RU2325903C2 - Pharmaceutical formulation of atorvastatin - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutics. Dry granulated pharmaceutical formulation containing atorvastatin or its pharmaceutically acceptable salt, in combination with at least one other active medicinal agent, method of specified formulations production, sets including such formulations, and treatment of hypercholesterolemia and/or hyperlipidemia, osteoporosis, benign prostate hyperplasia (BPG) and Alzheimer's disease by using pharmaceutical formulation in amount providing therapeutic effectiveness. Offered pharmaceutical formulation of atorvastatin is characterised with good solubility, bioavailability, dosage homogeneity, and method of atorvastatin production with low content of impurities and adequate stability.

EFFECT: production of atorvastatin formulation, characterised with good solubility, bioavailability, dosage homogeneity, and method of atorvastatin production with low content of impurities and adequate stability.

6 cl, 6 ex, 5 tbl

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority of provisional patent application US No. 60/477917, filed June 12, 2003

FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions containing atorvastatin and its pharmaceutically acceptable salts, and to a method for their preparation, to kits containing such compositions, as well as to methods of using such compositions for the treatment of patients suffering from hypercholesterolemia and / or hyperlipidemia, as well as osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease.

BACKGROUND OF THE INVENTION

The conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the pathway of cholesterol biosynthesis. This stage is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase, not allowing it to catalyze this transition. As such, all statins are powerful lipid-lowering agents.

Atorvastatin calcium, disclosed in United States Patent №5273995, which is incorporated herein by reference, is currently sold as Lipitor ^®, having the chemical name [R- (R *, R * )] - 2- ( 4-fluorophenyl) -β, δ, dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) trihydrate and the formula

Atorvastatin and its pharmaceutically acceptable salts are selective, competitive inhibitors of HMG-CoA reductase. As such, atorvastatin calcium is a powerful lipid lowering compound and is therefore useful as a hypolipidemic and / or hypocholesterolemic agent, as well as in the treatment of osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease.

A number of patents have been issued disclosing atorvastatin, atorvastatin preparations, as well as methods and key intermediates for the preparation of atorvastatin. These include United States Patents Nos. 4681893; 5,273,995; 5003080; 5097045; 5,103,024; 5124482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5280126; 5,397,792; 5342952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,686,104; 5,998,633; 6087511; 6126971; 6433213 and 6476235, which are incorporated into this description by reference.

Atorvastatin can exist in crystalline, liquid crystalline and non-crystalline, as well as amorphous forms.

Crystalline forms of atorvastatin calcium are disclosed in United States Patents Nos. 5969156 and 6121461, which are incorporated herein by reference. In addition, crystalline forms of atorvastatin are disclosed in United States Patent No. 6,057,729, which is incorporated herein by reference.

In addition, a number of published international patent applications disclose crystalline forms of atorvastatin, as well as methods for producing amorphous atorvastatin. These include: WO 00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO 02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO 02/083637; WO 02/083638; WO 03/011826; WO 03/050085; WO 03/070702 and WO 04/022053.

It has been described that amorphous forms of a number of drugs show different solubility characteristics and, in some cases, a different nature of bioavailability compared to the crystalline form (Konno, T., Chem. Pharm. Bull., 1990: 38: 2003-2007). For some therapeutic prescriptions, one bioavailability pattern may be preferable to another.

Due to variations in dissolution rate, it may be useful to prepare atorvastatin preparations in either crystalline or amorphous form. For example, for some possible uses of atorvastatin (for example, for emergency treatment of patients with strokes, as described in Takemoto, M .; Node, K .; Nakagami, H .; Liao, Y .; Grimm, M .; Takemoto, Y .; Kitakaze , M .; Liao, JK, Journal of Clinical Investigation, 2001; 108 (10): 1429-1437) rapid onset of action can be extremely useful in improving the effectiveness of the drug.

The preparation of atorvastatin solid preparations is described in United States Patents Nos. 5686104 and 6126971. In the method described therein, atorvastatin is combined with a stabilizing agent such as an alkali metal salt and excipients and wet granulated using a combination of water and a surfactant (Tween 80 ) Since alkali metal salts can sometimes affect the bioavailability of atorvastatin, there remains the need to present atorvastatin in a preparation to minimize the level of alkali metal salts.

To obtain and store standard dosage forms of atorvastatin, it is important to provide the active drug in its pure form. In addition, it is desirable to achieve such high purity and stability using as simple a preparation as possible. There remains a need to provide simple preparations and methods for preparing standard dosage forms of atorvastatin, which have low levels of impurities and provide adequate stability to provide commercially acceptable shelf life of dosage forms.

Since atorvastatin is a very effective drug, the preparations of this drug are usually quite diluted to obtain dosage forms of an adequate size for the manufacture and treatment of patients. When a drug is used in a diluted form, there is a risk that the segregation of the drug and excipients in the processes prior to the preparation of the drug in the final dosage form may result in some unit dosage forms being hypo- or hyper-effective. Monitoring the effectiveness of unit dosage forms is necessary to prevent individual patients from receiving the wrong and subtherapeutic or side-generating dose of the drug. Granulation is one way to prevent segregation. Although excipients can be selected so that unit dosage forms can be obtained without a granulation step, as described in the United States patent application filed by the same applicant, the file number of attorney PC25684, granulation can ensure that the drug and excipients are connected together in this way that segregation will not occur and the size of the granular particles will provide good fluidity. Wet granulation is one of the possibilities of producing atorvastatin in a form with a low probability of segregation and good fluidity (see the United States patent application filed by the same applicant, file number of attorney PC25685. However, wet granulation requires the preparation to be exposed to water and / or solvents. Such exposure increases the risk that the solid-state form of atorvastatin may change (for example, crystallize or change polymorphic form) or chemically split. Since the amount and rate of addition of the liquid will depend on factors such as the volume and surface area of the wet granulation vessels and the exact particle size of the drug and excipients used in a particular manufacturing period, there may be difficulties in scaling the processes wet granulation (for example, inconsistent performance). Therefore, it is an object of the present invention to propose atorvastatin such methods and preparations with and use of dry granulation in which segregation is minimized, flow of said composition is acceptable for commercial unit dosage forms, the drug is not exposed to solvent and is applied robust (scalable) process.

In dry granulation processes, usually a drug and at least some of the excipients are pressed together with the formation of tapes or bars. These pressed materials are then ground to a suitable size to prevent drug segregation and to provide good fluidity in the manufacturing process of unit dosage forms. The authors found that while the drug itself is pressed with the formation of bars, when grinding, this material mainly turns back into a fine powder with poor flow properties. Therefore, there remains a need to provide compositions suitable for dry granulation of atorvastatin, which will provide adequate drug flow, so that standard dosage forms with good weight control can be obtained.

The aim of the present invention is to provide compositions and methods for the manufacture of dosage forms of atorvastatin having good dosage uniformity, dissolution rate and bioavailability. Another objective of the present invention is to provide a stable and pure composition of atorvastatin in crystalline or amorphous form with minimal addition of alkali metal salts.

SUMMARY OF THE INVENTION

A first aspect of the present invention is a dry granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof.

A second aspect of the present invention is a method for producing a dry granulated atorvastatin pharmaceutical composition comprising:

a) combining atorvastatin or a pharmaceutically acceptable salt thereof and one or more excipients suitable for use in the dry granulation step;

b) mixing the mixture in a mixer;

c) pressing the mixture;

d) grinding, grinding or sieving the pressed material;

d) the possible addition of additional excipients and mixing the combination to obtain a composition.

A third aspect of the present invention is a dry-granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one other active drug.

A fourth aspect of the present invention is a method for manufacturing a dry-granulated atorvastatin pharmaceutical composition comprising:

a) combining atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one other active drug and one or more excipients suitable for use in the dry granulation step;

b) mixing the mixture together in a mixer;

c) pressing the mixture;

d) grinding, grinding or sieving the pressed material;

d) the possible addition of additional excipients and mixing the combination to obtain a composition.

A fifth aspect of the present invention is a therapeutic or commercial kit containing a container and a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, by dry granulation.

A sixth aspect of the present invention is a method of using the atorvastatin dry-granulated composition for treating patients suffering from hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

Atorvastatin can be readily prepared as described in United States Patents Nos. 4,681,893, 5,273,995 and 5,969,156, which are incorporated herein by reference. Atorvastatin hemi-salt is currently marketed as Lipitor ^® .

