Field of the Invention
The present invention relates to crystalline and amorphous magnesium salts of atorvastatin of structural formula I, processes for their preparation, pharmaceutical compositions thereof and methods of using compositions to treat mammals suffering from hypercholesterolemia.
(Formula Removed)
Background of the Invention
Atorvastatin (formula II) is a member of the class of drugs called statins. Statins are currently the most therapeutically effective drugs available for reducing low-density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease.
(Formula Removed)
Statins mechanism of action of has been elucidated in some detail. They interfere with the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase"). HMG-CoA reductase catalyses the conversion of HMG to mevalonate, which is the rate determining step in the
biosynthesis of cholesterol. This inhibition leads to a reduction in the concentration of cholesterol in the liver.
Summary of the Invention
In one aspect there is provided a crystalline form of magnesium salt of atorvastatin having XRD pattern essentially as shown in Figure I.
In another aspect there is provided a crystalline form of magnesium salt of atorvastatin having IR spectrum as shown in Figure II.
In yet another aspect there is provided a process for the preparation of crystalline form of magnesium salt of atorvastatin comprising contacting an alkali metal salt of atorvastatin salt with magnesium salt of an acid in a suitable solvent to form atorvastatin magnesium.
In another embodiment there is provided amorphous form of magnesium salt of atorvastatin having XRD pattern as shown in Figure III.
In yet another embodiment there is provided amorphous form of magnesium salt of atorvastatin having IR spectrum as shown in Figure IV.
In a further aspect there is provided a process for the preparation of amorphous atorvastatin magnesium comprising dissolving crystalline form of magnesium salt of atorvastatin in one or more solvents, and removing the solvent from the solution to obtain amorphous atorvastatin magnesium. One or more co-solvents may be added to the solution before solvent removal.
In another aspect there is provided a process for the preparation of amorphous atorvastatin magnesium. The process comprises dissolving crystalline form of magnesium salt of atorvastatin in one or more solvents, and adding an anti-solvent(s) to obtain amorphous atorvastatin magnesium.
In another aspect there is provided a pharmaceutical composition that comprises crystalline or amorphous form of atorvastatin magnesium and one or more of pharmaceutically acceptable excipients, diluents and carriers.
In another aspect there is provided a method of inhibiting HMG-CoA reductase comprising administering to a mammal, in need thereof, a therapeutically effective amount of crystalline or amorphous form of atorvastatin magnesium.
In another aspect there is provided a method of treating primary hypercholesterolemia, dysbetalipoproteinemia or homozygous familial hypercholesterolemia. The method includes administering to a mammal, in need thereof, a therapeutically effective amount of crystalline and / or amorphous form of atorvastatin magnesium.
Description of the Drawings Figure I is an XRD pattern showing peaks characteristic of crystalline form of magnesium salt of
atorvastatin. Figure II is an infrared spectrum showing characteristic absorption bands of crystalline form of
magnesium salt of atorvastatin. Figure III is an XRD pattern showing a halo that is characteristic of amorphous atorvastatin
magnesium. Figure IV is an infrared spectrum showing characteristic absorption bands of amorphous atorvastatin
magnesium.
Detailed Description of the Invention
The term "atorvastatin magnesium" as used herein refers to a salt, which includes atorvastatin anions and magnesium cations, in either crystalline or in amorphous form.
Further, the term "atorvastatin magnesium" also encompasses stoichiometric, as well as non-stoichiometric ratios, of atorvastatin anions and magnesium cations. The ratio of atorvastatin to magnesium is not required to be 1:1 in order to be termed atorvastatin magnesium. Atorvastatin magnesium may be formed as a salt having a 2:1 molar ratio between atorvastatin anions and magnesium cations (i.e., atorvastatin hemi-magnesium). Atorvastatin hemi-magnesium may be formed even when an excess of atorvastatin or an excess of magnesium salt of an acid is used in the salt formation.
Atorvastatin magnesium and particularly atorvastatin hemi-magnesium may exist in anhydrous, hydrated and solvated forms.
The crystalline form of magnesium salt of atorvastatin is characterized by the following
XRD pattern expressed in terms of the 26, d-spacings and relative intensities in one embodiment.
(Formula Removed)
The crystalline form of magnesium salt of atorvastatin may be characterized by its IR spectrum in potassium bromide as shown in Figure II. Characteristic absorption bands of the crystalline form of atorvastatin magnesium are observed at 510.01, 524.96, 614.29, 691.96, 716.37, 755.86,811.88,847.37,885.86,916.94,970.64, 1013.99, 1031.70, 1076.16, 1091.96, 1110.70, 1155.39, 1222.49, 1313.02, 1435.78, 1506.07, 1524.44, 1594.43, 1654.39, 1898.16, 1947.25, 2954.31, 3283.59, 3405.75, and 3667.28 cm'1
Also provided, in the present invention, is a process for preparing crystalline atorvastatin magnesium. The process comprises contacting atorvastatin alkali metal salts with the magnesium salt of an acid in a suitable solvent to form crystalline atorvastatin magnesium.
