Patent Application
20060205805
The present invention is directed to crystalline forms of Atorvastatin calcium, processes for their preparation and pharmaceutical compositions comprising these crystalline forms.
The present invention relates to crystalline forms of Atorvastatin calcium. Atorvastatin calcium is known by the chemical name, [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). Atorvastatin has the following formula:
Atorvastatin calcium is an orally-active hypocholesterolaernic, a her-selective HMG-CoA reductase inhibitor. Processes for the preparation of Atorvastatin calcium are described in U.S. Pat. No. 5,298,627, U.S. Pat. No. 5,273,995 and WO-A-97/03960, and publications by P. L. Brower et al. in Tetrahedron Letters (1992), vol. 33, pages 2279-2282, K. L. Baumann et al. in Tetrahedron Letters (1992), vol. 33, pages 2283-2284 and A. Graul et al. in Drugs Future (1997), vol. 22, pages 956-968.
This calcium salt (2:1) is desirable since it enables Atorvastatin calcium to be conveniently formulated. The processes in the above mentioned patents and publications result in the preparation of amorphous Atorvastatin calcium.
The preparations of Atorvastatin calcium (2:1) described in WO-A-97/03958 and WO-A-97103959 result in the isolation of crystalline Atorvastatin calcium with the polymorphic forms III, and I, II, and IV, respectively. However, there is still a need to produce Atorvastatin calcium in a reproducible, pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications. Furthermore, it is economically desirable that the product is stable for extended periods of time without the need for specialized Storage conditions.
Surprisingly, there have now been found several novel crystalline forms of Atorvastatin calcium salt (2:1), herein designated as Form X, Form A, Form B1, Form B2, Form C, Form D and Form E. The novel forms of the present invention have a good thermal stability and/or good solubility characteristics.
Like any synthetic compound, Atorvastatin hemi-calcium salts can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in atorvastatin hemi-calcium salts or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
It is known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage. A particular degradation product of atorvastatin hemi-calcium is atorvastatin calcium epoxy dihydroxy (AED), having the formula:
AED may be characterized by data selected from: 1H NMR spectrum having hydrogen chemical shifts at about 1.20, 1.21, 2.37, 4.310, 6.032, 7.00, 7.06-7.29, 7.30, 7.39, 7.41, 7.56 ppm; a 13C NMR spectrum having carbon chemical shifts at about 16.97, 34.66, 103.49, 106.66, 114.72, 120.59, 125.79, 128.21, 128.55, 128.74, 129.06, 129.57, 132.38, 132.51, 135.15, 161.61, 163.23 ppm ; an MS (ESI+) spectrum having peaks at about having: m/z═472(MNa)+, 454 (MNa-H2O)+, 432(MH-H2O)+; 344 (FPhCOC(Ph)═C-CONHPh)+ by retention time of about 32 min and by a relative retention time of about 1.88, in HPLC analysis such as described in U.S. patent application Ser. No. 11/236,647 and International Patent Application PCT/US05/35159.
Accordingly, the present invention is directed to the following polymorphic Forms X, A, B1, B2, C, D and E of Atorvastatin calcium salt (2: 1).
A crystalline polymorph of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9 (s), 20.9 (w), 18.9 (w), 16.1 (w), 11.1 (m), 10.5 (m), 9.1 (m), 5.53 (m), 5.07 (w), 4.77 (vw), 4.55 (m), 4.13 (w), 3.69 (w); herein designated as Form X. Here and in the following the abbreviations in brackets mean: (vs)=very strong intensity; (s)=strong intensity; (m)=medium intensity; (w)=weak intensity; (W)=very weak intensity.
A crystalline polymorph of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 31.0 (w), 18.6 (m), 17.0 (w), 15.3(vw), 12.8(w), 11.2(m), 9.6 (s), 9.3 (w), 8.6 (w), 7.4(m), 6.5 (vw), 6.2 (w), 5.47 (w), 5.21 (m), 4.64 (vs), 4.46 (s), 4.14 (m), 3.97 (m), 3.74 (m), 3.62 (vw), 3.38 (w), 3.10 (m), herein designated as Form A.
Furthermore, the present invention is directed to atorvastatin hemi-calcium crystalline Form A, that is stable against the formation of the impurity AED.
