NZ566287A - Crystalline and amorphous sodium atorvastatin - Google Patents

Abstract

Disclosed is a crystalline sodium atorvastatin of form II which exhibits an X-ray diffraction pattern comprising 2 theta reflections of 6.85, 7.18, 8.33, 19.1 and 19.42 plus or minus 0.2. Also disclosed is a method to prepare said crystalline form comprising crystallization from ethanol and butanone, a composition comprising said crystalline form and the use of said crystalline form in the manufacture of a medicament for the treatment of a disease which is prevented, ameliorated or eliminated by administration of a lipid regulating agent e.g. hyperlipemia.

Description

566287 RECIEVED IPONZ 23 JULY 2010 CRYSTALLINE AND AMORPHOUS SODIUM ATORVASTATIN The present invention relates to crystalline sodium atorvastatin, to compositions 5 containing the same and to methods for the formation thereof.

Cerebrovascular disease is often considered to be one of the biggest threats to human health. According to one investigation, there are more than three million people who die of the disease annually in China, the disease being responsible for 50% of all 10 deaths. 75% of survivors lose their working abilities in different degrees and 4% are badly affected. Moreover, 80% of adults aged thirty or above may have cerebrovascular disease in one of its forms, such as hyperlipemia, hypertension, coronary heart disease (CHD), and cerebral apoplexy.

Atherosclerosis is the pathological basis of ischemic cerebrovascular disease (ICVD). Death rates due to central brain related coronary heart disease and cerebrovascular disease have recently increased and, therefore, research into treatments for atherosclerosis is becoming more and more important.

Atherosclerosis is the aggradation of blood ingredients, hyperplasia of smooth muscle cells and of collagenous fibre in the artery endothelium. The lesions, which result from an excessive, inflammatory-fibroproliferative response to various forms of injury to the endothelium and smooth muscle of the artery wall, affect large elastic arteries, such as the main artery and its first branch, and medium muscle arteries, such 25 as cerebral arteries, coronary arteries, renal arteries and arterial branches of arteries at the extremities. Lesions are commonly found at the openings of vas endothelium branches which are easily damaged. The lesions are plaque-distributed and force the vas to be harder, narrow or block the chamber and then result in absence of blood in the tissues and organs. Hence, the most likely effect is myocardial infarction and 30 cerebral infarction. The cause of atherosclerosis is not fully understood because of the many complex factors involved in this disease. In general, there are two main types of factors, the first being constitutional factors such as age, sex and familial inheriting factors, and the second being acquired factors, such as hyperlipemia, hypertension, 566287 RECIEVED IPONZ 23 JULY 2010 over-smoking, diabetes and over-adiposity. All of these will affect and increase the atherosclerosis owing to their collective multifactorial actions.

There are several kinds of anti-atherosclerosis drugs, such as lipid regulating agents, 5 anti-oxidants, diluents of fatty acids and protectors of arterial endothelium. The HMG-CoA Reductase Inhibitors are lipid regulating agents and include drugs of the statin family, such as mevastatin, lovastatin, simvastatin, fluvastatin and atorvastatin, which are considered to be the best cholesterol lowering statin medicines available. All are the first choice for treating diseases such as primary hyperlipemia, 10 heterozygote familial hiperlipemia, high lipoprotein (III), diabetes and renal hyperlipemia. There are a large number of scientists researching these kinds of medicines and they have already reported a number of technical methods. For example, the ability to obtain a high purity of HMG-CoA Reductase Inhibitor, as disclosed in Chinese patent application 9981076.0, relies on "displacement of color 15 spectrum" to separate the HMG-CoA Reductase Inhibitor.

Although this method results in a high purity of HMG-CoA Reductase Inhibitor with a high yield, a low cost and minimal effect on the ecological balance, it applies the "displacement of color spectrum" technique at the same time as utilising a 20 chromatographic column. The principle is traditional laminar analysis, which always takes a long time to perform and requires the skills of a professional researcher to operate it. In addition, it is difficult to perform in large-scale automated production.' Accordingly, this method is used to purify small quantities of HMG-CoA Reductase 25 Inhibitor at a laboratory scale only. It is not used for purifying atorvastatin because of the difficulty in regenerating the chromatographic column. Atorvastatin, which is a new generation of the statin family antihyperlipemias, is used, among other things, for common hyperlipemia or mixed hyperlipidemia, which result mainly from increased blood cholesterol. It is especially useful for patients who are unresponsive to other 30 medicines.