Atorvastatin alkali metal salts to be used in the process may be obtained from a compound of Formula III by using methods known in the literature. In particular, they may be obtained by a process comprising contacting the compound of Formula III with an acid to hydrolyse the ketal group, followed by addition of an alkali metal hydroxide to remove the tertiary butyl group along with the formation of a metal salt.
(Formula Removed)
Suitable acids include mineral acids, such as hydrochloric acid. Suitable hydroxides of alkali metals include sodium hydroxide, lithium hydroxide and potassium hydroxide.
Suitable solvents for preparing atorvastatin magnesium include any solvent capable of dissolving an alkali metal atorvastatin salt and from which crystalline atorvastatin magnesium may be isolated.
Suitable solvents for carrying out the process include hydroxylic solvents, such as water, lower alkanols or mixtures thereof. The hydroxylic solvents may be made acidic or basic by the addition of a mineral acid or alkali metal hydroxide if required.
Suitable lower alkanols include primary, secondary and tertiary alcohols having one to six carbon atoms; primary, secondary and tertiary alcohols having one to four carbon atoms, for example methanol, ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n-butanol, t-butanol and mixtures thereof.
Suitable magnesium salts of an acid to be used in the process may be a salt of any inorganic or organic acid, such as magnesium chloride, magnesium nitrate, magnesium sulphate, magnesium phosphate, magnesium carbonate, magnesium dihydrogenphosphate, magnesium oxalate, magnesium acetate, magnesium lactate, magnesium succinate, magnesium citrate or mixtures thereof.
Once atorvastatin magnesium is crystallized, either spontaneously, upon cooling, upon seeding, or by any other inducement, the crystal may be isolated by filtration or any other conventional means known in the art. The isolated crystals are dried by conventional means.
Also provided in the present invention is atorvastatin magnesium in an amorphous form. The amorphous atorvastatin magnesium may be characterized by its IR spectrum in potassium bromide as shown in Figure II. Characteristic absorption bands of amorphous atorvastatin magnesium are observed at 507.52, 574.31, 624.02, 691.61, 734.03, 752.18, 817.90, 841.92, 884.77,
1054.46, 1092.59, 1155.53, 1221.29, 1311.34, 1435.61, 1508.53, 1527.17, 1560.18, 1594.77, 1653.72, 1948.41, 2869.96, 2958.37, 3056.27, and 3406.52 cm"1
The amorphous atorvastatin magnesium may be prepared by dissolving crystalline form of magnesium salt of atorvastatin in one or more suitable organic solvent and adding an anti-solvent(s) to the solution to obtain amorphous atorvastatin magnesium.
Suitable organic solvents include one or more solvent (s) selected from the group of solvents that have the ability to dissolve crystalline atorvastatin magnesium. These solvents include tetrahydrofuran, dimethylsulphoxide, chloroform or mixtures thereof.
Any organic solvent in which atorvastatin magnesium is not soluble may be used as an anti-solvent. These anti- solvents include n-hexane, n-heptane, cyclohexane, hexane fraction, heptane fraction and mixtures thereof. For example, the solvent used for dissolving crystalline atorvastatin magnesium may be tetrahydrofuran and the anti- solvent may be cyclohexane.
The product is then recovered by filtration at ambient temperature. The filtered material is further dried to remove surface solvents in one or more of vacuum tray drier, tray drier, fluid bed drier or a rotary vacuum drier to obtain the amorphous atorvastatin magnesium.
The amorphous atorvastatin magnesium prepared according to the process of the present invention may be characterized by its XRD pattern (Figure III) as shown in the accompanied drawings. This XRD pattern (Figure III) shows no peaks, which are characteristic of a crystalline form of atorvastatin calcium (Figure I of the accompanying drawings) thus demonstrating the amorphous nature of the product.
Also provided in the present invention is another process for the preparation of amorphous atorvastatin magnesium. The process includes dissolving crystalline form of magnesium salt of atorvastatin in one or more solvents, and removing the solvent from the solution to obtain amorphous atorvastatin magnesium. One or more co-solvents may be added to obtain the solution.
Suitable solvents used to dissolve crystalline form of magnesium salt of atorvastatin are the same as described above.
Suitable co-solvents may be those in which magnesium salt of atorvastatin is not readily dissolved but is sparingly or moderately soluble, or the same as the anti-solvents described above but added in quantities which are not sufficient to precipitate atorvastatin magnesium. Suitable co-solvents include cyclohexane and toluene.