Atorvastatin exists in a number of morphological forms ranging from highly crystalline forms to forms with varying degrees of disorder. Some of these disordered forms nevertheless have some structure, as evidenced by X-ray powder diffraction patterns. For the purpose of the present invention, all forms of atorvastatin benefit from the present invention and are included in the scope of the present invention. Partially or completely disordered forms of atorvastatin particularly benefit from the invention. Partially or completely disordered forms of atorvastatin that are amorphous or predominantly amorphous benefit most from the present invention. Such forms can be obtained, for example, from crystalline atorvastatin using the methods disclosed in United States Patent No. 6087511, which is incorporated herein by reference. Alternatively, the amorphous substance can be obtained by the methods disclosed in the United States patent application belonging to the same applicant, attorney case number PC-25825. For the practical implementation of the present invention, non-crystalline and crystalline atorvastatin can be obtained by any method known in the art. Preferred forms of atorvastatin are described in United States patents 5969156, 6121461 and 6605729 and in international patent applications WO 01/36384, WO 02/41834, WO 02/43732, WO 02/051804, WO 02/057228, WO 02/057229, WO 03 / 011826, WO 03/050085, WO 03/070702 and WO 04/022053, which are incorporated herein by reference.

Atorvastatin can be used in the form in which it is obtained, or it can be processed in a way that changes the physical properties of the particles. For example, the material may be milled by any method known in the art. Non-exclusive examples of such methods include mechanical grinding and jet grinding. Particles obtained either directly during the formation of atorvastatin or after the grinding operation preferably have average particle diameters in the range of 1-200 μm; more preferably 5-150 microns.

Pharmaceutically acceptable salts of the addition of a base to atorvastatin are formed by metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine, chlorprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, for example, Berge, SM, et al., Pharmaceutical salts, J. Pharm. Sci. 1977; 66: 1).

Salts of the addition of a base to atorvastatin are obtained by contacting the free acid form with a sufficient amount of the desired base to obtain a salt in the traditional way. The free acid form can be restored by contacting the salt form with an acid and isolating the free acid in a conventional manner. Free acid forms differ somewhat from the corresponding salt forms in some physical properties, such as solubility in polar solvents, but otherwise for the purposes of the present invention, salts are equivalent to their corresponding free acids. In addition, atorvastatin can exist in unsolvated forms, as well as in solvated forms, including hydrated forms. In general, it is contemplated that solvated forms, including hydrated forms, are included within the scope of the present invention.

Those forms of atorvastatin that are at least partially disordered, or a mixture of crystalline and disordered forms of atorvastatin, benefit most from the present invention. By “partially disordered” is meant that the line width (peak width at half peak height) of any of the peaks measured using X-ray powder diffraction (PXRD) has a 2-theta value greater than about 2 °. The amorphous or predominantly amorphous form of atorvastatin, which particularly benefit from the present invention, is characterized by very broad, uncharacteristic peaks. It should be noted that the combination of crystalline and partially disordered forms of atorvastatin will show both sharp (i.e., 2-theta values less than 2 °) and wide peaks (i.e., more than 2 °), and such combinations of forms benefit from of the present invention.

Atorvastatin has been found to be an effective drug even at relatively low doses. Indeed, by maintaining a low dose for a given patient, side effects can be minimized while maintaining drug activity. Therefore, it is desirable to obtain atorvastatin in a form capable of providing the patient with a low dose. For the purposes of the present invention, the dose provided by the final dosage form of atorvastatin is preferably between 0.5 and 120 mgA (where mgA means milligrams of the active drug based on the free acid); more preferably between 5 and 80 mgA.

For convenience and ease of patient compliance, most drugs are delivered in the form of unit dosage forms. For solid dosage forms, such unit dosage forms are usually in the form of tablets, capsules, sachets, chewable tablets or instant dosage forms. In the present invention, the dosage form is preferably presented in the form of a capsule or tablet, most preferably in the form of a tablet. The preparation of these forms includes, as a necessary step, some type of powder filling, either by volume or by weight. For example, in the manufacture of tablets and capsules, the powder is loaded by volume into a punch or capsule, respectively. In order for the standard dosage forms to have the same activity (i.e. the amount of the drug per standard dosage form) within acceptable limits (relative standard deviation, RSD, less than 6% for compliance with Stage I and less than 7.8% for compliance with Stage II Pharmacopoeia United States, USP Guide), there should not be any significant segregation of the active drug for excipients. This is especially important for heavily diluted forms. The present invention discloses compositions that provide reproducible activity of a fixed mass of active atorvastatin with the addition of excipients. In addition, such activity control does not stop during the manufacturing process of unit dosage forms. In such compositions, before converting them to standard dosage forms based on them, atorvastatin is present with an activity deviation (mgA per gram of mixture) of less than 7.8% RSD; more preferably less than 6%. In addition, the present compositions provide good powder flowability, so that weight control continues to be exercised between the unit dosage forms obtained from such compositions (i.e., the deviation by weight of the unit dosage forms obtained from such compositions is minimal). Preferably, such compositions provide unit dosage forms with a weight control within 6% of RSD; more preferably within 5%; even more preferably within 4%. The combination of mass control with activity control allows us to provide, using the present compositions, unit dosage forms with atorvastatin activities per unit dosage form having an RSD of preferably less than 7.8%; more preferably less than 6.0%.

Measurement of the activity of standard dosage forms of atorvastatin is necessary when determining deviations in activity between standard dosage forms. Such activity is best determined during the extraction process against a standard with independently determined levels of drugs. Activity analysis is best carried out using reverse-phase high performance liquid chromatography (HPLC) methods similar to those known in the art for standards. RSD definitions for the purposes of this study are best carried out using sampling during the formation of a standard dosage form. More specifically, samples of unit dosage forms can be taken during their preparation at various points in time (at the beginning, middle and end of the process). In determining the RSD value, at least three unit dosage forms from each section should be evaluated. An alternative analytical technique for determining the activity of a sample of a drug involves the use of absorption spectroscopy in the ultraviolet and visible regions. In this technique, the absorption corresponding to atorvastatin is used to quantify the concentration of atorvastatin in the sample (care should be taken that no excipient has interfering absorption), as is known in the art.

The present invention discloses methods and compositions that provide a clean and stable form of atorvastatin. The term “impurities” means substances in a drug substance that are present starting from the synthesis and purification process, and any drug-based substances formed in the preparation of a unit dosage form. The term "decomposition product" refers to any drug-based substances formed after the preparation of a unit dosage form. The analysis of impurities and decomposition products is carried out using reverse phase HPLC methods for the extracted samples, as is known in the art. Calculations of the amount of impurities and decomposition products are expressed as a percentage of the total area of the peak (s) of decomposition products or impurities divided by the percentage of the total area of all peaks related to the drug.

The particle sizes of atorvastatin and excipients play an important role in the efficiency of the dry granulation process in preventing segregation. As such, average particle sizes can be measured using a laser diffraction particle size measuring instrument, for example manufactured by Sympatec GmbH (Goslar, Germany). The average particle size for the purposes of the present invention can be considered such a size at which 50% of the particles have a diameter less than the specified value. Alternatively, particle size can be estimated using sieve analysis. To assess the average particle size, use the percentage of the total mass of the substance remaining on the sieves of certain sizes. The average particle size is the size of the sieve, which allows you to sift approximately 50% of the mass of the substance (50% is delayed).

In the preparation of atorvastatin compositions by dry granulation, combinations of diluents, binders, disintegrants, flavoring agents and lubricants are used to provide the properties required for a particular unit dosage form, as is known in the art. For example, to obtain tablets, such a combination provides sufficient compressive strength of the tablet and at the same time provides rapid disintegration in vivo. Although there is a large degree of freedom in obtaining an atorvastatin preparation satisfying these conditions, usually such preparations contain about 1-40% (w / w) of the drug, about 5-10% baking powder, about 0-10% binding agent, and about 0 , 5-2% of a lubricating agent, with the remaining percentage being diluents according to the invention. Preferred disintegrants include carboxymethyl cellulose, hydroxypropyl cellulose (low substituted), microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium aluminosilicate, methyl cellulose, potassium glycolamine, potassium glycolamine, potassium glycolamine, potassium glycolamine. Preferred binders include gum arabic, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, dextrin, gelatin, guar gum, hydroxypropyl methyl cellulose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polyethylene oxide, polymethacrylate, polymethine acrylate, polymethine acrylate. Preferred lubricants include calcium stearate, glyceryl palmitostearate, magnesium oxide, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and magnesium stearate.