It is thought that some of the statin family medicines have good efficacy when they are used with other antihyperlipemia drugs, however, atorvastatin has been shown to 566287 RECIEVED IPONZ23 JULY 2010 have sufficient efficacy when administered alone. Hence, the sales of atorvastatin are increasing dramatically such that it is now the best selling statin family medicine on the market.

Chinese patent application number 02815070.8 discloses methods for the production of crystalline calcium atorvastatin. It discloses two crystalline forms, VI and VII of [R-(R<*>, R<*>)]-2-(4-Fluorophenyl)-beta, delta-dihydroxy-5-(l -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt. According to the methods, nine steps are needed to isolate Form VI and five steps to 10 isolate Form VII. The crystalline calcium atorvastatin produced is more than 99.0% pure by HPLC, however, due to the complex purifying process, the methods used are very expensive. The methods also require the use of nitrile as a purifying agent which is not only harmful to the environment, but also to the workers involved.

It is, therefore, an object of the present invention to seek to alleviate these problems.

A further object of the present invention is to provide crystalline sodium atorvastatin in various polymorphic forms and processes for the preparation thereof.

According to a first aspect of the present invention, there is provided crystalline sodium atorvastatin.

According to another aspect of the present invention, there is provided crystalline sodium atorvastatin which exhibits an X-ray diffraction pattern comprising peaks 25 expressed in degrees two-theta at approximately 6.85 ± 0.2, 7.18 ± 0.2, 8.33 ± 0.2, 19.1 ±0.2 and 19.42 ±0.2.

According to another aspect of the present invention, there is provided crystalline sodium atorvastatin which exhibits an X-ray diffraction pattern comprising peaks 30 expressed in degrees two-theta at approximately 3.67 ± 0.2, 5.05 ± 0.2, 6.85 ± 0.2, 7.18 ± 0.2, 8.33 ± 0.2, 8.62 ± 0.2, 9.38 ± 0.2, 10.02 ± 0.2, 10.35 ± 0.2, 10.71 ± 0.2, 11.76 ± 0.2, 12.66 ± 0.2, 13.87 ± 0.2, 16.01 ± 0.2, 16.38 ± 0.2, 17.1 ± 0.2, 19.1 ± 0.2, 566287 RECIEVED IPONZ23 JULY 2010 19.42 ± 0.2, 20.88 ± 0.2, 21.16 ± 0.2, 22.9 ± 0.2, 23.6 ± 0.2, 30.12 ± 0.2, 33.12 ± 0.2, 37.92 ±0.2 and 41.47 ±0.2.

Also provided by the present invention is crystalline sodium atorvastatin which 5 exhibits an X-ray diffraction pattern substantially the same as shown in figure 2.

According to further aspect of the present invention, there is provided a method for the preparation of crystalline sodium atorvastatin, the method comprising: - (a) adding amorphous sodium atorvastatin to a first organic solvent to form a 10 first solution; (b) adding a second organic solvent to the first solution to form a second solution; (c) allowing sodium atorvastatin to crystallize out from the solution; and (d) collecting the crystallized sodium atorvastatin.

Preferably, the first organic solvent is an alcohol, more preferably a straight or branched Q to Cg alcohol, further preferably ethanol.

In preferred embodiments, the second organic solvent is a ketone, more preferably 20 butanone.

Preferably, the amorphous sodium atorvastatin is added to the first organic solvent at a ratio of about 8 to lOg amorphous atorvastatin for about every 40g to lOOg first organic solvent.

Preferably, the second organic solvent is added to the first solution at a ratio of about 50 to lOOg second organic solvent for about every 8 to lOg amorphous atorvastatin used in step (a).