The process of removal of solvent includes concentration, evaporation, flash evaporation, spray drying, freeze drying or lyophilization of a solution of atorvastatin magnesium.
The atorvastatin magnesium may be formulated into pharmaceutical compositions. The pharmaceutical compositions include crystalline or amorphous form of magnesium salt of atorvastatin as an active ingredient along with one or more pharmaceutically acceptable excipients, diluents and/or carriers. The pharmaceutical composition may be in the form of oral, buccal, rectal, topical and parenteral (including subcutaneous, intramuscular, and ophthalmic administration) dosage forms. These dosage forms also include solid dosage form, such as powder, tablets, capsules, suppositories, sachets, troches and lozenges, as well as liquid suspensions and elixirs.
A method of inhibiting HMG-CoA reductase comprising administering to a mammal, in need thereof, a therapeutically effective amount of crystalline or amorphous form of atorvastatin magnesium is provided.
Also provided is a method of treating primary hypercholesterolemia, dysbetalipoproteinemia or homozygous familial hypercholesterolemia. The method includes administering to a mammal, in need thereof, a therapeutically effective amount of crystalline and / or amorphous form of magnesium salt of atorvastatin. The therapeutically effective amount of crystalline and / or amorphous form of magnesium salt of atorvastatin may be administered as a component of any of the pharmaceutical compositions described herein.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The following examples illustrate various implementations of the invention without being limiting.
EXAMPLE 1 PREPARATION OF CRYSTALLINE ATORVASTATIN MAGNESIUM
To a solution of (4R-cis)-l,l-Dimethylethyl-6-{2[2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenyl amino)-carbonyl]-lH-pyrrol-lyl]ethyl-2,2-dimethyl-l,3-dioxane-4-acetate in methanol, IN hydrochloric acid (90.3ml) was added at 20-26°C in 15 minutes. The reaction mixture was stirred for 6 hours at the same temperature till the reaction was completed.
The pH of the resulting mixture was adjusted to about 12 by adding 10% w/v aqueous sodium hydroxide solution (107.5 ml) at 25-30°C and the resulting mixture was stirred for 6 hours at 25-30°C. The pH of the reaction mixture was monitored and maintained at about 12 throughout the course of the reaction by adding 10% w/v aqueous sodium hydroxide solution. After the reaction was completed, the mass was filtered and concentrated.
Water, methanol and methyl tertiary butyl ether were added to the concentrated mass at room temperature. The reaction mixture was stirred and then allowed to settle. The organic layer was separated and discarded. The aqueous layer was washed with methyl tertiary butyl ether (170 ml) and 6N hydrochloric acid was slowly added to adjust the pH to 7.8 to 8.0. The reaction mixture was heated to 45-55°C and an aqueous solution of magnesium acetate tetrahydrate in deionized water was slowly added at the same temperature. The reaction mixture was stirred for 1 hour at room temperature, filtered and washed with deionized water. The product was dried under vacuum (30 mm Hg) at 50-55°C, till the moisture content was about 3-7% w/w, to get 38 grams of crystalline atorvastatin magnesium.
EXAMPLE 2
PREPARATION OF CRYSTALLINE ATORVASTATIN MAGNESIUM FROM
ATORVASTATIN CALCIUM
IN Hydrochloric acid (50ml) was added gradually to a suspension of [R-(R*, R*)]-atorvastatin calcium (50g) in deionized water (750ml) at room temperature to adjust the pH to 3.5 to 4.0. The mixture was extracted with ethyl acetate. The organic layer was washed with 20% aqueous brine (150ml) and concentrated under vacuum at 40-45°C to get the residue. To the resulting residue, methanol was added and then recovered completely under vacuum at 40-45°C twice to remove traces of ethyl acetate. Methanol (500ml) was again added to the residue at room temperature. An aqueous sodium hydroxide solution (8g in 400 ml deionized water) was added gradually to it and the mixture was stirred for 2 hours at room temperature. The pH of the reaction mixture was adjusted to 7.8 to 8.0 by adding IN hydrochloric acid (25ml) slowly at room temperature. An aqueous solution of magnesium acetate tetrahydrate (lOg in 1200ml deionized water) was added in 60 minutes at room temperature and stirred for 1 hour at room temperature. The solid separated was filtered and dried to get 45 g of crystalline atorvastatin magnesium
A suspension of atorvastatin magnesium in methanol (169 ml) and water (957 ml) was stirred for 12 hours at room temperature. The suspension was filtered and washed with a mixture of methanol (67.5 ml) and water (382.5 ml) and dried to get 44 g of pure crystalline atorvastatin magnesium.
