KR100724515B1 - Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing atorvastatin hemi-calcium forms i, viii and ix - Google Patents

Abstract

The present invention provides a novel form of atorvastatin, designated IXa, XIV, XVI and XVII, and a novel method for preparing the same, and a method for preparing atorvastatin hemicalcium Forms I, XIII and IX.

Description

Novel crystalline form of atorvastatin hemicalcium, a method for preparing the same, and a novel method for preparing atorvastatin hemicalcium forms I, VIII, and IX ATORVASTATIN HEMI-CALCIUM FORMS I, VIII AND IX}

Cross-References to Related Applications

This application is directed to U.S. Provisional Application Nos. 60 / 357,181, filed February 15, 2002, and 60 / 425,325, filed November 12, 2002, both of which are incorporated herein by reference. Claim the benefit of priority.

FIELD OF THE INVENTION

The present invention relates to a novel method for preparing polymorphic crystalline forms of atorvastatin hemicalcium and crystalline forms of atorvastatin hemicalcium.

Atorvastatin, represented by the formula (I) in lactone form, ([R- (R *, R *)]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl)- 3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid) and its calcium salt represented by the formula (II) are well known in the art, in particular US Pat. No. 4,681,893, 5,273,995 and co-pending US Ser. No. 60 / 166,153, filed Nov. 17, 2000, all of which are incorporated herein by reference.

Methods for preparing atorvastatin and hemicalcium salts thereof are described in US Patent Application Publication No. 2002/0099224; US Patent No. 5,273,995; 5,298,627; 5,298,627; US 5,003,080; 5,097,045; 5,097,045; 5,124,482; 5,124,482; 5,149,837; 5,149,837; 5,216,174; 5,216,174; 5,245,047; 5,280,126; 5,280,126; Baumann, K.L. Et al., Tet. Lett. 1992, 33, 2283-2284, which are hereby incorporated by reference in their entirety, and in particular, teach how to prepare atorvastatin and atorvastatin hemicalcium. .

Atorvastatin is a member of the group of drugs called statins. Statin drugs are currently the most therapeutically effective drugs useful for lowering the concentration of low density lipoprotein (LDL) particles in the bloodstream of patients at risk of developing cardiovascular disease. High levels of LDL in the bloodstream form coronary lesions that interfere with blood flow and can destroy blood clots and promote their formation. See Goodman and Gilman, The Pharmacological Basis of Therapeutics 879 (9th edition, 1996). Reducing plasma LDL levels has been shown to reduce the risk of pathogenesis in patients with cardiovascular disease and in patients without cardiovascular disease but with hypercholesterolemia. See Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.

 The mechanism of action of statin drugs has been elucidated in some detail. The drug inhibits the synthesis of cholesterol and other sterols by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase enzyme (“HMG-CoA reductase”) in the liver. HMG-CoA reductase promotes the conversion of HMG to mevalonate, which is a rate determining step for cholesterol biosynthesis, and blocking this step reduces intrahepatic cholesterol concentrations. Very low density lipoprotein (VLDL) is a biological vehicle that carries cholesterol and triglycerides from the liver to peripheral cells. VLDL catalyzes in peripheral cells that release fatty acids that can accumulate in adipocytes or be oxidized by muscle. VLDL is converted to medium density lipoprotein (IDL), which is either removed by the LDL receptor or converted to LDL. Reduced cholesterol production increases the number of LDL receptors, thus reducing the production of LDL particles by metabolism of IDL.

Atorvastatin hemicalcium salt trihydrate is marketed under the trade name LIPITOR by Warner-Lambert Co. Atorvastatin was first disclosed and known in US Pat. No. 4,681,893. Hemicalcium salts represented by formula (II) are described in US Pat. No. 5,273,995. Patent 5,273,995 teaches that the hemicalcium salt is obtained by crystallization from a brine solution resulting from the substitution of CaCl ₂ and sodium salt and is further purified by recrystallization from a 5: 3 mixture of ethyl acetate and hexane.

The present invention provides a novel crystalline form of atorvastatin hemicalcium in both solvated and hydrated states. The production (polymorphism) of different crystalline forms is a property of some molecules and molecular complexes. Single molecules such as atorvastatin of formula (I) or salt complexes of formula (II) can produce a variety of solids that possess distinct physical properties such as melting point, X-ray diffraction pattern, near infrared absorption fingerprint, and NMR spectrum. The difference in the physical properties of the polymorph is due to the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid. Thus, polymorphs are unique solids that share the same molecular formula, which is not yet clear whether the physical properties are advantageous and / or disadvantageous compared to other forms of the polymorph group. One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solutions, specifically their solubility in gastric juice of patients. For example, when absorption through the small intestine is slow, it is desirable that drugs that are unstable in the gastric or intestinal environment of the patient slowly dissolve and do not accumulate in harmful environments. On the other hand, when the efficacy of the drug correlates with the peak of the blood's concentration in the drug, shares properties with the statin drug, and the provided drug is rapidly absorbed by the GI system, the more rapidly dissolving form is slower in the same amount. It shows increased efficacy compared to the form in which it is dissolved.

Forms I, II, III, and IV of atorvastatin hemicalcium are tasks of US Pat. Nos. 5,959,156 and 6,121,461 assigned to Warner-Lambert, and crystalline atorvastatin hemicalcium Form V is a co-owned proprietary WO 01/36384. (PCT Application PCT / US00 / 31555). Patent No. 5,959,156 claims that atorvastatin hemi calcium type I has better filtration and drying characteristics than the amorphous form of known atorvastatin hemicalcium. According to the above patent 5,959,156, Form I powder X showing peaks at 9.150, 9.470, 10.266, 10.560, 11.853, 12.195, 17.075, 19.485, 21.626, 21.960, 22.748, 23.335, 23.734, 24.438, 28.915 and 29.234 ° 2θ It is characterized by a line diffraction pattern.