The first organic solvent preferably comprises at least about 75% organic solvent in solution. Preferably, the crystallized sodium atorvastatin is collected by filtration. It is preferred that the collected crystallized sodium atorvastatin is dried, more preferably dried under vacuum. 566287 RECIEVED IPONZ23 JULY 2010 In further embodiments of the present invention, the method comprises the following additional steps for the preparation of amorphous sodium atorvastatin for use in step (a):- (i) preparing a third solution comprising sodium atorvastatin; 5 (ii) adjusting the pH of the third solution to an acid pH; (iii) adding a third organic solvent to form a fourth solution; (iv) isolating an organic layer; (v) adjusting the pH of the organic layer to an alkali pH; (vi) collecting precipitated amorphous sodium atorvastatin.

Preferably, the third solution comprises about 5% sodium atorvastatin.

Preferably, the pH of the third solution is adjusted by the addition of hydrochloric acid, preferably having a concentration of about 15 to 30%, more preferably about 15 15 to 20%. In preferred embodiments, the pH of the third solution is adjusted to between about 1 and 4.

Preferably, the third organic solvent is a halogen substituted Ci to C$ hydrocarbon, more preferably dichloromethane.

It is preferred that the third organic solvent is added to the third solution at a ratio of about 100 to 200g third organic solvent for about every lOg sodium atorvastatin in the third solution.

Preferably, the pH of the organic layer is adjusted by the addition of sodium hydroxide solution, preferably having a concentration of about 20 to 50%. In preferred embodiments, the pH of the organic layer is adjusted to between about 9 and 10.

Preferably, the precipitated amorphous sodium atorvastatin is collected by filtration.

Preferably, the precipitated amorphous sodium atorvastatin is dried, more preferably dried under vacuum. 566287 RECIEVED IPONZ 23 JULY 2010 According to a preferred embodiment, the precipitated amorphous sodium atorvastatin exhibits an X-ray diffraction pattern substantially the same as shown in figure 1.

According to another embodiment the precipitated amorphous sodium atorvastatin preferably exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 7.87 ± 0.2,18.18 ± 0.2, 18.87 ± 0.2 and 22.88 ± 0.2.

According to a further embodiment, the precipitated amorphous sodium atorvastatin 10 preferably exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 5.45 ± 0.2, 7.87 ± 0.2, 9.52 ± 0.2, 11.02 ± 0.2, 14.2 ± 0.2, 16.4 ± 0.2,18.18 ± 0.2, 18.87 ± 0.2,19.76 ± 0.2, 22.88 ± 0.2, 32.27 ± 0.2, 33.35 ± 0.2, 37.86 ± 0.2, 39.99 ± 0.2, 41.13 ± 0.2 and 44.95 ± 0.2.

A further aspect of the present invention relates to amorphous sodium atorvastatin.

According to another aspect of the present invention, there is provided amorphous sodium atorvastatin which exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 7.87 ± 0.2, 18.18 ± 0.2, 18.87 ± 0.2 20 and 22.88 ± 0.2.

According to a further aspect of the present invention, there is provided amorphous sodium atorvastatin which exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 5.45 ± 0.2, 7.87 ± 0.2, 9.52 ± 0.2, 25 11.02 ±0.2, 14.2 ±0.2, 16.4 ±0.2, 18.18 ±0.2, 18.87 ±0.2, 19.76 ± 0.2, 22.88 ± 0.2, 32.27 ± 0.2, 33.35 ± 0.2, 37.86 ± 0.2, 39.99 ± 0.2, 41.13 ± 0.2 and 44.95 ± 0.2.

Also provided by the present invention is amorphous sodium atorvastatin which exhibits an X-ray diffraction pattern substantially the same as shown in figure 1.

Further provided by the present invention is amorphous sodium atorvastatin produced by any of the methods described herein. 566287 RECIEVED IPONZ23 JULY 2010 The present invention also relates to crystalline sodium atorvastatin produced by any of the methods described herein.

Preferably, the crystalline sodium atorvastatin has a purity of at least 95%, more 5 preferably at least 98%, further preferably at least 99%.

Preferably, the amorphous sodium atorvastatin has a purity of at least 90%, more preferably at least 93%, further preferably at least 96%, preferably still at least 98%.

