-CoA reductase inhibitors.

BRIEF DESCRIPTION QF THE DRAWING FIGURES

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:

FIG. 1 shows a characteristic X-ray powder diffraction pattern for crystalline atorvastatin lactone Form I.

Fig. 2 shows a characteristic infrared absorption spectrum of crystalline atorvastatin lactone Form I in potassium bromide. [Vertical axis: Transmission (%); horizontal axis: wave number (cm^'1)].

Fig. 3 gives Thermo gravimetric analysis of crystalline atorvastatin lactone Form I.

Fig. 4 shows Differential scanning calorimetry thermogram of crystalline atorvastatin lactone Form I. FIg. 5 shows a characteristic X-ray powder diffraction pattern for crystalline atorvastatin lactone Form II.

Fig. 6 shows a characteristic infrared absorption spectrum of crystalline atorvastatin lactone Form II in potassium bromide. [Vertical axis: Transmission (%); horizontal axis: wave number (cm^""1)].

Fig. 7 shows a characteristic X-ray powder diffraction pattern for atorvastatin lactone in amorphous form.

Fig. 8 shows a characteristic infrared absorption spectrum of atorvastatin lactone in amorphous form in potassium bromide [vertical axis: Transmission (%); horizontal axis: wave number (cm^"1)].

DETAILED DESCRIPTION OF THE INVENTION

The present, invention describes the crystalline atorvastatin lactone Form I, Form II and amorphous form, which may exist in hydrated forms and are intended to be encompassed within the scope of the present invention. Crystalline atorvastatin lactone

Form I, Form II and amorphous form differ from each other in their physical properties, spectral data and methods of preparation and characterized by their X-ray powder diffraction patterns, Thermo gravimetric analysis (TGA) and/or by their infra red absorption spectrum (IR).

X-ray powder Diffraction

Crystalline atorvastatin Form I, Form II and amorphous form are characterized by their X-ray powder diffraction pattern. Thus the X-ray diffraction patterns of crystalline Form I, Form II and amorphous form of atorvastatin lactone are measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of 2Θ, d-spacings and relative intensities.

Methodology

Continuous Θ/2Θ coupled scan: 5.01° to 45.00° in 2Θ, scan rate of 37min. Infrared absorption spectrometer (IR)

Methodology

All infrared measurements are made on Thermo Nicolet FT IR spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal centimeter.

Thermo Gravimetric analysis (TGA)

Methodology

TGA thermogram is recorded on TGA Q50 equilibrated at 25⁰C and with a ramp of 5°C/min

Crystalline atorvastatin lactone Form I is characterized by powder X-ray diffraction pattern as shown in Fig. 1 with major peaks shown in Table 1, which lists the 20, d- spacings and relative intensities (>20%).

Table 1

Crystalline atorvastatin lactone Form I is further characterized by IR with absorption bands at 3271 (m), 3177(m), 3124(w), 3O35(w), 2970(m), 2927(w), 1732(s), 1662(s), 1600(s), 1541(s), 1508(m), 1499(m), 1480(w), 1441(s), 1317(s), 1247(m), 1224(m), 1163(m), 1108(m), 1075(s), 1019(s), 949(w), 859(s), 811(m), 759(s), 701 (s), 694(s), 617(m), 572(w), 510(m), 458 (w); wherein (w) = weak intensity; (m) medium intensity; (s) = strong intensity as depicted in Fig. 2.

Crystalline atorvastatin lactone Form I is DMSO solvate of atorvastatin lactone having 17-22% of DMSO content i.e. about 2 moles of DMSO is solvated to the one mole of atorvastatin lactone, which is analyzed by its TGA data as shown in Fig. 3. After desolvation the DMSO content of this Form is reduced to less than 0.5% and Form changes to amorphous atorvastatin lactone as depicted from its X-ray powder diffraction. The amount of DMSO is further confirmed by HPLC and GC quantification.

The present invention also provides the process for the preparation of crystalline atorvastatin lactone Form I, which comprises dissolving atorvastatin lactone in aromatic solvent like toluene, to get the clear solution followed by the slow addition of DMSO at ambient temperature. The final product is filtered under suction and dried under vacuum. The Form I is having a melting point 127-13O⁰C and moisture content 0.3-0.5%.

Crystalline atorvastatin lactone Form II is characterized by X-ray powder diffraction pattern as shown in Fig. 5 with major peaks shown in Table 2, which lists the 2Θ, d- spacings and relative intensities (>20%).