Co-owned co-pending application US Patent Application No. 2002/0115709 discloses atorvastatin hemicalcium VII form, a process for its preparation, and a pharmaceutical composition containing the same.

Co-owned co-pending application US 2002/0183378 discloses Type VI, VIII, IX, Type X, Type XI and Type XII atorvastatin hemicalcium, methods for their preparation and pharmaceutical compositions containing them. have.

According to the above-mentioned U.S. Patent Application 2002/0183378, the atorvastatin hemicalcium VIII forms 6.9, 9.3, 9.6, 16.3, 17.1, 19.2, 20.0, 21.6, 22.4, 23,9, when using conventional CuK _α radiation Form powder X-ray diffraction patterns exhibiting peaks at 24.7, 25.6, and 26.5 ± 0.2 ° 2θ. Additional peaks are 4.8, 5.2, 5.9, 7.0, 8.0, 9.3, 9.6, 10.4, 11.9, 16.3, 17.1 (wide), 17.9, 18.6, 19.2, 20.0, 20.8, 21.1, 21.6, 22.4, 22.8, 23.9, 24.7 , 25.6, 26.5, and 29.0 ± 0.2 ° 2θ.

Synchrotron X-ray powder diffraction analysis was performed on Form VIII to determine its crystal system and unit cell dimensions. Form VIII has a monoclinic unit cell with lattice dimensions a = 18.55-18.7 mm 3, b = 5.52-55.5 mm 3, c = 31.0-31.2 mm 3 and the β angle between the a and c axes is 97.5-99.9 ° It was understood that.

Atorvastatin hemicalcium Form VIII shows a magic angle spinning solid phase ¹³ C NMR spectrum of cross-polarization with resonance at the following chemical shift sites: 17.8, 20.0, 24.8, 25.2, 26.1, 40.3, 40.8, 41.5, 43.4, 44.1, 46.1, 70.8, 73.3, 114.1, 116.0, 119.5, 120.1, 121.8, 122.8, 126.6, 128.8, 129.2, 134.2, 135.1, 137.0, 138.3, 139.8, 159.8, 166.4, 178.8, 186.5 ppm . Form VIII is characterized by solid phase ¹³ C nuclear magnetic resonance values with chemical shifts between the lowest ppm and other resonance values: 2.2, 7.0, 7.4, 8.3, 22.5, 23.0, 23.7, 25.6, 26.3, 28.3, 53.0, 55.5, 96.3, 98.2, 101.7, 102.3, 104.0, 105.0, 108.8, 111.0, 111.4, 116.4, 117.3, 119.2, 120.5, 122.0, 142.0, 148.6, 161.0, and 168.7.

Atorvastatin hemicalcium Form VIII may be present as an ethanol solvate containing up to about 3 weight percent ethanol. Samples of atorvastatin hemicalcium Form VIII may also contain up to 7% water as determined by Karl-Fisher assay.

U.S. Patent Application 2002/0183378 teaches that atorvastatin hemicalcium VIII form can be obtained by slurrying atorvastatin hemicalcium in a mixture of ethanol and water at high temperature, preferably at about 78-80 ° C.

The application also provides Form VIII as a starting material by treating Form V with a mixture of EtOH: H ₂ O (preferably about a 5: 1 ratio) at high temperature, preferably 78-80 ° C. under reflux. I teach that I can. Particularly preferred EtOH: H ₂ O mixtures for this process contain about 4% by volume of water in ethanol. As heating, it was observed that atorvastatin Form V gradually dissolved and became cloudy regardless of whether seeding was performed at a time point of 78 to 80 ° C. At this point, the suspension is rapidly cooled to room temperature.

U.S. Patent Application 2002/0183378 also teaches that atorvastatin hemicalcium can be obtained by treatment in EtOH, preferably high purity EtOH, preferably EtOH at high temperatures. Under these conditions, atorvastatin dissolves and reprecipitates. MeOH can be added under reflux. The added MeOH can adversely affect the yield, but can increase the chemical purity of the product. The starting material for preparing Form VIII in this way may be a crystalline form of atorvastatin hemicalcium, preferably forms I and V and mixtures thereof or amorphous atorvastatin hemicalcium. The amount of EtOH or a mixture of EtOH and water is preferably about 10 to about 100 ml / g, more preferably about 20 to about 80 ml / g.

Form VIII may also be prepared by suspending atorvastatin hemicalcium in any 1-butanol / water and ethanol / water mixture for a time sufficient to convert atorvastatin hemicalcium to form VIII. The 1-butanol / water mixture should contain about 20% by volume of 1-butanol at high temperature, preferably at reflux.

U.S. Patent Application 2002/0183378 discloses that atorvastatin hemicalcium IX forms 4.7, 5.2, 5.7, 7.0, 7.9, 9.4, 10.2, 12.0, 17.0, 17.4, 18.2, 19.1, 19.9, using conventional CuK _α radiation. , Powder X-ray diffraction patterns showing peaks at 21.4, 22.5, 23.5, 24.8 (wide), 26.1, 28.7, 30.0 ± 0.2 ° 2θ. The crystal system and unit cell dimensions of Form IX are measured using Synchrotron X-ray powder diffraction analysis. Form IX has a monoclinic crystal lattice having lattice dimensions of a = 18.75 to 18.85 mm 3, b = 5.525 to 5.54 mm 3, c = 30.9 to 31.15 mm 3 and a β angle between the a and c axes from 96.5 to 97.5 °.