To improve the fluidity of the atorvastatin compositions and minimize the segregation from excipients during the dry granulation process, the drug can be pressed with excipients. However, the authors found that in the case of atorvastatin, due to the fragility of this drug, only some excipients form acceptable dry granules with this drug. Acceptable excipients can be defined as those excipients which, when dry granulated (i.e., pressed and crushed) in the presence of atorvastatin, provide a significant reduction in the amount of small drug particles remaining in the mixture that are not related to the excipient. For the purpose of the present invention, fine particles of a drug (or "fine fraction") can be defined as particles passing through a 200 mesh sieve. The authors can also define the granulation factor as: granulation factor (FG) = 1 - [(percentage of atorvastatin in the form of a fine fraction in granulation) / (percentage of atorvastatin in the form of a fine fraction in an ungranulated mixture)]. To determine the granulation factor for a given excipient or combination of excipients, a drug mixture with selected excipients is first prepared. This mixture is sieved through sieves using a sieving device such as Sonic Sifter ^™ (Alien Bradley Sonic Sifter, Advantech Manufacturing, New Berlin, Wl). The percentage of atorvastatin in the form of a fine fraction is determined by multiplying the mass by the activity of the fine fraction and dividing by the total weight of the drug in the mixture. The same analysis can be carried out on a substance that has been subjected to dry granulation with atorvastatin. From these analyzes, the overall ability of a given excipient or set of excipients to form preparations with a low tendency to segregation can be determined. The authors found that excipient or combinations of excipients with atorvastatin, which provide a minimal tendency to segregation in the process of obtaining a standard dosage form, can be characterized as having granulation factors preferably between 0.4 and 1.0; more preferably between 0.5 and 1.0; and even more preferably between 0.6 and 1.0.

The authors found that when determining excipients suitable for dry granulation with atorvastatin and compressing mixtures under conditions feasible with dry granulation on a commercial scale, it is important to determine the true tendency of atorvastatin mixtures to segregate. One of the important criteria that should be taken into account when granulating atorvastatin is the solid fraction of briquettes or mixture tapes, especially when the granulate is subjected to an additional pressing stage, for example, as it happens during tablet formation. The solid fraction is an indicator of the amount of compression remaining in the material. As such, the first step involves determining the true density of the mixture, i.e. density of substances without air spaces between particles. This density can be measured using methods such as helium pycnometry or similar methods, as is known in the art. Also, this value can be estimated as the weighted average of the true density values of each of the components. The solid part of the dry granulate is the ratio of the density of the briquette (or tape) to the true density of the material from which this briquette is made. The regulation of the solid part is achieved by adjusting the compressive forces during the pressing process. The authors found that in order to achieve good binding of atorvastatin while ensuring sufficient compressibility for subsequent tabletting, the solid fraction in the granules after granulation should preferably be between 0.55 and 0.85; more preferably between 0.60 and 0.80.

Another criterion for achieving acceptable dry atorvastatin granules is the tensile strength of briquettes or ribbons. The tensile strength of a bar (or tape) can be measured using appropriate equipment known in the art, such as, for example, a CT5 tensile strength tester (Engineering System (NOTTM), Nottingham, England). For this measurement, preferably rectangular briquettes having dimensions of 10 × 22 × 2 mm are used. The authors found that the preferred tensile strength for finally obtained acceptable granules of atorvastatin is from 0.5 to 7.0 megapascals (MPa); more preferably from 0.8 to 6.0 MPa. Preferred are combinations of such substances with atorvastatin, which can achieve the preferred tensile strength in the range of preferred solid parts. Examples of such substances include lactose and microcrystalline cellulose.

An example of a substance unable to achieve the desired tensile strength is mannitol.

By constructing the relationship between the solid part and the tensile strength, it is possible to find the interval of solid parts suitable to provide the preferred tensile strength for a given mixture of atorvastatin and excipient or a combination of excipients. The authors found that interpolation of the measured values can be applied, assuming an exponential approximation of the least squares method.

Preferred excipients are diluents, which in a preparation with atorvastatin are preferably contained in an amount of more than or equal to 40% (wt.) Of the total composition; more preferably more than 50% (wt.), even more preferably more than 60% (wt.). Preferred diluents when tested in binary mixtures with atorvastatin provide granulation factors, preferably between 0.4 and 1.0; more preferably between 0.5 and 1.0; and even more preferably between 0.6 and 1.0. As such, possible diluents are defined in "Handbook of Pharmaceutical Excipients, 3rd Edition" (A.H. Kibbe, Editor, Pharmaceutical Press, London, 2000). These include the following non-limiting examples: calcium phosphate, calcium sulfate, calcium carboxymethyl cellulose, cellulose, cellulose acetate, dextrates, dextrin, dextrose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, magnesium oxide , maltodextrin, maltose, polymethacrylates, pregelatinized starch, silicate microcrystalline cellulose, sodium chloride, sorbitol, starch, sucrose and talc.

When determining excipients suitable for use in dry granulation with atorvastatin, it is important to use the specific shape and particle size of atorvastatin that are desirable for the final dosage form. Similarly used excipient or combination of excipients will have properties that depend on the size and method of obtaining particles. Since pressing excipients with atorvastatin during the dry granulation process is generally more easy with excipients having smaller particle sizes, preferred excipients are generally smaller than those that would be preferred without granulation. As such, preferably excipients have average particle sizes between 20 and 200 microns, more preferably between 40 and 150 microns. These particle size ranges correspond to 50% by weight of the mixture passing through sieves having openings between 635 mesh (ASTM number, American Society for Testing of Materials, and 70 mesh, more preferably between 325 and 100 mesh . The preferred size for a given excipient depends on the specific properties of the form of atorvastatin used and should be determined experimentally in each case.

Therefore, more preferred excipients in combination with atorvastatin are diluents that provide large granulation factors, can achieve high tensile strength and have preferred average particle sizes preferably between 20 and 200 microns, more preferably between 40 and 150 microns. Particularly preferred excipients include microcrystalline celluloses having an average particle size of from 20 to 40 microns (such as Avical ^™ PH105, available from FMC Biopolymer, Philadelphia, PA), lactoses with a particle size interval of from 80 to 150 microns (such as dried when sprayed, the monohydrate of the substance or FastFlo ^TM 316, available from Foremost Farms, Rothschild, WI; or anhydrous, quality, for direct tabletting, available from Quest International, Flavors & Food Ingredients CCL, Norwich, NY), xylitol (e.g. , quality C granular, available from Danisco Sweet eners, Thompson, IL), mannitol (such as Mannogen ^TM 2080 granular, available from SPI Polyols, New Castle, DE), sucrose (such as Di-Pac ^TM , available from Tate & Lyie Co. American Sugars Inc Brooklyn, NY) and dibasic anhydrous calcium phosphate (such as A-Tab ^™ , available from Rhodia, Chicago Heights, IL). Preferred preferred diluents comprise more than 50% (wt.) Of the diluent content of the atorvastatin composition by dry granulation; more preferably more than 60% (wt.), even more preferably more than 70% (wt.).

The standard dosage forms of atorvastatin formed using the dry granulation step with preferred excipients show a low level of impurities and degradation products related to the drug. Unexpectedly, such a low level of impurities and decomposition products was found even in the absence of added alkalizing agents or alkaline earth metal salts. Even more unexpectedly, such a low level of impurities and decomposition products is maintained even when the atorvastatin used was at least to some extent a disordered form of the drug. In particular, it was found that while the control standard dosage forms of atorvastatin granulated by the wet method exhibit high levels of degradation of the drug, the standard dosage forms granulated by the dry method have greater stability. Preferred are those standard dosage forms of atorvastatin, granularized by dry method, which contain a total of not more than about 2% of impurities and / or degradation products related to the drug, determined by the percentage of area of impurities / degradation products relative to the total area of all peaks having relation to the drug, as determined by HPLC; more preferably they contain less than 1%; even more preferably less than 0.7%. In addition, dry granular unit dosage forms of atorvastatin are preferred that provide stability such that when stored at 40 ° C and 75% relative humidity (OB) for four weeks, these unit dosage forms contain a total of no more than about 2 % impurities and decomposition products related to this drug, determined by the percentage of the area of impurities / decomposition products relative to the total area of all peaks related to l a medicament, as determined by HPLC; more preferably they contain less than 1%; even more preferably less than 0.7%.