EXAMPLE 3 PREPARATION OF AMORPHOUS ATORVASTATIN MAGNESIUM
Crystalline atorvastatin magnesium (70g) was dissolved in tetrahydrofuran (182 ml) at room temperature and stirred for 30 minutes. The solution was filtered through a celite bed and the bed was washed with tetrahydrofuran (28ml). The above solution was added to cyclohexane (2100 ml taken in a separate vessel) slowly for 2 hours while stirring moderately at 22-25°C. It was then stirred vigorously for 30 minutes at 22-25°C, and the separated solid was filtered and washed with cyclohexane (70ml). The material was dried under, vacuum at 60-70°C to get 66 g of the amorphous atorvastatin magnesium.
EXAMPLE 4 PREPARATION OF AMORPHOUS ATORVASTATIN MAGNESIUM
Crystalline atorvastatin magnesium (70g) was dissolved in tetrahydrofuran (182ml) at room temperature and was stirred for 30 minutes. The solution was filtered through a celite bed and was washed with tetrahydrofuran (28ml). The solvent was evaporated under vacuum at 60-70°C to give 66 g of the amorphous atorvastatin magnesium.

WE CLAIM;
1. A crystalline form of magnesium salt of atorvastatin.
2. The crystalline form of claim 1 having XRD pattern essentially as shown in Figure I.
3. The crystalline form of claim 1 having IR spectrum as shown in Figure II.
4. The crystalline form of claim 1 having an XRD pattern comprising characteristic peaks at
29 values 8.60, 16.14, 17.96, and 21.44 ±0.2.
5. The crystalline form of claim 4, further comprising characteristic peaks at 20 values 9.66
and 11.3410.2.
6. The crystalline form of claim 4, further comprising characteristic peaks at 29 values 8.80,
18.48, 18.62, 21.26,and 21.60 ± 0.2.
7. The crystalline form of claim 1, wherein the magnesium salt of atorvastatin is hemi-
magnesium.
8. A process for the preparation of crystalline magnesium salt of atorvastatin comprising
contacting an alkali metal salt of atorvastatin with magnesium salt of an acid in the presence
of a solvent to form crystalline atorvastatin magnesium.
9. The process of claim 8, wherein the alkali metal salt comprises one or more of atorvastatin
potassium, atorvastatin sodium and atorvastatin lithium.
10. The process of claim 8, wherein the magnesium salt of an acid comprises a magnesium salt
of any inorganic or organic acid.
11. The process of claim 8, wherein the magnesium salt of an acid comprises one or more of
magnesium chloride, magnesium nitrate, magnesium sulphate, magnesium phosphate,
magnesium carbonate, magnesium dihydrogenphosphate, magnesium oxalate, magnesium
acetate, magnesium lactate, magnesium succinate, and magnesium citrate .
12. The process of claim 8, wherein the solvent comprises one or more hydroxylic solvents.
13. The process of claim 12, wherein the hydroxylic solvents comprise water, lower alkanols
and mixtures thereof.
14. The process of claim 13, wherein the lower alkanols comprise primary, secondary and
tertiary alcohols having one to six carbon atoms.
15. The process of claim 13, wherein the lower alkanols comprise primary, secondary and
tertiary alcohols having one to four carbon atoms.
16. The process of claim 15, wherein the lower alkanols comprise one or more of methanol,
ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n-butanol, and t-butanol.
17. Amorphous form of magnesium salt of atorvastatin.
18. Amorphous form of claim 17 having XRD pattern as shown in Figure III.
19. Amorphous form of claim 18 having IR spectrum as shown in Figure IV.
20. A process for the preparation of amorphous atorvastatin magnesium comprising:

a) dissolving crystalline atorvastatin magnesium in one or more solvents, and
b) removing the solvent from the solution to obtain amorphous atorvastatin magnesium.
21. The process of claim 20, wherein a co-solvent is added to the solution before solvent removal.
22. A process of the preparation of amorphous atorvastatin magnesium comprising:
a) dissolving crystalline atorvastatin magnesium in one or more solvents, and
b) adding anti-solvent(s) to the solution to obtain amorphous atorvastatin magnesium.

23. A pharmaceutical composition comprising atorvastatin magnesium of claim 1 or 17 and
one or more of pharmaceutically acceptable excipients, diluents and carriers.
24. A method of treating primary hypercholesterolemia, dysbetalipoproteinemia or homozygous
familial hypercholesterolemia comprising administering to a mammal in need thereof a
therapeutically effective amount of atorvastatin magnesium of claim 1 or 17.
25. A method of inhibiting HMG-CoA reductase comprising administering to a mammal in need
thereof a therapeutically effective amount of atorvastatin magnesium of claim 1 or 17.