Atorvastatin hemicalcium Form IX shows a magic angle spinning solid phase ¹³ C NMR spectrum of orthogonal polarization with resonance at the following chemical shift sites: 18.0, 20.4, 24.9, 26.1, 40.4, 46.4, 71.0, 73.4, 114.3, 116.0, 119.5, 120.2, 121.7, 122.8, 126.7, 128.6, 129.4, 134.3, 135.1, 136.8, 138.3, 139.4, 159.9, 166.3, 178.4, 186.6 ppm. Form IX is characterized by solid phase ¹³ C nuclear magnetic resonance with chemical shifts between the lowest ppm and other resonances: 2.4, 6.9, 8.1, 22.4, 28.4, 53.0, 55.4, 96.3, 98.0 , 101.5, 102.2, 103.7, 104.8, 108.7, 110.6, 111.4, 116.3, 117.1, 118.8, 120.3, 121.4, 141.9, 148.3, 160.4, 168.6.

U.S. Patent Application 2002/0183378 discloses that Form IX can be prepared by slurrying atorvastatin hemicalcium in butanol and separating Form IX by, for example, filtration or decantation of butanol, preferably filtration. Is disclosed. The preferable temperature range for slurrying is 78 ° C to reflux temperature of the solvent. Recovering the atorvastatin hemicalcium salt from the slurry can be facilitated by adding antisolvent to the slurry prior to separating Form IX. Preferred antisolvents include isopropanol and n-hexane. The starting material for preparing Form IX by the present method may be crystalline or amorphous atorvastatin hemicalcium, preferably Forms I and V, and mixtures thereof.

U.S. Patent Application 2002/0183378 discloses ethanol, preferably high purity ethanol, for a time sufficient to convert Form VIII to Form IX at room temperature (which may be from several hours to 24 hours, typically about 16 hours). It is taught that type IX can be prepared by suspending type VIII. Form IX is then recovered from this suspension. Form IX can also be prepared by maintaining Form VIII in a humid atmosphere.

U.S. Patent Application 2002/0183378 also discloses atorvastatin hemicalcium Form V in a mixture of 1-butanol and ethanol or water for a time sufficient to convert Form V to Form IX at reflux temperature, thereby removing Form IX from this suspension. It is taught that form IX can also be produced by withdrawal. The mixture preferably contains about 50% by volume of each component.

Although Form I eliminated some of the defects of amorphous materials in terms of product ease of use, there remains a need to further improve these properties and to improve other properties such as flowability, vapor impermeability and solubility. In addition, the discovery of novel polymorphic crystalline forms of drugs extends the reservoir of substances so that formulation professionals can design pharmaceutical formulations of drugs with targeted release profiles or other desirable properties.

Summary of the Invention

The present invention provides novel solid crystalline forms of atorvastatin hemicalcium, solvates and hydrates thereof.

More specifically, the present invention provides a novel solid crystalline atorvastatin hemicalcium characterized by a powder X-ray diffraction pattern exhibiting peaks at 9.3 and 9.5 ± 0.2 ° 2θ when using conventional CuK _α radiation. In addition, small peaks are observed at 15.7, 20.5, 21.1, 22.8, 23.8, 24.0, 25.3, 26.4, 26.8, 27.2, 29.2, and 31.6 ± 2 ° 2θ.

In another aspect, the present invention is a novel solid crystalline atorvastatin hemicalcium characterized by powder X-ray diffraction patterns exhibiting peaks at 7.6, 9.8, 16.5, 29.4 ± 0.2 ° 2θ when using conventional CuK _α radiation. It provides a manufacturing method.

In another aspect, the invention provides a novel crystalline form of atorvastatin hemicalcium characterized by a powder X-ray diffraction pattern exhibiting peaks at 16.5, 21.9, 29.5 ± 0.2 ° 2θ when using conventional CuK _α radiation. It provides a manufacturing method.

In another aspect, the present invention features a novel powder X-ray diffraction pattern exhibiting peaks at 7.8, 9.5, 10.2, 18.2, 19.1, 25.3, 26.2, 30.1 ± 0.2 ° 2θ when using conventional CuK _α radiation. One atorvastatin hemicalcium crystalline form and a novel process for its preparation are provided.

In another aspect, the present invention provides a novel method of preparing atorvastatin hemicalcium Form VIII.

In another aspect, the present invention provides a novel method of preparing atorvastatin hemicalcium Form IX.

In another aspect, the present invention provides compositions and formulations comprising the novel solid crystalline atorvastatin hemicalcium and mixtures thereof and a pharmaceutically acceptable carrier, as well as methods of treating hyperlipidemia in a novel form.

Detailed Description of the Preferred Embodiments

Some crystalline forms of atorvastatin hemicalcium of the present invention exist in a solvated and hydrated state. Luggage was analyzed by Karl-Fisher and thermogravimetric analysis.

Powder X-ray diffraction ("PXRD") analysis using conventional CuK _α radiation was performed by methods known in the art using SCINTAG powder X-ray diffraction model X'TRA equipped with a solid phase detector. Copper radiation (λ = 1.5418 Hz) was used. Measurement range: 2-40 ° 2θ. Samples were loaded using a round standard aluminum sample receiver with a round zero background correction plate at the bottom. The powdered samples were ground lightly and pressed into a glass plate to fill the round cavity of the sample receiver.

As mentioned above, co-owned co-pending US Patent Application Publication No. 2002/0183378 teaches that atorvastatin hemicalcium Form IX can be prepared using a mixture of 1-butanol and ethanol or water. It was found that suspending atorvastatin hemicalcium Form V in a mixture of 1-butanol and water (one or another diluent present in large amounts in this mixture) would result in a purer crystalline atorvastatin hemicalcium product. This product was named Form IXa. Atorvastatin hemicalcium IXa is characterized by a PXRD pattern (FIG. 2), which is similar in some ways to the PXRD pattern of Form IX disclosed in US Patent Application 2002/0183378, where the PXRD pattern is the same as FIG. 1. However, there is a difference between the two patterns. The most obvious difference exists in the case of about 9.5 ° 2θ. That is, although one distinct peak exists in the IX PXRD pattern, two distinct peaks are observed in the IXa pattern at 9.3 ° 2θ and 9.5 ° 2θ. In addition, there are small peaks at 15.7, 20.5, 21.1, 22.8, 23.8, 24.0, 25.3, 26.4, 26.8, 27.2, 29.2 and 31.6 ± 0.2 ° 2θ in the IXa type PXRD pattern.