Accordingly, the present invention describes a novel crystalline form of sodium atorvastatin, a novel amorphous form of sodium atorvastatin and processes for the preparation thereof.

It is anticipated that both the crystalline form of sodium atorvastatin and the 15 amorphous form of sodium atorvastatin disclosed herein will be useful in the treatment of a variety of diseases which are prevented, ameliorated or eliminated by the administration of a lipid regulating agent. Examples of such diseases include hyperlipemia, primary hyperlipemia, heterozygote familial hyperlipemia, renal hyperlipemia, mixed hyperlipemia, diabetes, atherosclerosis, hypertension, coronary 20 heart disease, cerebral apoplexy and ischemic cerebrovascular disease.

According to another aspect of the present invention, there is, therefore, provided a pharmaceutical composition comprising crystalline sodium atorvastatin or amorphous sodium atorvastatin as described herein.

According to a further aspect of the present invention, there is provided a composition for treating a disease which is prevented, ameliorated or eliminated by the administration of a lipid regulating agent, the composition comprising crystalline sodium atorvastatin or amorphous sodium atorvastatin as described herein.

Preferably, the disease is selected from hyperlipemia, primary hyperlipemia, heterozygote familial hyperlipemia, renal hyperlipemia, mixed hyperlipemia, diabetes, 566287 RECIEVED IPONZ 23 JULY 2010 atherosclerosis, hypertension, coronary heart disease, cerebral apoplexy and ischemic cerebrovascular disease.

Also provided by the present invention is a method of treating a disease which is 5 prevented, ameliorated or eliminated by the administration of a lipid regulating agent, the method comprising administering to a patient a therapeutically effective amount of crystalline sodium atorvastatin, amorphous sodium atorvastatin, or a pharmaceutical composition as described herein.

Preferably, the disease is selected from hyperlipemia, primary hyperlipemia, heterozygote familial hyperlipemia, renal hyperlipemia, mixed hyperlipemia, diabetes, atherosclerosis, hypertension, coronary heart disease, cerebral apoplexy and ischemic cerebrovascular disease.

By a therapeutically effective amount, it is meant an amount which is capable of preventing, ameliorating or eliminating the diseases mentioned herein.

The crystalline sodium atorvastatin or amorphous sodium atorvastatin can be mixed with a carrier, diluent or excipient therefor, all of which are well known in the art. For 20 example, suitable carriers may include pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatine capsules, suppositories, sterile injectable solutions and sterile packaged powders.

According to a further aspect of the present invention, there is provided a process for preparing the crystalline form of sodium atorvastatin with high purity, the method comprising the following steps: (a) preparation of amorphous sodium atorvastatin: starting with a sodium atorvastatin solution, adjust the pH to about 1-4 with acid solution, extract with 30 organic solvent, adjust the pH in the organic layer to about 9-10, and collect the precipitate by filtration. Obtain the amorphous sodium atorvastatin after drying under vacuum. 566287 RECIEVED IPONZ23 JULY 2010 (b) preparation of crystalline sodium atorvastatin: dissolve the obtained amorphous sodium atorvastatin in aqueous alcoholic solvent, add butanone, allow the sodium atorvastatin to crystallize out at low temperature. Collect the crystalline material by filtration and then dry under vacuum.

Preferably, the acid solution used is hydrochloric acid with a concentration ranging from about 15% to 30%. Preferably, the basic solution used is sodium hydroxide solution with a concentration ranging from about 20% to 50%. In preferred embodiments, the organic solvent used is dichloromethane, which is in a mass ratio of 10 about 10-20:1 against the amount of sodium atorvastatin in the solution. The aqueous alcoholic solvent used is preferably ethanol, the amount of ethanol used is preferably in a mass ratio of about 4-10:1 against the amount of sodium atorvastatin in solution, The ketone solvent used is preferably butanone, the amount of butanone used is preferably in a mass ratio of about 5-10:1 against the amount of sodium atorvastatin in 15 solution.

