MX2007000715A - Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation - Google Patents

Abstract

Provided are novel crystal forms of atorvastatin hemi-calcium referred to herein as Form XVIII and Form XIX and processes for their preparation and use. Also provided are atorvastatin hemi-calcium acetone solvates.

Description

NEW CRYSTALLINE SHAPES OF SORMICULTURE ATORVASTATIN AND PROCESSES FOR PREPARATION FIELD OF THE INVENTION The present invention relates to crystalline polymorphic forms of semicálcica atorvastatin and new processes for preparing crystalline forms of semicálcica atorvastatin.

BACKGROUND OF THE INVENTION Atorvastatin, (acid [R- (R *, R *)] -2 (4-fluorophenyl) -P, 6-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [(phenylamine) carbonyl] - 1 H-pyrrole-1-heptanoic acid), illustrated in the form of lactone in the formula (I) and its calcium salts of the formula (II) are well known in the art, and are described, inter alia, in the patents of the United States Nos. 4,681,893 and 5,273,893 and 5,273,995, which are incorporated herein by reference. p Processes for preparing atorvastatin and its semicálcic salt are also disclosed in U.S. Patent Application Publication No. 2002/0099224; U.S. Patent Nos. 5,273,995, 5,298,627, 5,003,080, 5,097,045, 5,124,482, 5,149,837, 5,216,174, 5,245,047, 5,280,126; Baumann, K.L. et al Tet. Lett. 1992, 33, 2283-2284, which are incorporated herein by reference in their entirety and in particular for teachings related to the preparation of atorvastatin and semicálcic atorvastatin.

Atorvastatin is a member of the class of drugs called statins. Statin drugs are currently the therapeutically most effective drugs available to reduce the concentration of low density lipoprotein (LDL) particles in the bloodstream of patients at risk of cardiovascular disease. A high level of "LDL" in the bloodstream has been linked to the formation of coronary lesions that obstruct the flow of blood and that can promote thrombosis. Goodman and Gilman, The Pharmacological Basis of Therapeutics 879 (9th ed, 1996). Reducing LDL levels in plasma has been shown to reduce the risk of clinical episodes in patients with cardiovascular disease and patients who do not have cardiovascular disease but who they have hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.

The mechanism of action of statin drugs has been clarified in detail. They interfere with the synthesis of cholesterol and other sterols in the liver by inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-coelizime A reductase ("HMG-CoA reductase"). HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, which is the average determination step in cholesterol biosynthesis, and thus its inhibition leads to the reduction in the concentration of cholesterol in the liver. Very low density lipoprotein (VLDL) is the biological vehicle for transporting cholesterol and triglycerides from the liver to peripheral cells. VLDL are catabolized in peripheral cells that release fatty acids that can be stored and oxidized by the muscle. VLDL is converted to intermediate density lipoprotein (IDL) that is extracted by an LDL receptor or converted to LDL. Decreased cholesterol production leads to an increase in the number of LDL receptors and corresponding reduction in the production of LDL particles by IDL metabolism.

Atorvastatin semicálcic salt trihydrate is marketed under the name LIPITOR® by Pfizer, Inc.

Atorvastatin was first disclosed to the public and claimed in U.S. Patent No. 4,681,893. The semicálcic salt illustrated in formula (II) is disclosed in U.S. Patent No. 5,273,995. The '995 patent teaches that the semicálcic salt is obtained by crystallization from a solution of salt solution resulting from the rearrangement of sodium salt with CaCl 2 and further purified by recrystallization from a 5: 3 mixture of ethyl acetate and hexane .

The incidence of different crystalline forms (polymorphism) is a property of some molecules and molecular complexes. A simple molecule, as the atorvastatin in the formula (I) or the salt complex of the formula (II) can give rise to a variety of solids that have different physical properties such as melting point, x-ray diffraction pattern, infrared absorption traces and spectrum N R. The differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent (complex) molecules in the solid. In this way, polymorphs are distinct solids that share the same molecular formula even if they have different advantageous and / or disadvantageous physical properties compared with other forms in the polymorph family. One of the most important physical properties of Pharmaceutical polymorphs is its solubility in aqueous solution, particularly its solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is low, it is often desirable for a drug that is unstable for diseases in the stomach or intestine of the patient to dissolve slowly so that it does not accumulate in a noxious environment. On the other hand, where the effectiveness of a drug correlates with peak bloodstream levels, a property is shared by the drug statin and if the drug is rapidly absorbed by the GI system, then a faster dissolution form is likely to exhibit increased effectiveness over an affordable amount of a slower dissolving form.