Atorvastatin hemicalcium Form IXa is a particularly crystalline, filterable, and pure substance, and is termed Form IXa because its internal structure is considered similar. Form IXa may be prepared by suspending atorvastatin hemicalcium Form V in a mixture of 1-butanol and water, ie, a mixture of 1-butanol or water that is about 85% to about 95%, more preferably about 90% of the mixture. Heating this suspension may facilitate the transition from Form V to Form IXa. In general, 16 hours is sufficient at about 85 ℃. Under these conditions, a yield of about 95% can be obtained, and the impurity concentration of this material can be significantly reduced. The impurity content of the starting atorvastatin hemicalcium may be reduced by at least about 50%. For example, when starting with Form V with chemical purity of about 1.3%, Form IX with chemical purity of about 0.7% can be obtained. Chemical purity was determined by high performance liquid chromatography ("HPLC"). HPLC was performed on a Spherisorb® S5, C8 column (250 x 4.6 mm) using the following eluent: Solvent A = 0.05 M KH ₃ PO ₄ [1N KOH: acetonitrile: methanol: THF ( 62: 26: 8: 4) to pH5]; Solvent B = methanol. This HPLC system is equipped with a UV detector and a Waters® pump set to detect at 254 nm.

Among the specific methods that can be used, the following methods are exemplified. Form V is suspended in a mixture of 90% 1-butanol and 10% water (v / v). This mixture is used in an amount of about 20 ml per gram of Form V. This suspension is refluxed at 90 ° C. for about 16 hours, after which time Form V is transformed to Form IX, which is recovered from the suspension by conventional means such as filtration.

According to another specific method, Form V is suspended in a mixture of 10% 1-butanol and 90% water (v / v). This mixture is used in an amount of about 20 ml per g of Form V. After refluxing this suspension for about 16 hours, after a certain time, Form V is transformed into Form IX, which is recovered by conventional methods.

The present invention further provides a novel polymorph of atorvastatin hemicalcium, named Form XIV. Atorvastatin hemicalcium Form XIV shows peaks in powder X-ray diffraction patterns obtained using conventional CuK _α radiation, ie 7.6, 9.8, 16.5, 18.1, 20.0, 20.4, 21.9, 22.4, 23.6, 29.4 ± 0.2 ° 2θ It is characterized by (Fig. 3). The most characteristic peaks are the peaks appearing at 7.6, 9.8, 16.5, and 29.4 ± 0.2 ° 2θ.

In general terms, Form XIV can be obtained from an atorvastatin hemicalcium suspension in water. According to US Pat. No. 5,969,156, atorvastatin hemicalcium Form I precipitates when calcium acetate is added to a solution of atorvastatin sodium in water. In addition, Form I can be prepared by suspending amorphous atorvastatin hemicalcium in water. In certain embodiments, Form I was obtained by seeding Form I in an aqueous mixture formed from Example 1, ie, atorvastatin sodium and calcium acetate, immediately after addition of the calcium acetate solution.

Suspension of atorvastatin hemicalcium or precipitation of atorvastatin hemicalcium from water produces Form I in some cases, as expected, as a result of studying US Pat. No. 5,969,156. On the contrary, the inventors obtained an unknown polymorph with a suspension of atorvastatin hemicalcium in water named Form XIV. Form XIV can be easily distinguished from Form I by the peaks appearing at 7.6, 16.5, 20.0, and 19.4 ° 2θ, which are not present in the Form I PXRD pattern. (Also obtained by precipitation from water, which should be seeded in Form I).

In Example 3 below, the suspension is not stirred or seeded with Form I crystals. Atorvastatin hemicalcium Form XIV suspends atorvastatin hemicalcium in water until a fine suspension is formed, and then keeps the suspension stable until the microcrystals are transformed into substantially white flakes. Can be prepared. The flakes can be separated from this suspension by conventional means such as decantation or filtration (filtration with or without aspiration, in which case they do not block the filter) to wash the crystals. The crystals of the fine suspension are so small that this suspension looks like an emulsion. Deformation from the fine suspension into flakes can be readily seen by visual observation of this suspension. Preferred parameters of the method are as follows. Preferred starting materials are atorvastatin hemicalcium Form V. Fine suspensions are typically formed over about 2 to about 10 hours, on average about 5 hours. The fine suspension is transformed into white flakes over about 1 to about 5 days, and longer times are preferred to form more completely and more easily filterable products. Other conditions for generating Form XIV may be found, but the best known method now is to suspend the atorvastatin hemicalcium in water that is not seeded with different polymorphs of atorvastatin. Form XIV was obtained in the laboratory without any seeding.

Form XIV crystals can be transformed into other crystal forms without contact with the solvent. This new type was named XVI type. Form XVI is characterized by a powder X-ray diffraction pattern (FIG. 4) showing peaks at 7.7, 9.9, 16.5, 17.7, 18.3, 20.0, 21.9, 29.5 ± 0.2 ° 2θ when using conventional CuK _α radiation. The most characteristic peaks appear at 16.5, 21.9 and 29.5 ± 0.2 ° 2θ.