Atorvastatin undergoes two main decomposition processes: lactonization and oxidation. The lactone is formed by internal condensation (loss of water) of alcohol and carboxylic acid with the formation of a six-membered ring. It is a major decomposition product of amorphous atorvastatin found by wet granulation and tablet formation, as described in United States Patents Nos. 6126971 and 5686104, especially in the absence of alkaline earth metal salts. The authors unexpectedly found that the level of lactone in standard dosage forms, both initial and when stored under accelerated aging at elevated temperature and humidity, can be significantly reduced by combining the excipients present and preparing standard dosage forms using a dry granulation process. Preferably, the level of atorvastatin lactone in standard dosage forms is less than 2% (determined by the ratio of the sum of the lactone peaks to the total peak area when using HPLC) after the preparation of these standard dosage forms and their storage at 40 ° C / 75% RH (where OB is relative humidity) for four weeks; more preferably less than 1%.

To minimize bioavailability problems and possible interactions with other drugs in combined dosage forms, in the practical implementation of the present invention, the level of alkaline earth metal salts in the preparation is preferably about 0-5% (wt.); more preferably about 0-3%; most preferably about 0-2%. It is also preferred that the level of other alkalizing agents in the formulation is about 0-5% (w / w); more preferably about 0-3%; most preferably about 0-2%.

Dry granulation of atorvastatin with excipients is preferably carried out by initially mixing atorvastatin with at least some of the preferred excipients. Preferably, the excipients in this mixture comprise from 50 to 95% (wt.) Of the mixture. This mixing process is preferably carried out using a high shear mixer, a V-mixer (or another double-shell mixer), a hopper mixer or a Turbula ^™ mixer shaker (commercially available from Willy A. Bachofen AG Maschinefabrik, Basel, Switzerland). Mixing is usually carried out first without adding a lubricant for a time sufficient to ensure complete mixing. At this point, a lubricant is usually added, followed by a short (approximately 1-10 minutes) period of additional mixing. This mixture is then pressed into bars or ribbons using a tablet press (such as a single position press or rotary tablet press). In the first case, the briquettes whetstones are obtained using combinations of a flat-surface matrix and punches. In both cases, the density of the briquettes or ribbons is preferably selected to obtain briquettes or ribbons having a tensile strength of from about 0.5 to 7.0 MPa, more preferably from about 0.8 to 6.0 MPa. These briquettes or ribbons are preferably milled, ground or sieved. Particle size is reduced by optimized methods designed to provide good performance while providing a suitable particle size distribution known in the art. Preferably, less than 30% (wt.) Of the crushed material should pass through a 200 mesh sieve and more than 70% (wt.) Should pass through a 60 mesh sieve. After grinding the material, other excipients can be added extragranularly to obtain the final mixture for the manufacture of unit dosage forms. These additives are preferably mixed using a high shear mixer, a V-mixer (or another double-shell mixer), a hopper mixer, or a Turbula ^™ shaker mixer. Mixing is usually carried out first without adding a lubricant for a time sufficient to ensure complete mixing. At this point, a lubricant is usually added, followed by a short (approximately 1-10 minutes) period of additional mixing. From this point on, granular material can be used to produce unit dosage forms. Such unit dosage forms include sachets, tablets, instant dosage forms, chewable dosage forms, and capsules. Preferred dosage forms include tablets and capsules. In the case of tablets, it may be desirable to coat them with a film intended to provide ease of swallowing, a patented or identifying appearance and / or protection of a given dosage form. The final dosage form is then packaged using procedures known in the art. For the present invention, the package is preferably in the form of cold formed foil-foil blisters, plastic blisters or hermetically sealed bottles containing desiccants. If desired, the package may contain active oxygen scavengers, as disclosed in EP1243524A2, which is incorporated herein by reference.

In the manufacture of unit dosage forms of atorvastatin using dry granulation, such unit dosage forms can be prepared without the manufacture of these preparations using methods not suitable for commercial production. For example, even granular material with a tendency to segregate can be loaded directly into the capsule. Therefore, the present invention is preferably used in conjunction with high-speed manufacturing equipment. More specifically, preferred formulations are provided with dry granules to control activity during production of a unit dosage form of less than 7.8% RSD (more preferably less than 6.0% RSD) using unified hardware to produce unit dosage forms at a speed greater than 10,000 unit dosage forms forms per hour; more preferably more than 25,000 standard dosage forms per hour; most preferably more than 50,000 unit dosage forms per hour. Preferred standardized hardware or mechanisms for the manufacture of unit dosage forms include standardized rotary tablet presses and standardized commercial capsule filling mechanisms. Non-exclusive examples of commercial rotary tablet presses include those manufactured by Niro Pharma Systems (Columbia, MD), Kilian and Company (Horsman, PA), Korsch (Berline, Germany) and Elizabet-Hata International (North Huntington, PA). Non-exclusive examples of commercial capsule filling equipment include those made by Capsugel (Morris Plains, NJ) and CaPlus Technologies (Phoenix, AZ).

The present invention provides atorvastatin compositions that are particularly well suited for products combined with other drugs, since granulation does not require the presence of a possibly solvent and / or otherwise destabilizing solvent and nevertheless maintains the uniformity of the atorvastatin content. This is especially true when the second drug (with excipients combined with it) can destabilize atorvastatin. Non-limiting examples of drugs that can benefit from the combination with atorvastatin compositions and methods of the invention include torcetralib and amlodipine and their pharmaceutically acceptable salts.

The atorvastatin compositions of the present invention can be combined with at least one other active drug to form unit dosage forms. Preferred unit dosage forms include tablets and capsules. When combining the atorvastatin composition with at least one other active drug to form a unit dosage form, the following non-limiting list provides possible options for such unit dosage forms: a) a mixture of atorvastatin granulate with another active drug per se (i.e., extragranular the addition of another drug to the dry granular composition of atorvastatin), as a mixture with excipients (i.e., the extragranular addition of another drug the agent and excipients for the dry granular composition of atorvastatin) or in the form of a granulate (i.e., a mixture of a granulate of another drug with a composition of atorvastatin, granulated by a dry method), formed into tablets or capsules; b) one dry granule of atorvastatin with another drug, molded into tablets or capsules; c) a two-layer tablet containing dry granular atorvastatin in one layer and another drug and possibly excipients in another layer.

The present invention relates to the treatment of diseases and conditions in a patient, such as hyperlipidemia and / or hypercholesterolemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease, with atorvastatin or its pharmaceutically acceptable salt, as described above, which can be introduced in a standard a dosage form having low levels of decomposition products and / or impurities contained in a therapeutic package or kit. The kit includes a unit dosage form and container. Typically, the kit includes instructions for administering this unit dosage form. The container may have any convenient form or shape known in the art, for example, it may be a paper box, a glass or plastic bottle or a blister pack containing individual dosage forms squeezed from the back according to the treatment regimen.

The following non-limiting examples illustrate preferred methods for the preparation of and use of the pharmaceutical compositions of the present invention for the inventors.

EXAMPLE 1

GENERAL METHOD FOR PRODUCING SPRAY-DRIED AMORPHOUS ATORVASTATIN

Spray-dried amorphous atorvastatin, an example of disordered atorvastatin, as described earlier in the Detailed Description of the invention and used in the following examples, was obtained in accordance with the simultaneously filed US patent application belonging to the same applicant, attorney case number PC-25825, by initial dissolution of calcium salts of atorvastatin (US Patent No. 5,273,995) in methanol to obtain a 5% (wt.) solution. This solution was sprayed in a Niro PSD-1 spray dryer at a speed of 170 g / min, using nitrogen as the spray gas. The inlet temperature was 195 ° C and the outlet temperature was 60 ° C. After spray drying, the powder was dried in trays in a dryer at 40 ° C for 12 hours.