The present invention thus provides a crystalline form of sodium atorvastatin with a high purity. The common practice to prepare calcium atorvastatin usually involves the replacement of sodium with calcium in solution in which the sodium atorvastatin 20 serves only as intermediate without isolation. Therefore, the quality of the isolated calcium salt is not satisfactory in terms of purity. The present invention provides a crystallization process for preparing crystalline sodium atorvastatin with high purity, which can be either used as a pharmaceutical ingredient or converted to calcium atorvastatin with high purity.

An example of the present invention will now be described with reference to the accompanying figures in which:- Figure 1 is the powder X-ray diffraction pattern for amorphous sodium 30 atorvastatin; and Figure 2 is the powder X-ray diffraction pattern for the crystalline sodium atorvastatin of the present invention. 566287 RECIEVED IPONZ23 JULY 2010 Crvstallisation Example 1 A solution (200g) containing lOg of sodium atorvastatin was added to a 500ml 3-neck flask. The pH was adjusted to 4, dichloromethane (200g) was added, and then the pH of the organic layer was adjusted to 10 with a 50% sodium hydroxide solution. The precipitate was collected by filtration and then dried under vacuum. Amorphous sodium atorvastatin, designated as Form I, (8.2g) was thus obtained having an X-ray 10 powder diffraction pattern was shown in Figure 1.

The amorphous sodium atorvastatin (8.2g) was dissolved in an 88% ethanol solution (50g). Butanone (60g) was then added. The sodium atorvastatin crystallized out on cooling. The crystalline sodium atorvastatin was collected by filtration and dried 15 under vacuum (7.5g). Highly pure crystalline sodium atorvastatin, designated as Form II, was obtained with an assay purity of 99.4% and a crystal form having an XRD spectrum shown in Figure 2.

Example 2 A solution (200g) containing lOg of sodium atorvastatin was added to a 500ml 3-neck flask. The pH was adjusted to 4, dichloromethane (200g) was added, and then the pH of the organic layer was adjusted to 10 with a 50% sodium hydroxide solution. The precipitate was collected by filtration and then dried under vacuum. Amorphous 25 sodium atorvastatin, designated as Form I, (8.2g) was thus obtained having an X-ray powder diffraction pattern was shown in Figure 1.

The amorphous sodium atorvastatin (8.2g) was dissolved in a 90% ethanol solution (70g). Butanone (80g) was then added. The sodium atorvastatin crystallized out on 30 cooling. The crystalline sodium atorvastatin was collected by filtration and dried under vacuum (7.5g). Highly pure crystalline sodium atorvastatin, designated as Form II, was obtained with an assay purity of 99.5% and a crystal form having an XRD spectrum shown in Figure 2. 566287 RECIEVED IPONZ23 JULY 2010 Example 3 Hydrochloric acid having a concentration of 15-20% was added to a solution containing sodium atorvastatin and the pH was adjusted to 1-4. Dichloromethane was 5 added to the solution and the organic layer was mixed with 20-50% sodium hydroxide solution until the pH was at 9-10. Generally, the amount of sodium hydroxide used was at a ratio of 10-20 times the amount of sodium atorvastatin used. The precipitate was then collected by filtration and dried under vacuum. Amorphous sodium atorvastatin, designated as Form I, was thus obtained having an XRD spectrum as 10 shown in Figure 1.

The amorphous sodium atorvastatin was dissolved in an ethanol solution at a ratio of about 4-10 times the amount of sodium atorvastatin used. Butanone was added to the solution at a ration of about 5-10 times the amount of sodium atorvastatin used. 15 Sodium atorvastatin was allowed to crystallize out at a lower temperature, collected by filtration and then dried under vacuum. Highly pure crystalline sodium atorvastatin, designated as Form II, was obtained having an XRD spectrum shown in Figure 2.

Example 4 A solution (200g) containing lOg of sodium atorvastatin was added to a 500ml 3-neck flask. The pH was adjusted to 4, dichloromethane (200g) was added, and then the pH of the organic layer was adjusted to 10 with a 50% sodium hydroxide solution. The 25 precipitate was collected by filtration and then dried under vacuum. Amorphous sodium atorvastatin, designated as Form I, (8.2g) was thus obtained having an X-ray powder diffraction pattern was shown in Figure 1.