Form XVI may be prepared by maintaining Form XIV at about 20 to about 50 ° C., preferably at about 22 ° C. or at room temperature, preferably exposed to air. Preferably, Form XIV is maintained under these conditions for about 3 hours. Other conditions under which Form XVI can be determined can be determined by experiment. The methods found so far for forming this XVI type can be provided.

The invention further provides a hydrated form of atorvastatin hemicalcium, designated Form XVII. Form XVII was obtained as a temporary product by precipitation from wet ethanol. As taught in US Patent Application Publication No. 2992/0183378 (or International Publication WO 01/36384 to PCT Application No. PCT / US00 / 31555), Form VIII is a mixture of 96% ethanol / water at a temperature of about 70 ° C. It can be prepared from a V-type dispersion. Using a method of at least 1 liter, the precipitated material is obtained as Form XVII and then dried.

Atorvastatin hemicalcium Form XVII is characterized by a powder X-ray diffraction pattern obtained through conventional X-ray peaks at 19.1, 20.6, 21.4 and 23.6 ± 0.2 ° 2θ when using conventional CuK _α radiation. Additional peaks are observed at 7.8, 9.5, 10.2, 18.2, 19.1, 25.3, 26.2, 30.1 ± 0.2 ° 2θ. Form XVII is also characterized by the X-ray powder diffraction pattern of FIG. 5. Form XVII is distinguished by type VIII [substance obtained by completely drying the material obtained by precipitation from 96% ethanol / 4% water] and a peak pattern in the range of 9 to 10 and 18 to 25 ° 2θ. In particular, Form VIII exhibits two distinct peaks at 19.2 and 20.0 ± 0.2 ° 2θ, while Form XVII exhibits one distinct peak at 19.1 ± 0.2 ° 2θ, but rarely at 20 ± 0.2 ° 2θ. .

Atorvastatin hemicalcium Form XVII can be prepared by suspending atorvastatin hemicalcium Form V in a mixture of 96% ethanol and 4% water (v / v), heating to about 78-80 ° C., and then cooling. Form XVII is isolated either as soon as this material begins to precipitate at reflux, or as soon as all material has precipitated, as soon as it is cooled to a temperature below room temperature, or as soon as all solids are separated from the mother liquor (eg For example, by filtration). Although there may be other ways to obtain Form XVII, the best known method currently is to suspend atorvastatin hemicalcium Form V in at least about 500 ml of a mixture of about 96% ethanol and about 4% water (v / v), and this suspension To reflux and then cooled. The solid is then recovered as Form XVII by conventional means, for example by filtration or decantation. An additional description of additional experiments is provided in Example 6. In this case, the reactor capacity should be at least about 1 liter.

The present invention also provides a novel method of preparing known forms of atorvastatin hemicalcium.

Atorvastatin hemicalcium Form I can be prepared by heating Form XIV to at least about 50 ° C, preferably at about 65 ° C. Preferably, Form XIV is maintained at high temperature for about 15 hours.

From the foregoing disclosure, it will be understood that when Form XVII is dried in a conventional manner, Form XVII is transformed into Form VIII. By conventional drying method is meant a drying method generally used by those skilled in the pharmaceutical industry. Any type of drying apparatus conventionally used in the pharmaceutical industry is suitable for practicing the present invention. The drying temperature is preferably about 40 to 70 ° C. (step temperature rise or one temperature). The time required to convert Form XVII to Form VIII depends on the amount of material used. It may be desirable to use a vacuum to convert from Form XVII to Form VIII by drying. Form VIII can also be prepared by drying Form XVII at temperatures as low as 40 ° C., ie below room temperature.

Atorvastatin hemicalcium Form IX is Form V in a mixture of 50% 1-butanol and 50% other organic solvent (s) such as acetone, 2-propanol, tetrahydrofuran, 1-propanol and methyl t-butyl ether It can be prepared by suspending. This mixture is used in an amount of about 20 ml per gram of Form V. Heating this suspension to reflux for about 16 hours, then Form V is transformed to Form IX, which is then recovered from the suspension in a conventional manner.

Atorvastatin hemicalcium types IXa, XIV, XVI and XVII are useful for reducing the concentration of plasma low density lipoproteins in patients suffering from or susceptible to hypercholesterolemia. To this end, it is preferred to administer to human patients in unit dosages of about 0.5 mg to about 100 mg. In most patients, a dose of about 2.5 to about 80 mg per day, more preferably a dose of about 2.5 to about 20 mg per day, lowers the plasma low density lipoprotein concentration in human patients. Whether such lowering is sufficient or whether the administration or the frequency of administration should be increased is within the skill level of a properly trained healthcare professional.

Another aspect of the invention is a pharmaceutical composition and dosage form containing a novel form of atorvastatin hemicalcium.

Compositions of the present invention include powders, granules, aggregates and other solid compositions containing the novel atorvastatin hemicalcium Forms IXa, Form XIV, Form XVI and Form XVII. In addition, the solid compositions of Form IXa, Form XIV, Form XVI and Form XVII contemplated by the present invention may also contain diluents such as cellulose derived materials such as powdered cellulose, microcrystalline cellulose, fine cellulose, methyl cellulose, Ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salt and other substituted and unsubstituted celluloses; Starch; Pregelatinized starch; Inorganic diluents such as calcium carbonate and calcium diphosphate and other diluents known in the pharmaceutical art. Still other suitable diluents include waxes, sugars and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, and pectin, dextrins and gelatin.

Additional excipients present within the scope of the present invention include binders such as acacia gum, pregelled starch, sodium alginate, glucose and other binders used for wet and dry granulation and direct compression tableting.

Excipients that may be present in solid compositions of types IXa, XIV, XVI and XVII atorvastatin hemicalcium further include disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose And the like. Moreover, excipients may include tableting lubricants such as magnesium and calcium stearate and sodium stearyl fumarate; Flavoring agent; Sweetener; Preservative; Pharmaceutically acceptable dyes and glidants such as silicon dioxide can be included.