As used herein, the term “stable” in reference to Atorvastatin hemi-calcium Form A relates to the formation of at least about 0.01% (w/w) of the impurity AED. The stability of Form A is measured by maintaining Form A at a temperature of about 40° C. at a relative humidity of about 75% for at least about 1 month, or at a temperature of about 25° C. at a relative humidity of about 60% for at least about 6 months. Stable Atorvastatin hemi-calcium Form A is a Form A in which no more than about 0.01% (w/w) of the AED impurity is formed when maintained under the conditions specified above.
A crystalline polymorph of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 27.9 (m), 17.0 (m), 14.2 (w), 12.1 (vs), 10.1 (s), 8.6 (m), 7.1 (m), 6.1 (w), 5.27 (m). 4.89 (rn), 4.68 (m), 4.46 (m), 4.22 (m), 3.90 (w), 3.70 (w), 2.36 (vw), herein designated as Form B1.
A crystalline polymorph of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 28.1 (m), 17.2 (m), 14.0 (w), 12.3 (s), 10.4 (s), 8.6 (m), 7.5 (w), 7.0 (m), 5.28 (m), 4.88 (m), 4.55 (m), 4.27 (m), 3.88 (w), 3.73 (m), herein designated as Form B2.
A crystalline polymorph of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 28.8 (m), 24.0 (m), 17.1 (m), 11.3 (s), 9.8 (w). 8.3 (w), 7.7 (w), 6.9 (vw), 5.64 (w), 5.21 (w), 4.59 (m), 4.39 (w), 4.16 (w), 3.70 (w), herein designated as Form C.
A crystalline polymorph of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (A) at 33.7 (w), 31.0 (m), 16.9 (m), 10.3 (s), 7.7 (w), 6.4 (w), 4.84 (s), herein designated as Form D.
A crystalline polymorph of [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (Å) at 26.8 (s), 9.4 (w), 4.6 (m) herein designated as Form E.
A discussion of the theory of X-ray powder diffraction patterns can be found in “X-ray diffraction procedures” by H. P. Klug and L. E. Alexander, J. Wiley, New York (1974).
Furthermore, the present invention is directed to processes for the preparation of Form X, Form A Form B 1, Form B2, Form C, Form D and Form E.
Form X can generally be prepared by drying of a solution of Atorvastatin calcium in an organic solvent. Examples of such organic solvents are alcohols, like methanol. Preferably, the solution in addition contains an organic non-solvent, like ethers, for example methyl tert-butyl ether. Drying can be carried out at elevated temperature, or, preferably, at ambient temperature. If desired, during the preparation process seeding with Form X can be carried out.
Form A can generally be prepared by suspending Form X or the amorphous form in an organic solvent, like an alcohol, especially isopropanol. It is preferred that the organic solvent contains as a further solvent some water. The amount of water is preferably about 0.1 to 5%, preferably about 0.5 to 2%, especially about I % by volume of the suspension. It is preferred that the suspension is treated at temperatures between 10 and 60° C. (preferably 30 to 50° C.), especially for a longer period of time, like 10 to 40 hours. If desired, during the preparation process seeding with Form A can be carried out.
Form A can also be prepared from Atorvastatin lactone upon subsequent reaction with NaOH to form Atorvastatin sodium followed by reaction with CaCl2 in an organic solvent, like an alcohol, especially isopropanol. It is preferred that the organic solvent contains as a further solvent some water. The amount of water is preferably 0.1 to 10%. If desired, during the preparation process seeding with Form A can be carried out.
Form A can also be prepared directly from Atorvastatin lactone upon reaction with Ca(OH)2 in an organic solvent, like an alcohol, especially isopropanol. It is preferred that the organic solvent contains as a further solvent some water. The amount of water is preferably 0.1 to 10%. If desired, during the preparation process seeding with Form A can be carried out.
Form A can also be prepared by the reaction of Atorvastatin ammonium salt with Ca(II)-acetate in an organic solvent or a mixture of organic solvents, preferably a mixture of tert-butyl methyl ether (TBME) and isopropanol. The solid formed in this reaction is isolated by filtration and than stirred as a suspension in an organic solvent, like an alcohol, especially isopropanol. It is preferred that the organic solvent contains as a further solvent some water.