Table 2

Crystalline atorvastatin lactone Form II is further characterized by IR with absorption bands at 3391(m), 3055(w), 2966(m), 2926(m), 171 l(s), 1656(s), 1594(s), 1529(m), 1509(s), 1433(s), 1315(s), 1238(m), 1225(m), 1172(w), 1154(m), 1074(m), 105 l(m), 843(m), 754(s), 691 (s), 622(m), 509(m); wherein (w) = weak intensity; (m) medium intensity; (s) = strong intensity as depicted in Fig. 6.

The present invention also provides a process for the preparation of crystalline atorvastatin lactone Form π, which comprises crystallizing atorvastatin lactone in a solvent such as alcohol, ketone, non-polar hydrocarbons or water and mixture thereof and then precipitated material as Form II is filtered under suction and dried under vacuum. The solvent used is selected from the group consisting of alcohol such as methanol, ethanol or isopropyl alcohol; ketone such as acetone; non-polar hydrocarbons such as hexane or heptane; or water and mixture thereof. The Form II is having a melting point of 97-99⁰C and moisture content 1 -4%.

Atorvastatin lactone in amorphous form is characterized by X-ray powder diffraction pattern as shown in Fig. 7. Atorvastatin lactone amorphous form is further characterized by IR with absorption bands at 3403(m), 2960(m), 2928(w), 173 l(s), 1654(s), 1595(s), 1528(m), 1508(m), 1436(s), 1313(s), 1224(m), 1156(s), 1073(s), 105 l(m), 842(s), 753(s), 692(s), 581(w), 508(w); wherein (w) = weak intensity; (m) = medium intensity; (s) = strong intensity as depicted in Fig. 8.

Tfie present invention also provides a process for the preparation of atorvastatin lactone in amorphous form, which comprises dissolving atorvastatin lactone in dichloromethane to get the clear solution followed by the slow addition of hexane. The precipitated oily material is stirred for a period of time to get solid material, which is filtered and dried under vacuum. The amorphous form is having a melting point of 108- 11O⁰C and moisture content 1.6-1.8%.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in any way.

Experimental Section

Example 1

Atorvastatin lactone crystalline Form I

Atorvastatin calcium (15.0 g) was suspended in distilled water (225 ml) Under stirring. To the suspension so obtained, hydrochloric acid (2.0 M) was added drop wise under stirring till solid product started precipitating. The reaction mixture was extracted in ethyl acetate (250 ml x 3). The combined organic layer was washed with brine solution and dried over sodium sulfate. Ethyl acetate was distilled off to get an oily product. Toluene (300 ml) was charged to the oily residue and refluxed with azeotropic removal of water for 4.0 hrs at 108-110⁰C. Toluene was distilled off to get an oily residue. This oily residue was dissolved in toluene (60.0 ml). To the clear solution so obtained, dimethyl sulfoxide (2.0 ml) was added under stirring. After the addition was complete the precipitated material was further stirred. The product was filtered under suction and dried under vacuum in oven. Crystalline atorvastatin lactone (9.0 g) as Form I was obtained. M.pt. 127-13O⁰C. Example 2

Atorvastatin lactone crystalline Form I

Atorvastatin lactone (2.0 g) was dissolved in toluene (12.0 ml). To the clear solution so obtained, dimethyl sulfoxide (0.34 ml) was added under stirring. After the addition was complete the precipitated material was further stirred. The product was filtered under suction and dried under vacuum in oven. Crystalline atorvastatin lactone (1.8 g) as Form I was obtained. M.pt. 127-13O⁰C.

Example 3

Atorvastatin lactone crystalline Form II

Atorvastatin lactone (2.0 g) was dissolved in isopropyl alcohol (5.0 ml) by stirring. To the clear solution so obtained hexane (50.0 ml) was added under stirring. After the addition was complete the precipitated material was further stirred. The product was filtered under suction and dried under vacuum in oven. Crystalline atorvastatin lactone (1.84 g) as Form II was obtained. M.pt. 97-99⁰C.

Example 4

Atorvastatin lactone amorphous form

Atorvastatin lactone (2.0 g) was dissolved in dichloromethane (4.0 ml). To the clear solution so obtained, hexane (20.0 ml) was added slowly under stirring. After the addition was complete the precipitated oily material was further stirred. Dichloromethane was distilled and hexane (20.0 ml) was added and stirred. The precipitated product was filtered under suction and dried under vacuum. Atorvastatin lactone (1.96 g) as amorphous form was obtained.

Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims

We Claim:

1. Crystalline polymorphic form I of atorvastatin lactone.

2. Crystalline atorvastatin lactone form I according to claim 1 having an X- ray powder diffraction pattern characterized by peaks at 18.0, 18.4, 20.3, 21.3 ± 0.2° 2θ values.

3. Crystalline atorvastatin lactone form I according to claim 2 having an X- ray powder diffraction pattern characterized by peaks at 6.0, 10.3, 18.0, 18.4, 20.3, 21.3, 22.6, 23.5, 23.8, 24.4, 24.6, 26.3, 26.9 ± 0.2° 2Θ values.