Such formulations include formulations suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular and intravenous), inhalation and intraocular administration. Although in any case the most appropriate route of administration will depend on the nature and severity of the condition to be treated and the most preferred route of administration of the invention is the oral route of administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

The formulations include solid formulations such as tablets, powders, capsules, suppositories, sachets, troches and rosin, and liquid suspensions and elixirs. Although this description is not intended to limit the invention, the invention is not intended to include a true solution of atorvastatin hemicalcium as the properties that distinguish between the solids of atorvastatin hemicalcium are lost. However, the use of the novel forms for preparing such solutions (to deliver solvates to a solution containing a proportion of solvates in combination with atorvastatin) is considered to be within the scope of the present invention.

Of course, the capsule formulation will contain a solid composition in a capsule that can be made of gelatin or other conventional encapsulating material. Tablets and powders can be coated. Tablets and powders may be coated with an enteric sheath. The enteric sheath powder type includes materials such as phthalic acid cellulose acetate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, copolymers of carboxymethylethylcellulose, styrene and maleic acid, copolymers of methacrylic acid and methyl methacrylate. Including coatings may be included and, if desired, they may be used with suitable plasticizers and / or extending agents. Coated tablets may have a coating on the surface of the tablet or may be tablets comprising powders or granules having an enteric sheath.

Preferred unit dosage forms of the pharmaceutical compositions of the present invention typically contain 0.5-100 mg of the novel atorvastatin hemicalcium IXa, XIV, XVI and XVII or each of the atorvastatin hemicalcium or mixtures thereof with other forms. It contains. More generally, the compounding amount of the atorvastatin hemicalcium type in the unit dosage form is 2.5 to 80 mg.

As described in various aspects of the invention, the following examples are provided for the purpose of illustrating certain embodiments of the invention. These examples are not intended to limit the invention in any way.

1 shows a characteristic powder X-ray diffraction pattern of atorvastatin hemicalcium IX type obtained with a conventional X-ray generator using a copper anode.

Figure 2 shows a characteristic powder X-ray diffraction pattern of atorvastatin hemicalcium IXa type obtained with a conventional X-ray generator using a copper anode.

Figure 3 shows a characteristic powder X-ray diffraction pattern of atorvastatin hemicalcium Form XIV obtained with a conventional X-ray generator using a copper anode.

4 shows a characteristic powder X-ray diffraction pattern of atorvastatin hemicalcium XVI form obtained with a conventional X-ray generator using a copper anode.

5 shows a characteristic powder X-ray diffraction pattern of atorvastatin hemicalcium Form XVII.

The manufacturing method of atorvastatin hemicalcium IXa type

Example 1

Atorvastatin hemicalcium salt Form V (5 g) was suspended in a mixture of 1-butanol (90 mL) and water (10 mL) at reflux temperature (85 ° C.) for 16 hours. The mixture was then cooled to room temperature and then cooled to 0 ° C. using an ice bath. The product was isolated by filtration and dried in a vacuum oven at 65 ° C. for 24 hours, yielding 4.73 g (95%) of atorvastatin hemicalcium crystal Form IXa.

Example 2

Atorvastatin hemicalcium salt Form V (5 g) was suspended in a mixture of 1-butanol (10 mL) and water (90 mL) at reflux for 16 h. The mixture was then cooled to room temperature and then cooled to 0 ° C. using an ice bath. The product was isolated by filtration and dried in a vacuum oven at 65 ° C. for 24 hours to give atorvastatin hemicalcium crystalline Form IXa.

The preparation of atorvastatin hemicalcium XIV type

Example 3

Atorvastatin hemicalcium Form V (1 g) was placed in a 500 ml beaker. To this was added water (240 mL). This suspension was mixed for 5 hours. Fine suspension was formed. It was left as it is for 3 days. After 3 days a white flake formed in the suspension. This suspension was filtered and analyzed by XRD. The resulting form was the new atorvastatin hemicalcium Form XIV.

The manufacturing method of atorvastatin hemicalcium XVI type

Example 4

Small amounts of Form XIV were exposed to air for 3 hours at room temperature and then analyzed by XRD. The resulting type was type XVI.

The preparation of atorvastatin hemicalcium XVII type

Example 5

Wet atorvastatin hemicalcium salt Form V (53 g) was added to an ethanol solution (about 485 mL) at high temperature (about 70 ° C.). The amount of water produced in ethanol was about 4%. This mixture was refluxed for about 2 hours. The mixture was cooled to 15-20 ° C. The solid was filtered off and washed with 96% ethanol. The material was then analyzed by X-ray powder diffraction to find that it contained Form XVII. As a result of drying by the usual drying method (40-70 degreeC), the atorvastatin hemicalcium Form VIII was produced.

Example 6

About 20 kg of atorvastatin hemicalcium Form V was added to a high temperature (about 70 ° C.) solution of ethanol (about 600 L). The amount of water produced in ethanol was about 4%, which was adjusted to the initial water content of Form V. This mixture was refluxed for about 2.5 hours. The mixture was cooled to 15-20 ° C. and stirred at this temperature for at least 3 hours. The solid was filtered off and washed with 96% ethanol. Subsequent analysis of the material by X-ray diffraction revealed that it contained Form XVII. Atorvastatin hemicalcium Form VIII was prepared by normal drying at 40 to 70 ° C.

The manufacturing method of atorvastatin hemicalcium IX type

Example 7

The atorvastatin hemicalcium salt Form V (1 g) in 1-BuOH (10 mL) and EtOH (10 mL) was heated to reflux for 1 hour. The mixture was then cooled to room temperature and further stirred at this temperature for 16 hours. Filtration and drying for 24 hours at 65 ° C. resulted in 0.98 g (98%) of atorvastatin hemicalcium Form IX.