Crystalline Forms I, II, III and IV of semicálcica atorvastatin are the objects of Patents Nos. 5,959,156 and 6,121,461, assigned to Warner-Lambert. Semi-calcic atorvastatin Form V is disclosed in International Publication No. WO 01/36384 (PCT Application No. PCT / USOO / 31555).

The discovery of new crystalline polymorphic forms of a drug expands the repertoire of materials that a scientific formulation has, with which to design a form of pharmaceutical dose of a drug with a target release profile or other desired characteristic.

EXTRACT OF THE INVENTION The present invention provides acetone solvates of solid crystalline semicálcic atorvastatin.

The present invention further provides a solid crystalline form of semicálcic atorvastatin characterized by a powder XRD pattern with peaks at 3.8, 8.0, 8.9 and 10.4 ± 0.2 degrees 2 theta. This form can be an acetone solvate.

The present invention further provides a solid crystalline form of semicálcic atorvastatin characterized by a powder XRD pattern with peaks at 3.3, 4.2, 5.6 and 8.2 ± 0.2 degrees 2 theta. This form can be an acetone solvate.

The present invention also provides methods for realizing the solid crystalline forms described above.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a X-ray diffraction pattern of form XVIII atorvastatin semicálcic powder.

Figure 2 is an X-ray powder diffraction pattern of acetone solvate of semicálcic atorvastatin Form XIX.

DETAILED DESCRIPTION OF THE INVENTION X-ray powder diffraction analysis ("PXRD") using a SCINTAG model X'TRA X-ray powder diffractometer equipped with a solid-state detector. Cooper Radiation of? = 1.5418 was used. The sample was introduced using a standard round aluminum sample holder with a zero-round bottom quartz plate in the bottom.

The present invention provides acetone solvates of semicálcic atorvastatin salt.

The invention further provides a solid crystalline semicálcic atorvastatin, characterized by an XRD pattern of powder with peaks at 3.8, 8.0, 8.9 and 10, ± 0.2 degrees 2 theta. This solid crystalline semicálcica atorvastatin is called Form XVIII.

Atorvastatin form XVIII can be an acetone solvate. Atorvastatin form XVIII may contain up to 1.5% acetone. Preferably, form XVIII atorvastatin may contain up to 1.4% acetone.

Atorvastatin form XVIII may also be characterized by an XRD pattern of powder with peaks at 3.0, 18.0, 18.8, 19.6 and 20.6 ± 0.2 degrees 2 theta.

Atorvastatin form XVIII may also be characterized by an XRD pattern of powder substantially as shown in Figure 1.

Form XVIII of atorvastatin may be substantially free of crystalline Form I of atorvastatin. In certain embodiments, Form XVIII of crystalline semicálcic atorvastatin contains less than 10%, preferably less than about 5% and even more preferably less than about 1% (by weight) of Form I of semicálcic atorvastatin.

Another aspect of the present invention is a process for preparing Atorvastatin Form XVIII. The method for preparing crystalline semicálcica atorvastatin Form XVIII comprises: a) dissolve semicálcica atorvastatin in acetone to form a solution; b) maintain the solution until a precipitate is obtained; and c) recovering the precipitate.

Preferably, the semicálcic atorvastatin of step (a) is Form V. Preferably, step (b) comprises stirring at room temperature for about 40 to 70 hours. Preferably the recovery step in step (c) comprises filtering and drying the precipitate.

The present invention further comprises providing a solid crystalline semicálcic atorvastatin, characterized by an XRD pattern of powder with peaks at 3.3, 4.2, 5.6 and 8.2 ± 0.2 degrees 2 theta. This solid crystalline semicálcica atorvastatin is called Form XIX.

Atorvastatin Form XIX may also be characterized by an XRD pattern of powder with peaks at 17.0, 19.2, and 22.0 ± 0.2 degrees 2 theta.

Atorvastatin Form XIX may also be characterized by an XRD pattern as substantially illustrated in Figure 2.

Atorvastatin Form XIX can be an acetone solvate. Atorvastatin Form XIX may contain up to 6.0% acetone. Preferably, Form XVIII atorvastatin may contain up to 5.9% acetone.

Form XIX of atorvastatin may be substantially free of crystalline Form I of atorvastatin. In certain embodiments, Form XIX crystalline semicálcic atorvastatin contains less than 10%, preferably less than about 5% and even more preferably less than about 1% (by weight) of Form I semicálcic atorvastatin.