EXAMPLE 2

Obtaining Amorphous Atorvastatin Tablets Using Moist Granulation

The following substances were added to a 950 cm ³ yellow bottle: 2.59 g of spray-dried amorphous atorvastatin obtained as described in Example 1, 78.00 g of microcrystalline cellulose (Avicel ^™ PH102, FMC Bioplymer, Philadelphia, PA), 101.41 g lactose (aqueous, Foremost Farms USA, Rothschild, Wl), 6.00 g of croscarmellose sodium (Ac-Di-Sol ^TM FMC Biopolymer, Philadelphia, PA) and 4,000 g of hydroxypropyl cellulose (Klucel ^TM EXF, Hercules Incorporated, Aqualon Division, Wilmington, DE). The substances were mixed in a bottle for 10 minutes using a Turbula ^™ agitator (Turbula Shaker Mixer, Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland) and then unloaded and sieved through a 30 mesh screen to liquidate the lumps. The material was then put back into the bottle and mixed using Turbula ^™ for another 10 minutes. Material mixed in a bottle was added to a Procept Mi-Mi-Pro wet shear apparatus (Pro-CepT nv, B-9060 Zelzate, Belgium) using a 1.7 L capacity. The materials were mixed in dry form for two minutes with a knife rotation speed of 1000 revolutions per minute (rpm) and an impeller rotation speed of 400 rpm, then the impeller rotation speed was increased to 600 rpm, while maintaining the rotation speed of the knife. At this point, 90 ml of water was added at a rate of 30 ml / min over three separate administrations (60 ml, 15 ml, 15 ml) with a total wet mixing time of 5.5 minutes. A good granulate formed with a minimum amount of fine particles. This material was discharged and sifted manually using a 10 mesh sieve. The sieved material was dried by placing it on a polyethylene-coated tray in a Gruenberg ^TM dryer (Gruenberg Oven Co., Willliamsport, PA) with hot air at 50 ° C. for 16 hours. The dried material was then milled using a Fitzpatrick L1A mill (The Fitzpatrick Co., Elmhurst, IL) with a 0.040 "Conidur crushing screen at 500 rpm. 5.469 g Ac-Di-Sol ^{TM was} added to 175.0 g of the mixture and mixed in bottle (950 cm ³ yellow glass bottle) using a Turbula ^™ stirrer for 5 minutes, then 1.822 g of magnesium stearate (Mallinckrodt Inc., St. Louis, Mo.) were added and the mixture was mixed using Turbula ^™ for another 3 minutes to complete preparation: Tablets (approximately 250) were made using an F-press (Manestry F-Pres, Liverpool, United Kingdom), with standard round concave shell udovaniem (SRC) 13/32 ", with a target weight of 450 mg (± 3%) and a predetermined hardness 12 kP (range 10-14 kP). As a result, 12 tablets were placed in 30 cm ³ bottles of high density polyethylene (HDPE), closed lids for induction heating (HIS), using an apparatus for closing by induction heating (Enercon Industries Corp., Menomonee, Wl). Samples were stored for 4 weeks at 40 ° C and 75% relative humidity (OB). Atorvastatin lactone levels were analyzed in the samples by adding one tablet to 50 ml of a 1: 1 (v: v) mixture of 0.05 M citrate-ammonium buffer (pH 7.4): acetonitrile and shaking for 20 minutes. The substance was then filtered using a Gelman Acrodisc polytetrafluoroethylene membrane (pore size 0.45 μm) and analyzed using high-performance liquid chromatography (HPLC) (Phenomenex, Ultremex C18 column, 25.0 cm × 4.6 mm, HPLC HP 1100 series, Agilent Corp., Wilmington, DE, injection volume 20 μl, flow rate 1.5 ml / min; mobile phase 53:27:20 (v: v: v) 0.05 M ammonium citrate (pH 4.0): acetonitrile : tetrahydrofuran; detection at 244 nm). It was found that the lactone level was 25.4% (based on the ratio of the lactone peak area to the total area of all peaks).

EXAMPLE 3

OBTAINING AMORPHOUS CALCIUM ATORVASTATIN TABLETS USING DRY GRANULATION

The following substances were added to a 950 cm ³ yellow bottle: 2.59 g of amorphous atorvastatin calcium obtained as described in Example 1, 78.00 g of microcrystalline cellulose (Avicel PH102 ^TM , FMC Corp., Philadelphia, PA), 101.41 g of aqueous lactose (REG 310; Foremost Farms USA, Rothschild, Wl), 4.00 g of hydroxypropyl cellulose (Klucel EXF ^TM ; Aqualon, Wilmington, DE), 6.00 g of croscarmellose sodium (Ac-Di-Sol ^TM FMC Corp., Philadelphia, PA) and 1.00 g of magnesium stearate (Mallinckrodt Co., St. Louis, MO).

The combination of the above ingredients was mixed using a Turbula ^™ agitator (Glen Mills, Clifton, NJ) for 10 minutes. The mixture was then passed through a stainless steel sieve (30 mesh) to eliminate lumps, and then mixed for another 10 minutes. The mixture was then subjected to dry granulation by briquetting with a 1 "flat surface tool using a Manesty single-position F-press (Manesty, Liverpool, UK) in 1.00 g briquettes with a strength of 3.5 kP (tablet strength was tested using Schleuniger Tablet Hardness Tester , Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland). Briquettes were milled using a Fitzpatrick L1A mill (Fitzpatrick Co., Elmhurst, IL) with a 0.040 "Conidur crushing screen at 500 rpm. The resulting milled material was returned to a glass bottle into which 6.00 g of croscarmellose sodium was added, and the contents were mixed for 5 minutes. Finally, 1.00 g of magnesium stearate was added to the yellow glass bottle and the contents were mixed using Turbula for 3 minutes. The tablets were made using the single-position F-npecca Manesty. A 13/32 "standard concave surface matrix (SRC) and punch were used to make tablets weighing 450 mg each. The average tablet strength was 13 kilopascals (kPa) in the range of 12-14 kPa. The average tablet weight was 447.9 mg with RSD 0.7%. Tablets were packaged, stored, and analyzed as described in Example 2, which showed atorvastatin lactone levels of 0.17% (based on the percentage of peak area of the lactone).

EXAMPLE 4

OBTAINING AND ANALYSIS OF MIXTURES OF AMORPHOUS CALCIUM ATORVASTATIN AND EXCIPIENTS - 5% OF THE MEDICINE

To each of ten 60 cm ³ yellow bottles was added 500 mg of amorphous atorvastatin, prepared as described in Example 1, and 9.4 g of one of the following excipients:

(a) xylitol (C granular, Danisco Sweeteners, Thomson, IL);

(b) mannitol (Mannogen ^TM 2080 granulated, SPI Polyols, New Castle, DE );

(c) sucrose (compressible ^{sugar, White Di-Pac TM, Tate} & Lyie Co. American Sugars Inc, Brooklyn, NY);

(d) lactose (spray dried monohydrate, Foremost Farms, Rothschild, Wl);

(e) lactose (anhydrous, direct tablet quality, Quest International, Flavors & Food Ingredients CCL, Norwich, NY);

(e) lactose (Fast Flo ^TM 316, Foremost Farms, Rothschild, Wl);

(g) microcrystalline cellulose (Avicel ^™ PH102, FMC Biopolymer, Philadelphia, PA);

(h) microcrystalline cellulose (Avicel ^™ PH105, FMC Biopolymer, Philadelphia, PA);

(i) microcrystalline cellulose (Avicel ^TM PH101, FMC Biopolymer, Philadelphia, PA);

(k) dibasic anhydrous calcium phosphate (A- ^TabTM , Rhodia, Chicago Heights, IL).

Each mixture was mixed for 15 minutes using a Turbula ^™ mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). 100 mg of magnesium stearate (from a plant source, Mallinckrodt, St. Louis, MO) was then added to each bottle and the mixture was mixed with Turbula for another 5 minutes. The sieved masses were obtained using (top to bottom) five separators, a 60 mesh sieve, a 200 mesh sieve and a tank below. A sheet of 6 "weighing paper was placed between the fourth and fifth separators. Each mixture was individually placed on a 60 mesh sieve and the sieved material was placed in a Sonic Stifter ^™ (Alien Bradley Sonic Stifter, Advantech Manufacturing, New Berlin, Wl.) The mixtures were sieved for 6 minutes with amplitudes of sifting and vibrating 6. Weights were determined in each sieve section and activity was analyzed by extracting samples with a 1: 1 (v: v) mixture of deionized water: acetonitrile and shaking for 30 minutes, then the material was filtered using a Gelman Acrodisc ^™ polytetrafluoroethylene membrane ( pore size 0.45 μm) and analyzed using a UZ-Vis Spectrophotometer (Model 8453, Agilent Corp., Wilmington, DE) using an ultraviolet visible spectrophotometer. An external standard curve was used to quantify the content of atorvastatin. Extraction masses and volumes for each The sample is shown in Table 1. The results are presented in Table 4.