The amorphous sodium atorvastatin (8.2g) was dissolved in a 85% ethanol solution 30 (50g). Butanone (60g) was then added. The sodium atorvastatin crystallized out on cooling. The crystalline sodium atorvastatin was collected by filtration and dried under vacuum (7.5g). Highly pure crystalline sodium atorvastatin, designated as RECIEVED IPONZ23 JULY 2010 566287 Form II, was obtained with an assay purity of 99.4% and a crystal form having an XRD spectrum shown in Figure 2.

A solution (200g) containing lOg of sodium atorvastatin was added to a 500ml 3-neck flask. The pH was adjusted to 4, dichloromethane (200g) was added, and then the pH of the organic layer was adjusted to 10 with a 50% sodium hydroxide solution. The precipitate was collected by filtration and then dried under vacuum. Amorphous sodium atorvastatin, designated as Form I, (8.2g) was thus obtained having an X-ray powder diffraction pattern was shown in Figure 1.

The amorphous sodium atorvastatin (8.2g) was dissolved in a 90% ethanol solution (70g). Butanone (60g) was then added. The sodium atorvastatin crystallized out on cooling. The crystalline sodium atorvastatin was collected by filtration and dried under vacuum (7.3g). Highly pure crystalline sodium atorvastatin, designated as Form II, was obtained with an assay purity of 99.5% and a crystal form having an XRD spectrum shown in Figure 2.

The sodium atorvastatin salt produced by the above methods had the following structure:- Example 5 F atorvastatin sodium salt I RECIEVED IPONZ 23 JULY 2010 566287 WO 2007/020421 PCT/GB2006/003035 Table 1: The XRD spectrum for the amorphous form obtained according to the examples above. 2theta (degree) d (A) I/Io I.cps FWHM .451 16.1985 .3 291 7.865 11.2313 74.7 2107 9.516 9.2868 .1 145 11.018 8,0237 9.5 269 14.201 6.2317 14.6 413 16.399 .4009 29.4 829 0.20 18.179 4.8758 100 2820 18.873 4.6982 67.2 1894 19.761 4.4890 29.1 821 22.875 3.8844 87.5 2468 0.36 32.271 2.7717 12.9 363 33.354 2.6842 7.0 197 37.860 2.3744 16.4 462 39.994 2.2525 6.2 176 41.129 2.1929 .0 140 44.947 2.0151 6.3 179 Peak Number: 16 Highest Peak: 2820 Total Diffraction Intensity: 3453641 Total Purity Intensity: 798951 Total Purity Intensity/Total Diffraction Intensity: 0.231 RECIEVED IPONZ 23 JULY 2010 566287 WO 2007/020421 PCT/GB2006/003035 Table 2: The XRD spectrum for the crystalline form obtained according to the examples above. 2theta (degree) d (A) I/Io I.cps FWHM 3.667 24.0769 57.2 1349 0.36 .045 17.5033 26.2 617 0.31 6.850 12.8933 70.2 1656 0.34 7.180 12.3016 76.5 1804 0.53 8.331 .6046 93.8 2213 0.31 8.615 .2556 52.4 1237 0.20 9.375 9.4252 29.2 688 0.31 .022 8.8190 32.7 772 0.22 .347 8.5426 36.9 871 0.25 .712 8.2518 .5 365 0.22 11.760 \ 7.5189 i 17.8 420 0.34 12.658 6.9874 11.1 261 0.22 13.872 6.3784 11.4 269 0.22 16.006 .5325 36.5 860 0.34 16.376 .4086 47.2 1113 0.42 17.104 .1799 50.3 1186 0.56 19.100 4.6428 100 2359 0.50 19.423 4.5663 78.5 '1853 0.48 .879 4.2511 21.1 497 0.22 21.155 4.1963 .5 484 0.20 22.901 3.8801 23.4 551 0.25 23.602 3.7664 27.4 647 0.22 .121 2.9645 .2 240 0.20 33.120 2.7025 8.5 200 0.20 37.923 2.3706 .1 356 41.471 2.1756 7.7 182 566287 RECIEVED IPONZ23 JULY 2010 Peak Number: 26 Highest Peak: 2359 Total Diffraction Intensity: 3380617 Total Purity Intensity: 711366 5 Total Purity Intensity/Total Diffraction Intensity: 0.21