Example 8

Atorvastatin hemicalcium salt Form V (5 g) was suspended in a mixture of 1-butanol (50 mL) and acetone (50 mL) at reflux temperature (71 ° C.) for 17 hours. The mixture was then cooled to room temperature and then cooled to 0 ° C. using an ice bath. The product was isolated by filtration and dried in a vacuum oven at 65 ° C. for 24 hours to give 4.6 g (93%) of atorvastatin hemicalcium salt form IX.

Example 9

Atorvastatin hemicalcium salt Form V (5 g) was suspended in a mixture of 1-butanol (50 mL) and IPA (50 mL) at reflux temperature (91.5 ° C.) for 15 hours. The mixture was then cooled to room temperature and then cooled to 0 ° C. using an ice bath. The product was separated by filtration and then dried in a vacuum oven at 65 ° C. for 24 hours, yielding 4.7 g (94%) of atorvastatin hemicalcium salt form IX.

Example 10

Atorvastatin hemicalcium salt Form V (5 g) was suspended in a mixture of 1-butanol (50 mL) and THF (50 mL) at reflux temperature (80 ° C.) for 15 hours. The mixture was then cooled to room temperature and then cooled to 0 ° C. using an ice bath. The product was isolated by filtration and dried under vacuum at 65 ° C. for 24 hours, yielding 2.4 g (48%) of atorvastatin hemicalcium salt form IX.

Example 11

Atorvastatin hemicalcium salt Form V (5 g) was suspended in a mixture of 1-butanol (50 mL) and 1-propanol (50 mL) at reflux temperature (95 ° C.) for 16 hours. The mixture was then cooled to room temperature and then cooled to 0 ° C. using an ice bath. The product was isolated by filtration and dried under vacuum at 65 ° C. for 24 hours, yielding 4.8 g (96%) of atorvastatin hemicalcium salt form IX.

Example 12

Atorvastatin hemicalcium salt Form V (5 g) was suspended in a mixture of 1-butanol (50 mL) and MTBE (50 mL) at reflux temperature (73 ° C.) for 16 hours. The mixture was then cooled to room temperature and then cooled to 0 ° C. using an ice bath. The product was isolated by filtration and dried under vacuum at 65 ° C. for 24 hours, yielding 4.8 g (97%) of atorvastatin hemicalcium Form IX.

The present invention has been described and described by way of example with reference to specific embodiments. Those skilled in the art can understand that the present invention can be modified as described and illustrated without departing from the spirit and scope of the invention as defined by the appended claims below.

Claims (46)

Solid crystalline atorvastatin hemicalcium IXa characterized by a powder X-ray diffraction pattern exhibiting peaks at 9.3, 9.5, 15.7, 20.5, 21.1, 22.8, 23.8, 24.0, 25.3, 26.4, 26.8, 27.2, 29.2, and 31.6 ± 0.2 ° 2θ Molds and solvates thereof. delete The solid crystalline atorvastatin hemicalcium and solvate thereof of claim 1, wherein the powder X-ray diffraction pattern formed when using CuK _α radiation is substantially a powder X-ray diffraction pattern as follows:

(a) 85-95% for a time sufficient to convert atorvastatin hemicalcium Form V into atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift; Suspending atorvastatin hemicalcium Form V in a mixture selected from the group consisting of a mixture of 1-butanol and 5-15% water and a mixture of 5-15% 1-butanol and 85-95% water; And (b) recovering from this suspension solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift; A method for producing atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift. The method of claim 4, wherein the mixture consists of 90 volume% 1-butanol and 10 volume% water. The method of claim 4, wherein the mixture consists of 10 volume percent 1-butanol and 90 volume percent water. The method of claim 4, wherein the mixture is present in an amount of at least 20 ml per gram of atorvastatin hemicalcium Form V. 6. The method of claim 4, wherein the suspension is subjected to high temperature prior to recovery of the solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift. Heating. The method of claim 8, wherein the high temperature is the reflux temperature of the mixture. 10. The method of claim 9, wherein the reflux temperature is 85 ° C. The method of claim 4, wherein the time sufficient to convert Form V to solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift is 16 hours. What is below. The method of claim 4, wherein the solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift is at least 50% pureer than form V. 6. (a) 85-95% for a time sufficient to convert atorvastatin hemicalcium Form V into atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift; Suspending atorvastatin hemicalcium Form V in a mixture selected from the group consisting of a mixture of 1-butanol and 5-15% water and a mixture of 5-15% 1-butanol and 85-95% water; And (b) recovering from this suspension solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift; A solid crystalline atorvastatin hemicalcium and solvate thereof having at least one characteristic powder X-ray diffraction pattern of form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift prepared by a process comprising: (a) 90% by volume of 1% of atorvastatin hemicalcium Form V for a time sufficient to convert to atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift; Suspending the atorvastatin hemicalcium Form V in a mixture consisting of butanol and 10% by volume of water; And (b) recovering from this suspension solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form IXa or at least one characteristic solid phase ¹³ C NMR chemical shift with a chemical purity of at least 99.3%, wherein Said chemical purity being determined by high performance liquid chromatography separation and quantification by UV absorbance at 254 nm Solid crystalline and high purity atorvastatin hemicalcium and solvate thereof having at least one characteristic powder X-ray diffraction pattern of form IX or at least one characteristic solid phase ¹³ C NMR chemical shift prepared by a process comprising a. 7.6, 9.8, 16.5, 18.1, 20.0, 20.4, 21.9. Solid crystalline atorvastatin hemicalcium Form XIV and solvates thereof characterized by a powder X-ray diffraction pattern exhibiting peaks at 22.4, 23.6, and 29.4 ± 0.2 ° 2θ. delete 16. The solid crystalline atorvastatin hemicalcium and solvate thereof of claim 15, wherein the powder X-ray diffraction pattern formed when using CuK _α radiation is substantially a powder X-ray diffraction pattern as follows:

(a) suspending atorvastatin hemicalcium Form V in water; And (b) recovering the flakes from this suspension A method of making a solid crystalline atorvastatin hemicalcium and solvate thereof having at least one characteristic powder X-ray diffraction pattern of atorvastatin hemicalcium Form XIV or at least one characteristic solid phase ¹³ C NMR chemical shift. delete The method of claim 18, wherein the conversion process occurs over five days. The method of claim 18, wherein the finely suspended solids are produced over 2-10 hours after the atorvastatin hemicalcium is suspended in water. The method of claim 18, wherein the finely suspended solids are converted to flakes over 1 to 5 days. The method of claim 22, wherein the process of converting the finely suspended solids into flakes occurs over 5 days. Solid crystalline atorvastatin hemicalcium Form XVI and solvates thereof characterized by a powder X-ray diffraction pattern exhibiting peaks at 7.7, 9.9, 16.5, 17.7, 18.3, 20.0, 21.9, 29.5 ± 0.2 ° 2θ. delete The solid crystalline atorvastatin hemicalcium and solvate thereof of claim 24, wherein the powder X-ray diffraction pattern formed when using CuK _α radiation is substantially a powder X-ray diffraction pattern as follows:

(a) maintaining atorvastatin hemicalcium Form XIV crystals at 20-50 ° C .; And (b) recovering this crystal as a solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form XVI or at least one characteristic solid phase ¹³ C NMR chemical shift; A method of making a solid crystalline atorvastatin hemicalcium and solvate thereof having at least one characteristic powder X-ray diffraction pattern of form XVI or at least one characteristic solid phase ¹³ C NMR chemical shift. The method of claim 27, wherein the atorvastatin hemicalcium is maintained at 22 ° C. 29. The method of claim 27, wherein the atorvastatin hemicalcium is maintained in the air. Solid crystalline atorvastatin hemicalcium Form XVII and solvates thereof characterized by a powder X-ray diffraction pattern exhibiting peaks at 7.8, 9.5, 10.2, 18.2, 19.1, 20.6, 21.4, 23.6, 25.3, 26.2, 30.1 ± 0.2 ° 2θ. delete 31. The solid crystalline atorvastatin hemicalcium and solvate thereof of claim 30, wherein the powder X-ray diffraction pattern formed when using CuK _α radiation is substantially a powder X-ray diffraction pattern as follows:

(a) suspending atorvastatin hemicalcium Form V in a mixture of 96% ethanol and 4% water; (b) heating the suspension; (c) cooling the suspension; And (d) recovering from this suspension solid atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of atorvastatin hemicalcium Form XVII or at least one characteristic solid phase ¹³ C NMR chemical shift; A process for the preparation of solid crystalline atorvastatin hemicalcium and solvates thereof having at least one characteristic powder X-ray diffraction pattern of form XVII or at least one characteristic solid phase ¹³ C NMR chemical shift. The method of claim 33, wherein the mixture is used in an amount of at least 500 ml. 34. The method of claim 33, wherein the suspension is heated to 78 to 80 ° C. A pharmaceutical composition comprising atorvastatin hemicalcium selected from the group consisting of atorvastatin hemicalcium IXa, XIV, XVI and XVII or a mixture thereof and a pharmaceutically acceptable carrier.  A method for preparing a pharmaceutical formulation comprising combining atorvastatin forms IXa, XIV, XVI and XVII or a mixture thereof with a pharmaceutically acceptable carrier. A pharmaceutical formulation comprising atorvastatin hemicalcium Form IXa, Form XIV, Form XVI, Form XVII or mixtures thereof. delete (a) heating the atorvastatin hemicalcium Form XIV crystals to at least 50 ° C; And (b) recovering this crystal as solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of atorvastatin hemicalcium Form I or at least one characteristic solid phase ¹³ C NMR chemical shift; A method of making a solid crystalline atorvastatin hemicalcium and solvate thereof having at least one characteristic powder X-ray diffraction pattern of Form I or at least one characteristic solid phase ¹³ C NMR chemical shift. 41. The method of claim 40, wherein the atorvastatin hemicalcium Form XIV is heated to 65 ° C. (a) heating form V in ethanol to provide atorvastatin hemicalcium Form XVII; (b) drying Form XVII to transform it into atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form VIII or at least one characteristic solid phase ¹³ C NMR chemical shift; And (c) recovering atorvastatin having at least one characteristic powder X-ray diffraction pattern of Form VIII or at least one characteristic solid phase ¹³ C NMR chemical shift; A process for the preparation of solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form VIII or at least one characteristic solid phase ¹³ C NMR chemical shift. 43. The method of claim 42, wherein said drying step comprises heating Form XVII to a high temperature. 44. The method of claim 43, wherein the high temperature is between 40 and 70 degrees Celsius. (a) suspending atorvastatin hemicalcium Form V in a mixture of 50% 1-butanol and 50% other organic diluent; And (b) recovering from this suspension atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of Form IX or at least one characteristic solid phase ¹³ C NMR chemical shift; A process for the preparation of solid crystalline atorvastatin hemicalcium having at least one characteristic powder X-ray diffraction pattern of form IX or at least one characteristic solid phase ¹³ C NMR chemical shift comprising a. 46. The method of claim 45, wherein said organic diluent is selected from the group consisting of acetone, 2-propanol, tetrahydrofuran, 1-propanol and methyl t-butyl ether.

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