Table 1 Sample preparation conditions for HPLC analysis. Dilution includes a stock solution formed by combining the analyte amount with an extraction volume, and diluting it with the indicated amount of a 1: 1 (v: v) mixture of acetonitrile: water. Example 60 mesh screen material 200 mesh screen material Fine particles The analyzed amount (g) Extraction Volume (ml) The analyzed amount (g) Extraction Volume (ml) The analyzed amount (g) Extraction Volume (ml) 4a 8.9 one hundred 0.6 500 0.3 500 (5: 1 dilution) 4b 3.9 2000 0.7 500 0.5 1000 (5: 1 dilution) 4c 5,0 500 4.2 500 0.5 1000 (5: 1 dilution) 4g 0.2 one hundred 7.2 1000 2.1 1000 4d 1.3 500 5.2 500 (5: 1 dilution) 3,1 500 (4: 1 dilution) 4th 0,038 25 7.2 500 (6.67: 1 dilution) 2,3 1000 4g 0.017 10 5,0 500 4.8 500 (5: 1 dilution) 4z 0.007 10 0,070 25 9.8 1000 (5: 1 dilution) 4i 1,1 1000 1.9 1000 4k 0.2 fifty 7.8 500 (6.67: 1 dilution) 1.8 1000 (4: 1 dilution)

EXAMPLE 5

OBTAINING AND ANALYSIS OF MIXTURES OF AMORPHOUS CALCIUM ATORVASTATIN AND EXCIPIENTS - 40% OF THE MEDICINE

To each of ten 60 cm ³ yellow glass bottles were added 4.0 g of amorphous atorvastatin, prepared as described in Example 1, and 5.8 g of one of the following excipients:

(a) xylitol (C granular, Danisco Sweeteners, Thomson, IL);

(b) mannitol (Mannogen ^TM 2080 granulated, SPI Polyols, New Castle, DE );

(c) sucrose (compressible ^{sugar, White Di-Pac TM, Tate} & Lyie Co. American Sugars Inc, Brooklyn, NY);

(d) lactose (spray dried monohydrate, Foremost Farms, Rothschild, Wl);

(e) lactose (anhydrous, direct tablet quality, Quest International, Flavors & Food Ingredients CCL, Norwich, NY);

(e) lactose (Fast Flo ^TM 316, Foremost Farms, Rothschild, Wl);

(g) microcrystalline cellulose (Avicel ^™ PH102, FMC Biopolymer, Philadelphia, PA);

(h) microcrystalline cellulose (Avicel ^™ PH105, FMC Biopolymer, Philadelphia, PA);

(i) microcrystalline cellulose (Avicel ^TM PH101, FMC Biopolymer, Philadelphia, PA);

(k) dibasic anhydrous calcium phosphate (A- ^TabTM , Rhodia, Chicago Heights, IL).

Each mixture was mixed for 15 minutes using a Turbula ^™ shaker mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). 200 mg of magnesium stearate (from a plant source, Mallinckrodt, St. Louis, MO) was then added to each bottle and the mixture was mixed with Turbula for another 5 minutes. Sifting and analysis of activity was carried out as described in example 4, the extraction volumes are shown in Table 2. The results of the analysis are presented in Table 4.

Table 2. Conditions for obtaining samples for HPLC analysis. Dilution includes a stock solution formed by combining the analyte amount with an extraction volume, and diluting it with the indicated amount of a 1: 1 (v: v) mixture of acetonitrile: water. Example 60 mesh screen material 200 mesh screen material Fine particles The analyzed amount (g) Extraction Volume (ml) The analyzed amount (g) Extraction Volume (ml) The analyzed amount (g) Extraction Volume (ml) 5a 5.7 1000 0.2 500 1.9 1000 (20: 1 dilution) 5 B 1.7 1000 0.9 500 0.9 1000 (10: 1 dilution) 5c 3.3 500 2,5 500 2.0 1000 (20: 1 dilution) 5g 0.1 500 2,8 1000 (10: 1 dilution) 1.8 1000 (20: 1 dilution) 5d 1,1 500 3,5 1000 (14.3: 1 dilution) 2,5 1000 (20: 1 dilution) 5th 0.024 one hundred 3.4 1000 (20: 1 dilution) 2.6 1000 (10: 1 dilution) 5g 0,034 10 (10: 1 dilution) 5,0 1000 (20: 1 dilution) 2.2 1000 (10: 1 dilution) 5h 0.012 10 (10: 1 dilution) 0.018 10 (10: 1 dilution) 4.9 1000 (20: 1 dilution) 5i 1,5 1000 (5: 1 dilution) 1,6 1000 (5: 1 dilution) 5k 0.2 500 4.9 1000 (16.7: 1 dilution) 4.7 1000 (20: 1 dilution)

EXAMPLE 6

OBTAINING AND ANALYSIS OF DRY GRANULATES OF MIXTURES OF AMORPHOUS CALCIUM ATORVASTATIN AND EXCIPIENTS

For a dry granulation process for each excipient and for atorvastatin, the true density was measured at 25.1 ° C ± 0.9 ° using a Micro-Ultrapycnometer 1000 (Quantachrome Corp., Boynton Beach, FL) with very high purity helium, at an overpressure of inlet 20 pounds per square inch (117.9 kPa). All density measurements were carried out using a large cell (bowl volume 4.5 cm ³ ) with a tool programmed to control in multi-pass mode (maximum number of passes 15, passes for average 3, 0.1% deviation, flow purge mode, purge time 15 minutes). These values were obtained from one experiment or from the average of two experiments with a new sample for each of them. The masses of the samples were at least one gram (weight range 1.1 to 2.7 grams).

(a) It was assumed that the true density of a 5% (wt.) mixture of atorvastatin with xylitol is a weighted average of the true densities of xylitol (1.49 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.48 g / cm ³ . The briquettes were made of a mixture obtained as described in Example 4a using an F-press with a rectangular equipment of 10 × 22 mm. The thickness and masses were varied to achieve the density range and the corresponding solid fractions (i.e., briquette density divided by 1.48 g / cm ³ ), in which case the thickness, masses and solid fractions were 1.90 mm, 500 mg, 0 , 80; 2.16 mm, 597 mg, 0.84; 2.05 mm, 599 mg, 0.89; and 2.01 mm, 606 mg, 0.92. The corresponding deformation forces for briquettes were measured using a CT5 Tester tensile strength meter (Engineering System (NOTTM), Nottingham, England), and it was found that they are 0.034, 0.042, 0.152 and 0.163 kg. These values were converted to tensile strength by dividing the strain force by the square of the thickness (multiplied by 22.07 to obtain values in megapascals, MPa), and corresponded to the following values of 0.21, 0.20, 0.80 and 0.89 MPa . Since the sample could not achieve the required tensile strength of 1.0 MPa, a maximum solid fraction of 0.92 was used to obtain briquettes. Based on this, mixture briquettes were prepared using a 0.50 "round tool with a flat surface on an F-press, weighing 351 mg per briquette and 2.0 mm thick. These briquettes (10 g in total) were grinded using Mini Comil 193 (Quadro Engineering Incorporated, Waterloo, Ontario, Canada) with a 0.040 "crushing screen operating at 900 rpm. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the analysis results are presented in Table 4.