4. Crystalline form of atorvastatin lactone according to claim 3 having a substantially similar X-ray powder diffraction pattern as depicted in Figure 1.

5. Crystalline atorvastatin lactone form I according to claim 1 characterized by an infra red spectroscopy having absorption bands (cm^"1) at 3271, 3177, 2970, 1732, 1662, 16_.00, 1541, 1441, 1317, 1247, 1224, 1019, 759, 701, 694.

6. Crystalline atorvastatin lactone form I according to claim 5 characterized by an infra red spectroscopy having absorption bands (cm^"1) at 3271, 3177, 3124, 3035, 2970, 2927, 1732, 1662, 1600, 1541, 1508, 1499, 1480, 1441, 1317, 1247, 1224, 1163, 1108, 1075, 1019, 949, 859, 811, 759, 701, 694, 617, 572, 510, 458.

7. Crystalline atorvastatin lactone form I according to claim 1, wherein said polymorphic form I containing 17-22 % of DMSO.

8. Process for preparing crystalline atorvastatin lactone form I comprising:

(a) dissolving atorvastatin lactone in toluene;

(b) adding dimethyl sulfoxide and separating the resultant precipitate to obtain the final product.

9. Process according to claim 8, wherein atorvastatin lactone is taken as oil or a solid in step (a).

10. Crystalline polymorphic form II of atorvastatin lactone.

11. Crystalline atorvastatin lactone form II according to claim 10 having an X-ray powder diffraction pattern characterized by peaks at 9.2, 16.6, 18.9, 19.3, 20.0, 20.5, 23.5, 24.0 ± 0.2° 2Θ values.

12. Crystalline atorvastatin lactone form II according to claim 11 having an X-ray powder diffraction pattern characterized by peaks at 7.5, 9.2, 11.6, 11.7, 12.5, 16.6, 18.1, 18.9, 19.3, 20.0, 20.5, 21.2, 22.6, 23.5, 24.0, 24.6, 26.9, 28.9 ± 0.2° 2Θ values.

13. Crystalline form of atorvastatin lactone according to claim 12 having a substantially similar X-ray powder diffraction pattern as depicted in Figure 5. 5

14. Crystalline atorvastatin lactone form II according to claim 10 characterized by an infrared spectroscopy having absorption bands (cm^"1) at 3391, 2966, 2926, 1711, 1656, 1594, 1529, 1509, 1433, 1315, 1238, 1225, 1074, 1051, 754, 691.

15. Crystalline atorvastatin lactone form II according to claim 14 10 characterized by an infrared spectroscopy having absorption bands (cm^"1) at 3391,

3055, 2966, 2926, 1711, 1656, 1594, 1529, 1509, 1433, 1315, 1238, 1225, 1172, 1154, 1074, 1051, 843, 754, 691, 622, 509.

16. Process for preparing crystalline atorvastatin lactone form II comprising:

(a) . crystallizing atorvastatin lactone in a solvent such as alcchol, i 5 ketone, non-polar hydrocarbons or water and a mixture thereof;

(b) separating the resultant precipitate to obtain the final product.

17. Process according to claim 16, wherein the alcohol is selected from a group comprising isopropyl alcohol, ethanol or methanol.

18. Process according to claim 16, wherein the ketone is acetone. 0

19. Process according to claim 16, wherein the non-polar hydrocarbon is selected from hexane or heptane.

20. Process according to claim 16, wherein atorvastatin lactone is taken as oil or a solid in step (a).

21. Amorphous form of atorvastatin lactone. 5

22. Amorphous form of atorvastatin lactone according to claim 21 having a substantially similar X-ray powder diffraction pattern as depicted in Figure 7.

23. Amorphous form of atorvastatin lactone according to claim 21 characterized by an infra red spectroscopy having absorption bands (cm^"1) at 3403, 2960, 1731, 1654, 1595, 1508, 1436, 1313, 1224, 1156, 1073, 842, 753, 692. 0

24. Amorphous form of atorvastatin lactone according to claim 22 characterized by an infra red spectroscopy having absorption bands (cm^"1) at 3403, 2960, 2928, 1731, 1654, 1595, 1528, 1508, 1436, 1313, 1224, 1156, 1073, 1051, 842, 753, 692, 581, 508.

25. Process for preparing atorvastatin lactone in amorphous form comprising:

(a) dissolving atorvastatin lactone in dichloromethane;

(b) adding hexane to the solution; (c) removing the dichloromethane; and

(d) adding hexane and separating the resultant precipitate to obtain the final product.

26. Process according to claim 25, wherein atorvastatin lactone is taken as. oil or a solid in step (a).