KR20070032376A - Novel crystalline form of atorvastatin hemi-calcium and preparation method thereof - Google Patents

Abstract

The present invention relates to novel crystalline forms of atorvastatin hemi-calcium, referred to herein as XVIII or XVIII, and methods of making and using the same. The present invention also provides atorvastatin hemi-calcium acetone solvate.

Description

Novel crystalline form of atorvastatin hemi-calcium and its preparation method {NOVEL CRYSTAL FORMS OF ATORVASTATIN HEMI-CALCIUM AND PROCESSES FOR THEIR PREPARATION}

Cross-Reference to Related Applications

This application claims priority to Provisional Application No. 60 / 590,945, filed Jul. 22, 2004, which is incorporated herein by reference.

Field of invention

The present invention relates to crystalline polymorphs of atorvastatin hemi-calcium and to novel processes for preparing atorvastatin hemi-calcium crystalline forms.

Atorvastatin represented by the following 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 formula (II) are known in the art and in particular US Pat. Nos. 4,681,893 and 5,273,995 Which is incorporated herein by reference.

Methods for preparing atorvastatin and its hemi-calcium salts are also 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 incorporated herein by reference in their entirety, and in particular, teach how to prepare atorvastatin and atorvastatin hemi-calcium.

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 the plasma LDL concentration is believed to reduce the risk of pathogenesis in patients with cardiovascular disease and in patients with but not having cardiovascular disease. 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 step in determining the rate of cholesterol biosynthesis, which, when inhibited, reduces cholesterol concentrations in the liver. Ultra low density lipoprotein (VLDL) is a biological carrier 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 hemi-calcium salt trihydrate is marketed under the trade name LIPITOR® by Pfizer, Inc. Atorvastatin was originally published in US Pat. No. 4,681,893 and claimed as a right. Hemi-calcium salts represented by Formula II are disclosed in US Pat. No. 5,273,995. Patent 5,273,995 teaches that the hemi-calcium 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 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 points, X-ray diffraction patterns, infrared absorption fingerprints, and NMR spectra. 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, in particular their solubility in gastric juice of patients. For example, when absorption through the small intestine is slow, it is desirable that the drug that is unstable to the environment of the patient's stomach or intestine is slowly dissolved and does not accumulate in a harmful environment. On the other hand, the efficacy of the drug correlates with the highest concentration in the blood of the drug, a property shared by statin drugs, provided that the drug dissolves more rapidly when the drug is rapidly absorbed by the gastrointestinal system. There is a tendency to show increased efficacy over slower dissolving forms.

Forms I, II, III, and IV of atorvastatin hemi-calcium are the subjects of US Pat. Nos. 5,959,156 and 6,121,461 assigned to Warner-Lambert. Crystalline atorvastatin hemi-calcium Form V is disclosed in co-owned WO 01/36384 (PCT Application PCT / US00 / 31555).

The discovery of new crystalline polymorphs of drugs expands the reporting of materials from which formulation experts can design pharmaceutical formulations of drugs with the desired release profile or other desired properties.

Summary of the Invention

The present invention provides a solid crystalline atorvastatin hemi-calcium acetone solvate.

The invention further provides a solid crystalline form of atorvastatin hemi-calcium characterized by a powder XRD pattern having peaks at 3.8, 8.0, 8.9 and 10.4 ± 0.2 ° 2θ. The type may be acetone solvate.

The present invention also provides a solid crystalline form of atorvastatin hemi-calcium characterized by a powder XRD pattern having peaks at 3.3, 4.2, 5.6 and 8.2 ± 0.2 ° 2θ. The type may be acetone solvate.

The present invention also provides a method for preparing the above solid crystalline form.

Brief description of the drawings

1 is a powder X-ray diffraction pattern peculiar to atorvastatin hemi-calcium XVIII.

Fig. 2 is a powder X-ray diffraction pattern peculiar to atorvastatin hemi-calcium XVIII acetone solvate.