Another aspect of the invention is a process for preparing Atorvastatin Form XIX. A method for preparing crystalline semicálcic atorvastatin Form XIX comprises preforming an increased process in scale to prepare Form XVIII. Preferably, the amount of semicálcic atorvastatin and acetone are scaled up by a factor of about 4 to 8. More preferably, the amount of semicálcic atorvastatin and acetone are increased in scale by a factor of about 6. It is within the skill of those skilled in the art, guided by the present disclosure, to choose the appropriate amount of semicálcic atorvastatin and acetone to obtain the desired crystalline form, either Form XVIII o Form XIX, with the use of, at most, routine experimentation.

Solid crystalline semicálcica atorvastatin Forms XVIII and XIX are effective in reducing the low density lipoprotein level of a patient suffering from or prone to hypercholesterolemia. To this end, Form XVIII or Form XIX will commonly be administered to human patients at a dose of approximately 0.5 mg to 100 mg. For most human patients, a dose of 2.5 mg to 80 mg per day approximately, more particularly of 2.5 to 20 mg per day approximately, reduces the level of low density lipoprotein in the plasma. Whether this decrease is sufficient or if the dose or frequency of the dose should be increased is a determination that is within the skill level of properly trained medical personnel.

In another aspect, the invention provides compositions and dosage forms comprising the solvate forms of semicálcic atorvastatin and mixtures thereof. The compositions of the invention include powders, granulates, aggregates and other solid compositions comprising Forms XVIII and / or XIX of solid crystalline semicálcic atorvastatin. In addition, the solid compositions of Forms XVIII and XIX which are contemplated in the present invention may further include diluents, such as, for example, cellulose-derived materials, such as, for example, cellulose powder, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, salts of carboxymethyl cellulose and other substituted and unsubstituted celluloses; starch, pregelatinized starch; inorganic diluents such as calcium carbonate and calcium disphosphate and other diluents known in the pharmaceutical industry. Still other suitable diluents include sugars, sugars and alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.

Other excipients that are within the contemplation of the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in dry and wet granulation and direct compression tablet processes. The excipients which are also in a solid composition of Forms XVIII and XIX of semicálcica atorvastatin also include disintegrants such as sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose and others. In addition, excipients including lubricants for tabletting include magnesium and calcium stearate and sodium stearyl fumarate, flavors, sweeteners, preservatives, parenterals (including subcutaneous, intramuscular and intravenous), administration by inhalation and ophthalmic. Although the most appropriate route in any case will depend on the nature and severity of the disease to be treated, the preferred route of the present invention is oral. The doses may conveniently be presented in a dosage form and prepared by any of the methods well known in the art.

The dosage forms include solid dosage forms, such as tablets, powders, capsules, suppositories, pills, as well as liquid suspensions and elixirs. While the description is not intended to limit, the invention also does not claim to belong to the true solutions of semicálcica atorvastatin with which the properties that distinguish the solid forms of semicálcica atorvastatin are low. However, the use of novel ways to prepare such solutions (for example to deliver, in addition to atorvastatin, a solvate to said solution in a certain proportion with a solvate) is considered to be within the contemplation of the invention.

The capsule doses will of course contain the solid composition in a capsule which may be made of gelatin or other conventional encapsulation material. The tablets and powders may be coated. The tablets and powders may be coated with an enteric coating. The enteric coated powder forms can have coatings comprising italic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and similar materials, and if desired, can be employed with suitable extension agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with enteric coverage.

Preferred doses of pharmaceutical compositions of the present invention commonly contain 0.5 to 100 mg of new semicálcic atorvastatin forms XVIII and XIX and mixtures thereof, or mixtures with other forms of semicálcic atorvastatin. More usually, the combined weight of semicálcic atorvastatin dose is approximately 2.5 to 80 mg.

The crystalline forms of the present invention used to prepare pharmaceutical formulations may be substantially pure with respect to other crystalline forms, ie, the pharmaceutical formulations may contain less than about 10%, preferably less than 5% and even more preferably less than 1% (by weight) approximately of other crystalline forms of semicálcica atorvastatin. In particular, pharmaceutical formulations comprising Form XVIII may contain less than about 10%, preferably 5%, and even more preferably 1% (by weight) of Form I. Pharmaceutical formulations comprising Form XIX may contain less than about about 10%, preferably less than about 5%, and even more preferably less than about 1% (by weight) of Form I. In certain embodiments, the pharmaceutical formulations may contain less than about 10%, preferably less than 5%, and more preferably less than about 1% (by weight) of amorphous atorvastatin.