(b) It was assumed that the true density of a 5% (wt.) mixture of atorvastatin with mannitol is a weighted average of the true densities of mannitol (1.45 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.44 g / cm ³ . The briquettes were made from a mixture prepared as described in Example 46 using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.98 mm, 460 mg, 0.73; 1.77 mm, 422 mg, 0.754; 1.61 mm, 394 mg, 0.77; 1.43 mm, 386 mg, 0.84; 2.07 mm, 552 mg, 0.84; 2.14 mm, 532 mg, 0.78 and 2.13 mm, 596 mg, 0.88. The corresponding values of tensile strength for briquettes were 0.19, 0.25, 0.39, 1.03, 0.98, 0.40 and 1.92 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.84. Based on this, briquettes of the mixture were prepared as described in Example 6a, with a weight of 305 mg per briquette and a thickness of 1.95 mm. In addition, briquettes with a tensile strength of 3.30 MPa were obtained using 320 mg / briquette with a thickness of 1.90 mm. Both briquettes were ground, as described in Example 6a. Both samples of the material were analyzed for particle size distribution by means of a sieve analysis as described in Example 4. The last sample was analyzed for activity as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(c) It was assumed that the true density of a 5% (wt.) mixture of atorvastatin with sucrose, quality for direct tabletting, is the weighted average of the true densities of sucrose (1.52 g / cm ³ ) and atorvastatin obtained as described in Example 1 ; 1.24 g / cm ³ , i.e. 1.51 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 4c using an F-press with a rectangular equipment of 10x22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.56 mm, 397 mg, 0.76; 1.43 mm, 398 mg, 0.83; 2.10 mm, 604 mg, 0.86; 2.14 mm, 500 mg, 0.70 and 1.83 mm, 498 mg, 0.81. The corresponding values of tensile strength for briquettes were 0.76, 2.06, 2.15, 0.34 and 1.15 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.78. Based on this, a mixture of briquettes (311 mg / briquette, 2.00 mm thick) was obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(d) It was assumed that the true density of a 5% (wt.) mixture of atorvastatin with lactose monohydrate is the weighted average of the true densities of lactose (1.49 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.48 g / cm ³ . The briquettes were made from a mixture prepared as described in Example 4d using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.54 mm, 415 mg, 0.81; 1.72 mm, 456 mg, 0.81; 1.92 mm, 478 mg, 0.76; 1.76 mm, 395 mg, 0.68; 1.98 mm, 488 mg, 0.75 and 1.84 mm, 506 mg, 0.83. The corresponding values of tensile strength for briquettes were 1.55, 1.05, 0.74, 0.35, 0.60 and 1.83 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.78. Based on this, briquettes mixtures (302 mg / briquette, 2.02 mm thick) were obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(e) The true density of the 5% (wt.) mixture of atorvastatin with anhydrous lactose was assumed to be the weighted average of the true densities of lactose (1.50 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.49 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 4e using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.82 mm, 427 mg, 0.71; 1.66 mm, 440 mg, 0.80; 1.58 mm, 430 mg, 0.82 and 1.82 mm, 479 mg, 0.80. The corresponding values of tensile strength for briquettes were 0.68, 2.16, 2.52 and 1.80 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.75. Based on this, briquettes mixtures (286 mg / briquette, 2.02 mm thick) were obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(f) The true density of the 5% (wt.) mixture of atorvastatin with lactose FastFlo ^™ was assumed to be the weighted average of the true densities of lactose (1.54 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.53 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 4e using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.98 mm, 476 mg, 0.70; 1.80 mm, 440 mg, 0.72; 1.72 mm, 411 mg, 0.70; 1.80 mm, 342 mg, 0.55 and 1.73 mm, 475 mg, 0.80. The corresponding values of tensile strength for briquettes were 1.10, 1.27, 1.16, 0.13 and 2.61 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.70. Based on this, a mixture of briquettes (272 mg / briquette, 2.01 mm thick) was obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(g) It was assumed that the true density of a 5% (wt.) mixture of atorvastatin with microcrystalline cellulose (Avicel ^™ PH102) is a weighted average of the true densities of microcrystalline cellulose (1.58 g / cm ³ ) and atorvastatin obtained as described in Example 1 1.24 g / cm ³ , i.e. 1.56 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 4g using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 2.56 mm, 417 mg, 0.47; 1.83 mm, 418 mg, 0.66; 1.60 mm, 420 mg, 0.76; 2.29 mm, 382 mg, 0.48; 1.70 mm, 383 mg, 0.65 and 1.91 mm, 347 mg, 0.52. The corresponding values of tensile strength for briquettes were 0.22, 3.36, 6.99, 0.64, 2.58 and 1.03 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.56. Based on this, briquettes mixtures (226 mg / briquette, 2.01 mm thick) were obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(h) It was assumed that the true density of a 5% (wt.) mixture of atorvastatin with microcrystalline cellulose (Avicel ^™ PH105) is a weighted average of the true densities of microcrystalline cellulose (1.55 g / cm ³ ) and atorvastatin obtained as described in Example 1 1.24 g / cm ³ , i.e. 1.53 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 4c using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.87 mm, 432 mg, 0.68; 1.55 mm, 387 mg, 0.73; 2.21 mm, 390 mg, 0.52; 1.63 mm, 329 mg, 0.59; 2.18 mm, 311 mg, 0.42 and 1.35 mm, 258 mg, 0.56. The corresponding values of tensile strength for briquettes were 4.17, 7.99, 1.29, 2.62, 0.27 and 2.31 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.51. Based on this, a mixture of briquettes (211 mg / briquette, 2.03 mm thick) was obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(i) It was assumed that the true density of a 5% (wt.) mixture of atorvastatin with microcrystalline cellulose (Avicel ^™ PH101) is a weighted average of the true densities of microcrystalline cellulose (1.56 g / cm ³ ) and atorvastatin obtained as described in Example 1 1.24 g / cm ³ , i.e. 1.54 g / cm ³ . Briquettes were made from a mixture obtained as described in Example 4i using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 2.06 mm, 541 mg, 0.77; 2.09 mm, 506 mg, 0.71; 1.96 mm, 478 mg, 0.71; 1.96 mm, 478 mg, 0.71; 2.20 mm, 432 mg, 0.57 and 1.84 mm, 450 mg, 0.72. The corresponding values of tensile strength for briquettes were 7.25, 4.96, 5.11, 1.79 and 5.11 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.50. Based on this, briquettes mixtures (208 mg / briquette, 2.06 mm thick) were obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(k) It was assumed that the true density of a 5% (wt.) mixture of atorvastatin with dibasic anhydrous calcium phosphate (A- ^TabTM ) is a weighted average of the true densities of calcium phosphate (2.78 g / cm ³ ) and atorvastatin obtained, as described in Example 1; 1.24 g / cm ³ , i.e. 2.70 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 4k using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 2.22 mm, 706 mg, 0.53; 1.82 mm, 598 mg, 0.55; 2.29 mm, 796 mg, 0.58 and 2.05 mm, 598 mg, 0.49. The corresponding values of tensile strength for briquettes were 0.98, 1.55, 2.32 and 0.49 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.53. Based on this, a mixture of briquettes (357 mg / briquette, 1.94 mm thick) was obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 4.

(l) It was assumed that the true density of the 40% (wt.) mixture of atorvastatin with xylitol is the weighted average of the true densities of xylitol (1.49 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.39 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 5a using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.66 mm, 434 mg, 0.84; 2.03 mm, 535 mg, 0.85; 1.95 mm, 530 mg, 0.88; 2.00 mm, 431 mg, 0.69; 2.14 mm, 587 mg, 0.88 and 2.28 mm, 595 mg, 0.84. The corresponding values of tensile strength for briquettes were 0.62, 0.98, 1.19, 0.09, 1.31 and 0.71 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.86. Based on this, a mixture of briquettes (296 mg / briquette, 1.92 mm thick) was obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(m) It was assumed that the true density of the 40% (wt.) mixture of atorvastatin with mannitol is a weighted average of the true densities of mannitol (1.45 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.37 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 56 using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.97 mm, 426 mg, 0.71; 1.97 mm, 455 mg, 0.76; 1.79 mm, 460 mg, 0.84; 1.97 mm, 485 mg, 0.81; 1.90 mm, 519 mg, 0.90 and 1.93 mm, 516 mg, 0.88. The corresponding values of tensile strength for briquettes were 0.63, 0.84, 2.13, 1.74, 2.91 and 2.72 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.76. Based on this, briquettes of the mixture were obtained as described in Example 6a, with a mass of 269 mg / briquette and a thickness of 2.00 mm. In addition, briquettes with a tensile strength of 2.18 MPa were prepared using 300 mg / briquette with a thickness of 1.98 mm. Both briquettes were ground as described in Example 6a. Both samples of the material were analyzed for particle size distribution by sieve analysis as described in Example 4. The last sample was analyzed for activity as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(n) It was assumed that the true density of the 40% (wt.) mixture of atorvastatin quality with sucrose for direct tabletting is the weighted average of the true densities of sucrose (1.52 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.41 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 5c using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 2.08 mm, 403 mg, 0.62; 2.00 mm, 466 mg, 0.74; 1.66 mm, 412 mg, 0.79; 1.73 mm, 467 mg, 0.86; 2.12 mm, 478 mg, 0.72; 1.82 mm, 481 mg, 0.84 and 1.83 mm, 478 mg, 0.83. The corresponding values of tensile strength for briquettes were 0.20, 0.74, 1.43, 2.07, 0.46, 2.31 and 1.98 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.77. Based on this, briquettes mixtures (298 mg / briquette, 2.13 mm thick) were obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(o) It was assumed that the true density of the 40% (wt.) mixture of atorvastatin with lactose monohydrate is a weighted average of the true densities of lactose (1.49 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.39 g / cm ³ . Briquettes were made from a mixture obtained as described in Example 5g using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 2.09 mm, 541 mg, 0.83; 1.90 mm, 471 mg, 0.80; 1.54 mm, 331 mg, 0.69 and 2.18 mm, 594 mg, 0.88. The corresponding values of tensile strength for briquettes were 1.79, 1.34, 0.73 and 2.62 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.74. Based on this, mixture briquettes (265 mg / briquette, 1.96 mm thick) were prepared and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(p) The true density of the 40% (wt.) mixture of atorvastatin with anhydrous lactose was assumed to be the weighted average of the true densities of lactose (1.50 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.40 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 5e using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.85 mm, 400 mg, 0.69; 1.97 mm, 467 mg, 0.76; 2.07 mm, 501 mg, 0.77; 2.01 mm, 527 mg, 0.84 and 2.00 mm, 398 mg, 0.64. The corresponding values of tensile strength for briquettes were 0.81, 1.58, 1.52, 2.80 and 0.37 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.72. Based on this, briquettes mixtures (278 mg / briquette, 2.08 mm thick) were obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(p) The true density of the 40% (w / w) mixture of atorvastatin with lactose (FastFlo ^™ ) was assumed to be the weighted average of the true densities of lactose (1.54 g / cm ³ ) and atorvastatin obtained as described in Example 1; 1.24 g / cm ³ , i.e. 1.42 g / cm ³ . The briquettes were made from the mixture obtained as described in Example 5e using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 2.26 mm, 360 mg, 0.50; 1.97 mm, 375 mg, 0.60; 2.14 mm, 409 mg, 0.60; 1.92 mm, 437 mg, 0.72 and 2.17 mm, 530 mg, 0.77. The corresponding values of tensile strength for briquettes were 0.99, 0.44, 0.43, 1.15 and 2.02 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.70. Based on this, mixture briquettes (262 mg / briquette, 1.99 mm thick) were prepared and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(c) The true density of the 40% (wt.) mixture of atorvastatin with microcrystalline cellulose (Avicel ^™ PH102) was assumed to be the weighted average of the true densities of microcrystalline cellulose (1.58 g / cm ³ ) and atorvastatin obtained as described in Example 1 1.24 g / cm ³ , i.e. 1.44 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 5g using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.90 mm, 343 mg, 0.56; 1.88 mm, 400 mg, 0.66; 2.10 mm, 441 mg, 0.65 and 2.30 mm, 366 mg, 0.49. The corresponding values of tensile strength for briquettes were 0.78, 2.28, 1.88 and 0.29 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.59. Based on this, briquette mixtures (223 mg / briquette, 2.04 mm thick) were prepared and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(t) It was assumed that the true density of the 40% (wt.) mixture of atorvastatin with microcrystalline cellulose (Avicel ^™ PH105) is a weighted average of the true densities of microcrystalline cellulose (1.55 g / cm ³ ) and atorvastatin obtained as described in Example 1 1.24 g / cm ³ , i.e. 1.43 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 5c using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.91 mm, 335 mg, 0.55; 1.82 mm, 312 mg, 0.54; 1.90 mm, 399 mg, 0.66; 2.23 mm, 393 mg, 0.55; 2.10 mm, 445 mg, 0.67 and 1.82 mm, 433 mg, 0.75. The corresponding values of tensile strength for briquettes were 0.85, 0.66, 2.22, 0.76, 2.00 and 4.42 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.58. Based on this, briquettes mixtures (228 mg / briquette, 2.03 mm thick) were obtained and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(y) It was assumed that the true density of the 40% (wt.) mixture of atorvastatin with microcrystalline cellulose (Avicel ^TM PH101) is a weighted average of the true densities of microcrystalline cellulose (1.56 g / cm ³ ) and atorvastatin obtained as described in Example 1 1.24 g / cm ³ , i.e. 1.43 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 5i using an F-press with a rectangular equipment of 10 × 22 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.59 mm, 368 mg, 0.73; 2.24 mm, 397 mg, 0.56; 1.97 mm, 460 mg, 0.73; 1.81 mm, 363 mg, 0.63; 1.69 mm, 394 mg, 0.73 and 1.97 mm, 381 mg, 0.61. The corresponding values of tensile strength for briquettes were 3.66, 0.75, 3.90, 1.62, 3.72 and 1.50 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.58. Based on this, briquettes mixtures (209 mg / briquette, 2.00 mm thick) were prepared and ground as described in Example 6a. Material samples were analyzed as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