Claims (39)

566287 RECIEVED IPONZ 23 JULY 2010 - 16- What we claim is:

1. Crystalline sodium atorvastatin which exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 6.85 ± 0.2, 7.18 ± 0.2, 8.33 ± 0.2, 19.1 ± 0.2 and 19.42 ±0.2. 5

2. Crystalline sodium atorvastatin which exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 3.67 ± 0.2, 5.05 ± 0.2, 6.85 ± 0.2, 7.18 ± 0.2, 8.33 ± 0.2, 8.62 ± 0.2, 9.38 ± 0.2, 10.02 ± 0.2, 10.35 ± 0.2, 10.71 ± 0.2, 11.76 ± 0.2, 12.66 ± 0.2, 13.87 ± 0.2, 16.01 ± 0.2, 16.38 ± 0.2, 17.1 ± 0.2, 19.1 ± 0.2, 19.42 ± 0.2, 20.88 ± 0.2, 21.16 ± 0.2, 22.9 ± 0.2, 23.6 ± 0.2, 30.12 ± 0.2, 33.12 ± 0.2, 37.92 ± 0.2 and 41.47 ± 0.2. 10

3. Crystalline sodium atorvastatin which exhibits an X-ray diffraction pattern substantially the same as shown in figure 2.

4. Crystalline sodium atorvastatin according to any preceding claim, which has a purity of at least 95%.

5. Crystalline sodium atorvastatin according to claim 4, which has a purity of at least 98%. 15

6. Crystalline sodium atorvastatin according to claim 5, which has a purity of at least 99%.

7. A method for the preparation of crystalline sodium atorvastatin, the method comprising (a) adding amorphous sodium atorvastatin to a first organic solvent to form a first solution; 20 (b) adding a second organic solvent to the first solution to form a second solution; (c) allowing sodium atorvastatin to crystallize out from the solution; and (d) collecting the crystallized sodium atorvastatin, wherein the first organic solvent is ethanol and the second organic solvent is butanone.

8. A method according to claim 7, wherein the amorphous sodium atorvastatin is added to 25 the first organic solvent at a ratio of about 8 to lOg amorphous atorvastatin for about every 40g to lOOg first organic solvent. 566287 RECIEVED IPON2 23 JULY 2010 - 17-

9. A method according to claim 7 or 8, wherein the second organic solvent is added to the first solution at a ratio of about 50 to lOOg second organic solvent for about every 8 to lOg amorphous atorvastatin used in step (a).

10. A method according to any one of claims 7 to 9, wherein the first organic solvent 5 comprises at least about 75% organic solvent in solution.

11. A method according to any one of claims 7 to 10, wherein the crystallized sodium atorvastatin is collected by filtration.

12. A method according to any one of claims 7 to 11, wherein the collected crystallized sodium atorvastatin is dried. 10

13. A method according to claim 12, wherein the collected crystallized sodium atorvastatin is dried under vacuum.

14. A method according to any one of claims 7 to 13, comprising the following additional steps for the preparation of amorphous sodium atorvastatin for use in step (a):-(i) preparing a third solution comprising sodium atorvastatin;

15 (ii) adjusting the pH of the third solution to an acid pH; (iii) adding a third organic solvent to form a fourth solution; (iv) isolating an organic layer; (v) adjusting the pH of the organic layer to an alkali pH; (vi) collecting precipitated amorphous sodium atorvastatin. 20 15. A method according to claim 14, wherein the third solution comprises about 5% sodium atorvastatin.

16. A method according to claim 14 or 15, wherein the pH of the third solution is adjusted by the addition of hydrochloric acid.

17. A method according to claim 16, wherein the hydrochloric acid has a concentration of 25 about 15 to 20%.

18. A method according to any one of claims 14 to 17, wherein the pH of the third solution is adjusted to between about 1 and 4. RECIEVED IPONZ 23 JULY 2010 566287 - 18-

19. A method according to any one of claims 14 to 18, wherein the third organic solvent is a halogen substituted Ci to C6 hydrocarbon.