Alternatively, the pharmaceutical formulations of the present invention may also contain one or both Form XVIII or Form XIX in a mixture with other forms of atorvastatin. However, it is preferred that the formulations or pharmaceutical compositions of the present invention contain -100% by weight, especially 50-100% by weight of at least one of the forms XVIII or Form XIX, based on the total amount of atorvastatin in the formulation or composition. Preferably, said amount of the new Form XVIII or Form XIX of atorvastatin semicálcica is 75-100% by weight, especially 90-100% by weight. Highly preferred is an amount of 95-100% by weight.

As used herein, "room temperature" or "TA" indicates a temperature at about 18-25 ° C, preferably 20-22 ° C.

"Therapeutically acceptable amount" means the amount of crystalline form, which, when administered to the patient to treat a disease or other unexpected medical malady, is sufficient to have a beneficial effect with respect to that disease or condition. The "therapeutically effective amount" will vary depending on the crystalline form, the disease or disease and its severity, and the age, weight, etc., of the patient to be treated. Determining the therapeutically effective amount of a given crystalline form is within the skill of the person skilled in the art and requires no more than routine experimentation.

Certain processes of the present invention include crystallization of a particular solvent. One skilled in the art will appreciate that the crystallization conditions can often be modified in some way without affecting the crystalline form obtained. For example, when semicálcica atorvastatin is mixed in a solvent to form a solution, heating the mixture may be desirable to completely dissolve the starting material. If the heating does not clarify the mixture, the mixture can be diluted or filtered. To filter, the hot mixture can pass through paper, fiberglass, or other membrane material, or a clarifying agent such as celite. Depending on the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Conditions can also be changed to induce precipitation. A preferred way to induce precipitation is to reduce the solubility of the solvent. The solubility of the solvent can be reduced, for example, by cooling the solvent. The precipitation can also be induced by evaporation of the solvent or by adding an anti-solvent.

The crystalline forms of the present invention can be distinguished by PXRD standards. The crystalline forms have peak positions PXRD features in the average of 2-40 degrees two theta. According to these chaeristic peak positions, the expert can identify the crystalline forms and also identify and quantify their impurities in a crystalline form.

One skilled in the art will appreciate that there is some uncertainty about the PXRD measurements, generally in the order of approximately ± 0.2 degrees 2 theta for each peak. In such a manner, peak PXRD data are presented herein in the form of "PXRD pattern with peaks at A, B, C, etc., ± 0.2 degrees 2 theta". This indicates that, for the crystalline form in question, the peak in A could, in a certain instrument or in some operation, appear between A ± 0.2 degrees 2 theta, the B peak could appear in B ± 0.2 degrees 2 theta , etc. This certain and inevitable uncertainty in the identification of individual peaks does not translate into uncertainty with respect to identifying individual crystalline forms since it is generally the particular combination of peaks at specified ranges, not a particular peak, which serves to unambiguously identify crystalline forms.

The particle size distribution (PSD) of the active ingredient is one of key parameters of a formulation. For mix the particle size, the following methods can be employed: strainer, sedimentation, electrozone detection (blade counter), microscopy, low angle light scattering (LALLS). The new forms of the invention have a preferred maximum particle size of 500 μm. Preferably, the particle size is less than 300 μm, less than 200 μm, and less than 100 μm, or less than 50 μm.

Having described the invention with reference to certain preferred embodiments, other embodiments will be apparent to one skilled in the art from the consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of the use of the invention. It will be apparent to those skilled in the art that many modifications to the materials and methods can be practiced without departing from the scope of the invention.

EXAMPLES Example 1: Procedure to prepare Form XVIII A crystal precipitate of salt of atorvastatin semicálcica Form V (lOg) in Acetone (70ml) was mixed at room temperature for 8 hours to obtain a complete solution. The obtained solution was mixed at room temperature for an additional 40 hours to obtain a massive precipitate. Acetone (280 ml) was added to dilute the precipitate. The product was separated by filtration and dried in a vacuum oven at 40 ° C for 20 hours to obtain 6.6 g of crystal salt of semi-calcic atorvastatin form XVIII. The acetone level was 13890 ppm (1.4%).

Example 2: Procedure to prepare Form XIX A crystal precipitate of semicálcica atorvastatin salt Form V (60g) in Acetone (420ml) was mixed at room temperature for 8 hours to obtain complete dissolution. The obtained solution was mixed at room temperature for an additional 64 hours to obtain a massive precipitate. The product was separated by filtration and washed with acetone (4x250ml) and dried in a vacuum oven at 40 ° C for 21 hours to obtain 59.4g of crystal salt of semi-calcium salt of atorvastatin Form XIX. The acetone level was 58.695 ppm (5.9%).