Powder X-ray diffraction ("PXRD") analysis was performed using a SCINTAG powder X-ray diffractometer model X'TRA with a solid-state detector. Copper radiation of λ = 1.5418 was used. Samples were introduced using a round standard aluminum sample holder with a circular zero background correction plate at the bottom.

The present invention provides atorvastatin hemi-calcium salt acetone solvate.

The invention further provides a solid crystalline atorvastatin hemi-calcium characterized by a powder XRD pattern having peaks at 3.8, 8.0, 8.9 and 10.4 ± 0.2 ° 2θ. The solid crystalline atorvastatin hemi-calcium is represented as XVII type.

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

The atorvastatin XVIII form can be further characterized by a powder XRD pattern with peaks at 3.0, 18.0, 18.8, 19.6 and 20.6 ± 0.2 ° 2θ.

The atorvastatin XVII type may be further characterized by an XRD pattern as substantially shown in FIG. 1.

Form XVII of atorvastatin may be substantially free of crystalline Form I of atorvastatin. In certain embodiments, the crystalline atorvastatin hemi-calcium Form XVII contains less than about 10 wt%, preferably less than about 5 wt%, more preferably less than about 1 wt% atorvastatin hemi-calcium Form I.

Another aspect of the present invention is a method for preparing atorvastatin XVII type. The preparation method of the crystalline atorvastatin hemi-calcium XVIII type

(a) dissolving atorvastatin hemi-calcium in acetone to form a solution;

(b) leaving the solution until a precipitate is obtained; And

(c) recovering the precipitate

It includes.

Preferably, the atorvastatin hemi-calcium of step (a) is form V. Step (b) preferably comprises stirring at about room temperature for about 40 hours to about 70 hours. The recovery step in step (c) includes filtering and drying the precipitate.

The invention further provides a solid crystalline atorvastatin hemi-calcium characterized by a powder XRD pattern having peaks at 3.3, 4.2, 5.6 and 8.2 ± 0.2 ° 2θ. The solid crystalline atorvastatin hemi-calcium is represented as XVII type.

The atorvastatin XVIII form can be further characterized by a powder XRD pattern having peaks at 17.0, 19.2 and 22.0 ± 0.2 ° 2θ.

The atorvastatin XVII type can be further characterized by an XRD pattern substantially as shown in FIG. 2.

Atorvastatin Form XVII can be an acetone solvate. Atorvastatin Form XVII can contain up to 6.0% acetone. It is preferable that the atorvastatin XVII type contains 5.9% or less of acetone.

Form XVII of atorvastatin may be substantially free of crystalline Form I of atorvastatin. In certain embodiments, the crystalline atorvastatin hemi-calcium Form XVII contains less than about 10 wt%, preferably less than about 5 wt%, more preferably less than about 1 wt% atorvastatin hemi-calcium Form I.

Another aspect of the present invention is a method for preparing atorvastatin XVII type. Processes for the preparation of crystalline atorvastatin hemi-calcium Form XVIII include performing a large scale process of Form XVIII. It is preferred to increase the amount of atorvastatin hemi-calcium and acetone from about 4 to about 8 times. More preferably, the amount of atorvastatin hemi-calcium and acetone is increased about 6 times. Within the skill of one of ordinary skill in the art described by the present disclosure, there is a step of selecting only an appropriate amount of atorvastatin hemi-calcium and acetone to obtain a predetermined crystal form of XV-type or XV-type by using only ordinary experiments at the maximum. .

Atorvastatin hemi-calcium solid crystalline Form XVIII and Form XVIII are useful for reducing the concentration of plasma low density lipoproteins in patients with or susceptible to hypercholesterolemia. To this end, it is typical to administer to human patients in unit dosages of about 0.5 mg to about 100 mg. In most human patients, a dose of about 2.5 mg to about 80 mg per day, more preferably a dose of about 2.5 mg to about 20 mg per day, lowers plasma low density lipoprotein levels. The determination of whether such lowering is sufficient or whether the administration or the frequency of administration increases is within the skill level of a properly trained healthcare professional.