The amount of water is preferably 0.1 to 10%. It is preferred that the suspension is treated at temperatures between 10 and 60° C., especially for a longer period of time, like 10 to 60 hours. If desired, during the preparation process seeding with Form A can be carried out.
Form B 1 can generally be prepared by suspending Form X or the amorphous form in acetonitrile containing a further organic solvent, like tetrahydrofuran. It is preferred that the suspension is treated at temperatures between 10 and 50° C. (preferably ambient temperature), especially for a longer period of time, like 10 to 40 hours. If desired, during the preparation process seeding with Form B 1 can be carried out.
Form B2 can generally be prepared by suspending Form X or the amorphous form in acetonitrile, preferably pure acetonitrile. It is preferred that the suspension is treated at temperatures between 10 and 50° C. (preferably 30 to 50° C.), especially for a longer period of time, like 10 to 40 hours. If desired, during the preparation process seeding with Form B2 can be carried out.
Form C can generally be prepared by suspending Form X or the amorphous form in a mixture of isopropanol and water, and treating the suspension at ambient temperature for a longer period of time, like 10 to 40 hours. If desired, during the preparation process seeding with Form C can be carried out.
Form D can generally be prepared by suspending Form X or the amorphous form in a mixture of ethanol and water at temperatures between about 20 to 60° C. for a longer period of time, like 10 to 40 hours. If desired, during the preparation process seeding with Form D can be carried out.
Form E can generally be prepared by evaporation of a solution of any form of Atorvastatin, preferably Form X, in 2-butanone or from solvent mixtures of 2-butanone with heptane or ethylacetate or ternary mixtures of 2-butanone, heptane and ethylacetate. Evaporation is preferably carried out slowly, for example within 10 to 40 hours.
Another object of the present invention are pharmaceutical compositions comprising an effective amount of crystalline polymorphic Form X, Form A, Form B1, Form B2, Form C, Form D or Form E, and a pharmaceutically acceptable carrier.
The polymorphic forms may be used as single components or mixtures.
As to the novel polymorphic forms of Atorvastatin calcium it is preferred that these contain 25-100% by weight, especially 50-100°/0 by weight, of at least one of the novel forms, based on the total amount of Atorvastatin calcium. Preferably, such an amount of the novel polymorphic forms of Atorvastatin calcium is 75-100% by weight, especially 90-100% by weight. Highly preferred is an amount of 95-100% by weight.
The following Examples illustrate the invention in more detail. Temperatures are given in degrees Celsius.
Atorvastatin calcium Form X is prepared by dissolving 127 mg Atorvastatin calcium in a mixture of 2.0 ml methanol and 6.0 ml methyl tert.-butyl ether and drying of the solution at ambient temperature. Form X is characterized by a x-ray powder diffraction pattern as shown in
Form A is prepared by suspending 100 mg of Form X in 3.0 ml isopropanol together with 50 μl H2O and stirring of this suspension at 40° C. After 9 hours an additional amount of 50 μl of water is added to the suspension and stirring is continued at 40° C. for another 20 hours. The suspension is filtrated and crystalline Form A is obtained. Form A is characterized by a x-ray powder diffraction pattern as shown in
Atorvastatin calcium crystal Form BI is prepared by suspending 145 mg of Atorvastatin calcium Form X in a mixture of 1.0 ml acetonitrile and 1.0 ml of tetrahydrofuran at ambient temperature. While the cap of the reaction vial is left open some of the tetrahydrofuran evaporates which leads to a slow reduction of the solubility of Atorvastatin calcium in the system. After 3.5 hours an additional amount of 1.0 ml of acetonitrile is added to the reaction container and stirring is continued for about 15 hours at ambient temperature. After filtration of the suspension crystal form B1 is obtained. Form B1 is characterized by a x-ray powder diffraction pattern as shown in