20. A method according to claim 19, wherein the third organic solvent is dichloromethane.

21. A method according to any one of claims 14 to 20, wherein the third organic solvent is 5 added to the third solution at a ratio of about 100 to 200g third organic solvent for about every 1 Og sodium atorvastatin in the third solution.

22. A method according to any one of claims 14 to 21, wherein the pH of the organic layer is adjusted by the addition of sodium hydroxide solution.

23. A method according to claim 22, wherein the sodium hydroxide solution has a 10 concentration of about 20 to 50%.

24. A method according to any one of claims 14 to 23, wherein the pH of the organic layer is adjusted to between about 9 and 10.

25. A method according to any one of claims 14 to 24 wherein the precipitated amorphous sodium atorvastatin is collected by filtration. 15

26. A method according to any one of claims 14 to 25, wherein the precipitated amorphous sodium atorvastatin is dried.

27. A method according to claim 26, wherein the precipitated amorphous sodium atorvastatin is dried under vacuum.

28. A method according to any one of claims 14 to 27, wherein the precipitated amorphous 20 sodium atorvastatin exhibits an X-ray diffraction pattern substantially the same as shown in figure 1.

29. A method according to any one of claims 14 to 27, wherein the precipitated amorphous sodium atorvastatin exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 7.87 ± 0.2, 18.18 ± 0.2, 18.87 ± 0.2 and 22.88 ± 0.2. 25 30. A method according to any one of claims 14 to 27, wherein the precipitated amorphous sodium atorvastatin exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 5.45 ± 0.2, 7.87 ± 0.2, 9.52 ± 0.2, 11.02 ± 0.2, 14.2 ± 0.2, 16.4 ± 566287

RECIEVED IPONZ 23 JULY 2010 - 19- 0.2, 18.18 ± 0.2, 18.87 ± 0.2, 19.76 ± 0.2, 22.88 ± 0.2, 32.27 ± 0.2, 33.35 ± 0.2, 37.86 ± 0.2, 39.99 ± 0.2, 41.13 ± 0.2 and 44.95 ± 0.2.

31. Crystalline sodium atorvastatin produced by a method according to any one of claims 7 to 30. 5

32. A pharmaceutical composition comprising crystalline sodium atorvastatin according to any one of claims 1 to 6 and 31.

33. A composition for treating a disease which is prevented, ameliorated or eliminated by the administration of a lipid regulating agent, the composition comprising crystalline sodium atorvastatin according to any one of claims 1 to 6 and 31. 10

34. A composition according to claim 33, wherein the disease is selected from hyperlipemia, primary hyperlipemia, heterozygote familial hyperlipemia, renal hyperlipemia, mixed hyperlipemia, diabetes, atherosclerosis, hypertension, coronary heart disease, cerebral apoplexy and ischemic cerebrovascular disease.

35. Use of therapeutically effective amount of crystalline sodium atorvastatin according to 15 any one of claims 1 to 6 and 31 or a pharmaceutical composition according to claim 32 in the manufacture of a medicament for treating a disease which is prevented, ameliorated or eliminated by the administration of a lipid regulating agent.

36. A use according to claim 35, wherein the disease is selected from hyperlipemia, primary hyperlipemia, heterozygote familial hyperlipemia, renal hyperlipemia, mixed hyperlipemia, 20 diabetes, atherosclerosis, hypertension, coronary heart disease, cerebral apoplexy and ischemic cerebrovascular disease.

37. Crystalline sodium atorvastatin according to any one of claims 1 to 6 or 31, defined as Form II.

38. Crystalline sodium atorvastatin substantially as herein described with reference to figure 25 2.

39. A method for the preparation of crystalline sodium atorvastatin substantially as hereinbefore described. 566287 RECIEVED IPONZ 23 JULY 2010 -20- Arrow International Limited Zhejiang Neo-Dankong Pharmaceutical Co. Ltd. By the patent attorneys for the applicants CULLENS