In another aspect, the present invention provides compositions and dosage forms comprising atorvastatin hemi-calcium solvate forms and mixtures thereof. Compositions of the present invention include powders, granules, aggregates and other solid compositions comprising Form XVIII and / or Form XVIII of atorvastatin hemi-calcium solid crystalline. In addition, the XVIII and XVIII solid compositions 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 salts 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, dextrin and gelatin.

Additional excipients present within the scope of the present invention include binders such as acacia rubber, pregelatinized starch, sodium alginate, glucose and other binders used for wet and dry granulation and direct compression tableting. Excipients that may also be present in solid compositions of XV-type and XV-type atorvastatin hemi-calcium further include disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, and the like. have. Moreover, excipients may include tableting lubricants such as magnesium and calcium stearate and sodium stearyl fumarate; Flavoring agents; Sweeteners; Contains preservatives. Formulations include formulations suitable for parenteral (including subcutaneous, intramuscular and intravenous), inhalation and ocular administration. In any case the most appropriate route of administration will depend on the nature and severity of the condition to be treated, but the most preferred route of administration of the present invention is the oral route of administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy.

Formulations include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, troches and lozenges, 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 hemi-calcium after the loss of properties that distinguish the solid form of atorvastatin hemi-calcium. However, new forms of use for preparing such solutions (in addition to atorvastatin, to deliver solvates in certain proportions of solvates) are 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 enteric coatings. Enteric coating powder forms include substances such as phthalic acid cellulose acetate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, copolymers of styrene and maleic acid, copolymers of methacrylic acid and methyl methacrylate And may be used with suitable plasticizers and / or extending agents as needed. Coated tablets may have a coating on the tablet surface or may be tablets comprising powders or granules having an enteric coating.

Preferred unit dosage forms of the pharmaceutical compositions of the invention typically contain 0.5 mg to 100 mg of one of the novel atorvastatin hemi-calcium Form XVII and XVII or mixtures thereof, or a mixture with other forms of atorvastatin hemi-calcium. More generally, the compounding amount of the atorvastatin hemi-calcium form of the unit dosage form is 2.5 mg to 80 mg.

The crystalline forms of the present invention used to prepare pharmaceutical formulations may be substantially pure relative to other crystalline forms, ie, the pharmaceutical formulation may contain less than about 10 weight percent, preferably less than about 5 weight percent, of other crystalline forms of atorvastatin hemi-calcium, More preferably less than about 1% by weight. In particular, pharmaceutical formulations containing Form XVII can contain less than about 10%, preferably less than about 5%, more preferably less than 1% by weight of Form I. Pharmaceutical formulations containing Form XVII may contain less than about 10%, preferably less than about 5%, more preferably less than about 1% by weight of Form I. In certain embodiments, the pharmaceutical formulation may contain less than about 10%, preferably less than about 5%, more preferably less than about 1% by weight of amorphous atorvastatin.

Alternatively, the pharmaceutical formulations of the present invention may also contain either or both of XVIII and XVIII in a mixture of other forms of atorvastatin. However, the pharmaceutical formulations or compositions of the present invention contain 25-100% by weight, in particular 50-100% by weight, of one or more of XVIII or XVIII, based on the total amount of atorvastatin in the formulation or composition. It is preferred that the amount of the novel XVIII or XVIII of this atorvastatin hemi-calcium is 75-100% by weight, in particular 90-100% by weight. Very preferred amount is 95-100% by weight.

As used herein, "room temperature" or "RT" means a temperature of about 18-25 ° C, preferably about 20-22 ° C.

By "therapeutically effective amount" is meant an amount of a crystalline form sufficient to provide a beneficial effect on the disease and condition when administered to a patient to treat the disease or other undesirable medical condition. A "therapeutically effective amount" can vary depending on the crystalline form, the disease or condition of the patient being treated and its severity, and age, weight, and the like. The therapeutically effective amount of a given crystalline form is determined within ordinary skill in the art and does not require more than a routine experiment.