Form B2 is prepared by suspending 117 mg of Atorvastatin calcium Form X in 2.0 ml of acetonitrile and stirring this suspension at 40° C. for about 18 hours. In order to reduce the viscosity of the suspension 1.0 ml of acetonitrile is added at ambient temperature to this suspension after the end of the crystallization process. The obtained product is crystal Form B2 which is characterized by an x-ray powder diffraction pattern as shown in
Form C is prepared by suspending 120 mg of Atorvastatin calcium Form X in a mixture of 3.0 ml isopropanol and 1.0 ml water. After one hour of stirring at ambient temperature 2.0 ml water are added and stirring is continued for 15 hours at the same temperature. After filtration of the suspension crystal Form C is obtained which is characterized by the x-ray diffraction pattern as shown in
Form D is prepared by suspending 124 mg of Form X in 3.0 ml of ethanol and by stirring this suspension at ambient temperature. After about 2 hours a suspension of high viscosity is obtained and 1.0 ml of water are added b the suspension, which reduces the viscosity substantially. After addition of water, the temperature is slowly raised to 40° C. and stirring is continued at 40° C. for about 16 hours. After filtration of the suspension crystal Form D is obtained which is characterized by the x-ray diffraction pattern as shown in
60 mg of Atorvastatin Form X are dissolved in 2.0 ml 2-butanone (e.g. Fluka No. 04380) and then 2.0 ml of heptane (e.g. Fluka No. 51745) are added at ambient temperature. This mixture is heated to 50° C. for a few minutes until all solid residues are dissolved. The mixture is then slowly cooled to 5° C. and later equilibrated at ambient temperature. At ambient temperature the solvent is slowly evaporated within about 10 to 20 hours. After complete evaporation of the solvent Atorvastatin Form E is obtained as a solid residue. The x-ray diffraction pattern of Form E is shown in
a) Preparation of Atorvastatin lactone III:
Diol acid 1 (5 g, 8.9 mmol) is dissolved in 10.7 ml ethanol and 5.6 ml 1.6 M NH3 in ethanol is added at room temperature. The solution is being stirred over 15 to 30 minutes and the solvent is subsequently removed under reduced pressure to give a colorless or slightly beige foam (5.15 g, approximately 100% yield).
Ammonium salt II (23.91 g, 41.7 mmol) is dissolved in 115 ml acetic acid. The yellow solution is being stirred at 35° C. for approximately 16 h. 200 ml dioxane are added twice and the mixture is being concentrated at 40° C. and 35 mbar pressure, respectively. The residue is dissolved in 200 ml TBME and being washing with water and brine and dried over magnesium sulfate. Removal of the solvent affords 21.4 g (approx. 95 % yield) Atorvastatin lacton III.
b) Preparation of Atorvastatin calcium Form A starting from Atorvastatin lactone III:
Lacton III (20.6 g, 38.2 mmol) is dissolved in 757 ml 2-propanol/water (19:1) and 1.41 g (0.5 eq) calcium hydroxide is added. The turbid solution is stirred at 40° C. for 3 d whereupon the solution turns into a thick suspension. White crystals of form A are collected by filtration and being dried at 70° C. and 20 mbar pressure overnight. Yield: 19.0 g, 86 %. The obtained crystalline Form A is stable against the formation of the impurity AED.
Ammonium salt II (2 g, 3.5 mmol) is dissolved in 20 ml TBME/isopropanol (1:2) and a solution of calciumacetat hydrate (0.5 eq) is added dropwise at room temperature. The precipitated calcium salt is collected by filtration and dried at 70° C. and 20 mbar. (Yield 1.6 g; approx. 80 %.) The obtained powder is subsequently being stirred in 58 ml 2-propanol/water (19:1) at 40° C. and seeded with 5 % crystals of form A. After 4 d Atorvastatin Calcium form A can be collected by filtration (yield 1.5 g, 91 %). The obtained crystalline Form A is stable against the formation of the impurity AED.
| Number | Date | Country | Kind |
|---|---|---|---|
| 00811249.2 | Dec 2000 | EP | regional |
This application is a continuation of U.S. patent application Ser. No. 10/130,197, which in turn is the U.S. national Stage application under 35 U.S.C.§371 of International Patent Application No.PCT/EP01/15012, having an international filing date of Dec. 19, 2001, and claims priority under 35 U.S.C. § 119 from European Patent Application No. 00811249.2, filed Dec. 27, 2000; the disclosures of the above being incorporated by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10130197 | Oct 2002 | US |
| Child | 11431184 | May 2006 | US |