Claims (32)

1. Acetone solvate of atorvastatin salt semicálcica.

2. Crystalline semicálcic atorvastatin characterized by the PXRD pattern having peaks at 3.8, 8.0, 8.9 and 10.4 ± 0.2 degrees 2 theta.

3. The crystalline semicálcic atorvastatin of claim 2, further characterized by the PXRD peaks at 3.0, 18.0, 18.8, 19.6 and 20, 6 ± 0.2 degrees 2 theta.

4. The crystalline semicálcica atorvastatin of the claim 2, which have a PXRD spectrum substantially as illustrated in Figure 1.

5. The crystalline semicálcic atorvastatin of claim 2 which is an acetone solvate.

6. The crystalline semicálcic atorvastatin of claim 5 containing up to about 1.5% acetone.

7. The crystalline semicálcic atorvastatin of claim 6, which contains up to about 1.4% acetone.

8. The crystalline seracalcium atorvastatin of claim 2 containing less than about 10% (by weight) of semicálcic atorvastatin Form I.

9. The crystalline semicálcic atorvastatin of claim 8 containing less than about 5% (by weight) of semicálcic atorvastatin Form I.

10. The crystalline semicálcic atorvastatin of claim 9 containing less than about 1% (by weight) of semicálcic atorvastatin Form I.

11. Atorvastatin crystalline semicálcica characterized because the PXRD pattern has peaks at 3.3, 4.2, 5.6 and 8.2 ± 0.2 degrees 2 theta.

12. The crystalline semicálcic atorvastatin of claim 11, further characterized by the PXRD peaks at 17.0, 19.2 and 22.0 ± 0.2 degrees 2 theta.

13. The crystalline semicálcic atorvastatin of claim 1, having a PXRD spectrum substantially as illustrated in Figure 2.

14. The crystalline semicálcic atorvastatin of claim 11 which is an acetone solvate.

15. The crystalline semicálcic atorvastatin of claim 14 containing up to about 6.0% acetone.

16. The crystalline semicálcic atorvastatin of claim 15, which contains up to about 5.9% acetone.

17. The crystalline semicálcic atorvastatin of claim 11 containing less than about 10% (by weight) of semicálcic atorvastatin Form I.

18. The crystalline semicálcic atorvastatin of claim 17 containing less than about 5% (by weight) of semicálcic atorvastatin Form I.

19. The crystalline semicálcic atorvastatin of claim 18 containing less than about 1% (by weight) of semicálcic atorvastatin Form I.

20. A method for preparing crystalline semicálcic atorvastatin characterized by a PXRD pattern having peaks at 3.8, 8.0, 8.9 and 10.4 ± 0.2 degrees 2 theta comprising: to. dissolve semicálcica atorvastatin in acetone to form a solution; b. keep the solution until the precipitate is obtained; and c. recover the precipitate.

21. The method of claim 20, characterized in that step (b) comprises stirring for about 40 to 70 hours.

22. The method of claim 20, characterized in that the temperature is approximately at room temperature.

23. A method for preparing crystalline semicálcic atorvastatin characterized by the PXRD peaks at 3.3, 4.2, 5.6 and 8.2 ± 0.2 degrees 2 theta comprising carrying out the process of claim 20, characterized in that the atorvastatin semicálcica and acetone are in scale by a factor of about 4 to 8.

24. The method of claim 23, characterized in that the amount of semicálcic atorvastatin and acetone are in scale by a factor of about 6.

25. A method for preparing crystalline semicálcic atorvastatin Form XVIII or Form XIX comprising: to. dissolve semicálcica atorvastatin in acetone to form a solution; b. keep the solution until the precipitate is obtained; and c. recover the precipitate.

26. The method of claim 25 characterized in that the acetone ratio of atorvastatin in step (a) is about lg: 7ml.

27. The method of claim 26 characterized in that the amount of atorvastatin dissolved in step (a) is adjusted to produce a precipitate of semi-calcium atorvastatin form XVIII in step (b).

28. The method of claim 27 characterized in that the amount of atorvastatin dissolved in step (a) is about 10 g.

29. The method of claim 25 characterized in that the amount of atorvastatin dissolved in step (a) is adjusted as to produce a precipitate of semi-calcium atorvastatin Form XIX in step (b).

30. The method of claim 29 characterized in that the amount of atorvastatin dissolved in step (a) is about 60g.

31. A pharmaceutical composition prepared to combine at least one pharmaceutically acceptable excipient with at least one of the crystalline forms of semicálcic atorvastatin of any of claims 2 and 11.

32. A method for treating a patient with hypercholesterolemia or hyperlipidemia comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 31.