Certain methods of the invention include a crystallization step from a particular solvent. Those skilled in the art will understand that often crystallization conditions can be somewhat modified without affecting the crystalline forms obtained. For example, when atorvastatin hemi-calcium is mixed in a solvent to form a solution, it may be desirable to warm the mixture to completely dissolve the starting material. If the mixture is not transparent by heating, the mixture can be diluted or filtered. To filter, the hot mixture can be passed through a paper, glass fiber or other membrane material, or a purifying agent such as celite. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration device to prevent premature crystallization.

It is also possible to induce precipitation by changing the above conditions. A preferred method of inducing precipitation is to reduce the solubility of the solvent. The solubility of the solvent can be reduced, for example, by cooling the solvent. Some of the solvent may also be evaporated or an antisolvent may be added to induce precipitation.

The crystalline forms of the present invention can be distinguished by their PXRD patterns. The crystalline form has a unique PXRD peak position in the 2-40 ° 2θ range. According to these unique peak positions, those skilled in the art can identify the crystalline forms and also identify and quantify these crystalline impurities.

Those skilled in the art will appreciate that some uncertainty included in the PXRD measurement is generally around ± 0.2 ° 2θ for each peak. Thus, in the present application, the PXRD peak data is represented in the form of "PXRD pattern having peaks at ± 0.2 ° 2θ, such as A, B, C, etc.". This means that for a given crystalline form, the peak at A may appear anywhere between A ± 0.2 ° 2θ, the peak at B anywhere between B ± 0.2 ° 2θ, etc. That means you can. Some unavoidable uncertainty of individual peak identifications does not lead to uncertainty with respect to individual crystallographic identifications, since generally certain combinations of peaks within a certain range, rather than any particular peak, serve to clearly identify the crystalline form.

The particle size distribution (PSD) of the active ingredient is one of the main parameters of the formulation. For the particle size measurement, the following main methods can be used: sieve, sedimentation, electrozone sensing (coulter counter), microscopy, low angle laser light scattering (LALLS). It is preferable that the maximum particle size of the novel type of this invention is 500 micrometers. The particle size is also preferably less than 300 μm, less than 200 μm, less than 100 μm or less than 50 μm.

While the present invention has been described with reference to certain preferred embodiments, other embodiments will be apparent to those skilled in the art from the specification of the present invention. The invention was further defined with reference to the following examples describing in detail the methods of making and using the compositions of the invention. It will be apparent to those skilled in the art that many variations in both materials and methods may be practiced without departing from the scope of the present invention.

Example  One: XⅧ Mold manufacturing procedure

A slurry of atorvastatin hemi-calcium salt crystalline Form V (10 g) in acetone (70 ml) was stirred for 8 hours at room temperature to dissolve completely. The resulting solution was stirred for an additional 40 hours at room temperature to give a mass precipitate. Acetone (280 ml) was added to dilute the slurry. The product was isolated by filtration and dried in a vacuum oven at 40 ° C. for 20 hours to give 6.6 g of atorvastatin hemi-calcium salt crystal Form XVII. Acetone concentration was 13890 ppm (1.4%).

Example  2: XⅨ Mold manufacturing procedure

A slurry of atorvastatin hemi-calcium salt crystalline Form V (60 g) in acetone (420 ml) was stirred for 8 hours at room temperature to dissolve completely. The resulting solution was stirred for an additional 64 hours at room temperature to obtain a large precipitate. The product was isolated by filtration, washed with acetone (4 × 250 ml) and dried in a vacuum oven at 40 ° C. for 21 hours to give 59.4 g of atorvastatin hemi-calcium salt crystals XVII type. Acetone concentration was 58695 ppm (5.9%).

Claims (32)

Atorvastatin hemi-calcium salt acetone solvate. Crystalline atorvastatin hemi-calcium characterized by a PXRD pattern with peaks at 3.8, 8.0, 8.9 and 10.4 ± 0.2 ° 2θ. 3. The crystalline atorvastatin hemi-calcium of claim 2, further characterized by PXRD peaks at 3.0, 18.0, 18.8, 19.6, and 20.6 ± 0.2 ° 2θ. 3. The crystalline atorvastatin hemi-calcium of claim 2, having a PXRD spectrum substantially as shown in FIG. 3. The crystalline atorvastatin hemi-calcium of claim 2, which is an acetone solvate. 6. The crystalline atorvastatin hemi-calcium of claim 5, containing up to about 1.5% acetone. 7. The crystalline atorvastatin hemi-calcium of claim 6, containing up to about 1.4% acetone. 3. The crystalline atorvastatin hemi-calcium of claim 2, containing less than about 10% by weight of atorvastatin hemi-calcium Form I. 9. The crystalline atorvastatin hemi-calcium of claim 8, containing less than about 5% by weight of atorvastatin hemi-calcium Form I. 10. The crystalline atorvastatin hemi-calcium of claim 9, containing less than about 1% by weight of atorvastatin hemi-calcium Form I. Crystalline atorvastatin hemi-calcium characterized by a PXRD pattern with peaks at 3.3, 4.2, 5.6 and 8.2 ± 0.2 ° 2θ. 12. The crystalline atorvastatin hemi-calcium of claim 11, further characterized by PXRD peaks at 17.0, 19.2, and 22.0 ± 0.2 degrees two theta. 12. The crystalline atorvastatin hemi-calcium of claim 11, having a PXRD spectrum substantially as shown in FIG. 12. The crystalline atorvastatin hemi-calcium according to claim 11, which is an acetone solvate. 15. The crystalline atorvastatin hemi-calcium of claim 14, containing up to about 6.0% acetone. The crystalline atorvastatin hemi-calcium of claim 15, containing up to about 5.9% acetone. 12. The crystalline atorvastatin hemi-calcium of claim 11, containing less than about 10% by weight of atorvastatin hemi-calcium Form I. 18. The crystalline atorvastatin hemi-calcium of claim 17, containing less than about 5% by weight of atorvastatin hemi-calcium Form I. 19. The crystalline atorvastatin hemi-calcium of claim 18, containing less than about 1% by weight of atorvastatin hemi-calcium Form I. A process for the preparation of crystalline atorvastatin hemi-calcium characterized by a PXRD pattern with peaks at 3.8, 8.0, 8.9 and 10.4 ± 0.2 ° 2θ, (a) dissolving atorvastatin hemi-calcium in acetone to form a solution; (b) leaving the solution until a precipitate is obtained; And (c) recovering the precipitate How to include. The method of claim 20, wherein step (b) comprises stirring for about 40 hours to about 70 hours. The method of claim 20, wherein the temperature is about room temperature. A process for the preparation of crystalline atorvastatin hemi-calcium characterized by PXRD peaks at 3.3, 4.2, 5.6 and 8.2 ± 0.2 ° 2θ, comprising the steps of claim 20, wherein the amount of atorvastatin hemi-calcium and acetone is reduced to about 4 times to about 8 times. The method of claim 23, wherein the amount of atorvastatin hemi-calcium and acetone is increased by about 6 times. As a method for producing crystalline atorvastatin hemi-calcium XVIII or XVIII, (a) dissolving atorvastatin hemi-calcium in acetone to form a solution; (b) leaving the solution until a precipitate is obtained; And (c) recovering the precipitate How to include. The method of claim 25, wherein the ratio of atorvastatin to acetone in step (a) is about 1 g: 7 ml. 27. The method of claim 26, wherein the amount of atorvastatin dissolved in step (a) is adjusted to produce a precipitate of atorvastatin hemi-calcium XVIII in step (b). The method of claim 27, wherein the amount of atorvastatin dissolved in step (a) is about 10 g. The method of claim 25, wherein the amount of atorvastatin dissolved in step (a) is adjusted to produce a atorvastatin hemi-calcium XVIII precipitate in step (b). The method of claim 29, wherein the amount of atorvastatin dissolved in step (a) is about 60 g. A pharmaceutical composition prepared by combining at least one of the crystalline forms of atorvastatin hemi-calcium of claim 2 or 11 with at least one pharmaceutically acceptable excipient. A method of treating a patient suffering from hypercholesterolemia and hyperlipidemia, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 31.

Images