(f) It was assumed that the true density of a 40% (wt.) mixture of atorvastatin with dibasic anhydrous calcium phosphate (A- ^TabTM ) is a weighted average of the true densities of calcium phosphate (2.78 g / cm ³ ) and atorvastatin obtained, as described in Example 1; 1.24 g / cm ³ , i.e. 2.16 g / cm ³ . The briquettes were made from a mixture obtained as described in Example 5k using an F-press with a rectangular equipment of 10 × 2 mm. The thickness, masses and solid fractions of the briquettes obtained as described in Example 6a were 1.92 mm, 525 mg, 0.57; 1.79 mm, 484 mg, 0.56; 1.87 mm, 485 mg, 0.54; 1.99 mm, 579 mg, 0.60 and 2.10 mm, 481 mg, 0.48. The corresponding values of tensile strength for briquettes were 1.56, 1.31, 1.13, 1.95 and 0.45 MPa. It was found that the most suitable solid fraction for a tensile strength of 1.0 MPa is a solid fraction of 0.54. Based on this, briquettes mixtures (294 mg / briquette, 1.97 mm thick) were obtained and ground as described in Example 4, with extraction volumes shown in Table 3, the final results are presented in Table 5.

Table 3 Sample conditions for HPLC analysis. Dilution includes a stock solution formed by combining the analyte amount with an extraction volume, and diluting it with the indicated amount of a 1: 1 mixture (v: v) acetonitrile: water Example 60 mesh screen material 200 mesh screen material Fine particles The analyzed amount (g) Extraction Volume (ml) The analyzed amount (g) Extraction Volume (ml) The analyzed amount (g) Extraction Volume (ml) 6a 4.9 500 (5: 1 dilution) 2,8 1000 1.7 1000 6b 1,5 1000 1.4 1000 0.5 1000 6c 4.3 500 (4: 1 dilution) 2.9 500 (4: 1 dilution) 1.8 1000 6g 3,5 1000 3.0 1000 2,4 1000 6d 4.0 500 (4: 1 dilution) 3,1 1000 2.2 1000 6th 4.6 500 (4: 1 dilution) 1,5 500 3.3 1000 6g 2,3 1000 4.0 500 (5: 1 dilution) 3.0 1000 6h 4.9 500 (5: 1 dilution) 1,2 500 3,5 500 (5: 1 dilution) 6i 2.2 1000 2,3 1000 5,0 500 (5: 1 dilution) 6k 4.2 500 (4: 1 dilution) 3.2 500 (4: 1 dilution) 2,4 1000 6l 3.2 1000 (10: 1 dilution) 1.8 500 (dilution 14.3: 1) 1,0 500 (10: 1 dilution) 6m 1.7 1000 (5: 1 dilution) 1,5 1000 (5: 1 dilution) 0.5 1000 (4: 1 dilution) 6n 4.9 1000 (20: 1 dilution) 2,5 1000 (10: 1 dilution) 1.8 1000 (6.67: 1 dilution) 6o 4.9 1000 (20: 1 dilution) 2.6 1000 (10: 1 dilution) 1,5 1000 (6.67: 1 dilution) 6p 2,8 1000 (10: 1 dilution) 2,3 1000 (10: 1 dilution) 1.3 500 (10: 1 dilution) 6p 3.0 1000 (10: 1 dilution) 1,5 500 (10: 1 dilution) 1.7 500 (10: 1 dilution) 6s 2.2 1000 (10: 1 dilution) 3,1 1000 (10: 1 dilution) 1.7 1000 (10: 1 dilution) 6t 2,5 1000 (10: 1 dilution) 1,0 500 (10: 1 dilution) 3.0 1000 (10: 1 dilution) 6y 2.2 1000 (10: 1 dilution) 2.2 500 (10: 1 dilution) 2.2 1000 (10: 1 dilution) 6ph 2,5 1000 (10: 1 dilution) 2,4 500 (20: 1 dilution) 2.0 500 (20: 1 dilution)

Table 4 Comparison of simple mixtures and dry granules with atorvastatin and a number of diluents (with atorvastatin in an amount of 5% (wt.)), Showing the beneficial effects on the segregation of certain diluents Example 60 mesh screen material 200 mesh screen material Fine particles Granulation factor Mass (g) Activity (mgA / g) Mass (g) Activity (mgA / g) Mass (g) Activity (mgA / g) 4a 9,010 9.9 0.628 35.5 0.318 837.7 0.56 6a 5,026 31.5 2,937 29.9 1,722 64.6 4b 8,003 3.9 1,406 7.3 0.557 782.6 0.74 6b 4,788 39.0 1,549 37.8 1,413 54,2 4c 5,197 1.9 4,201 2,3 0.554 686.8 0.49 6c 4,495 25,4 3,057 13.7 1,816 81.8 4g 0.221 7.3 7,613 21.1 2,149 78.7 0.23 6g 3,622 40.9 3,162 21.3 2,394 58.5 4d 1,414 1,5 5,418 1.8 3,145 126.3 0.57 6d 4,167 37.3 3,272 20,0 2,221 70.3 4th 0,081 38.5 7,593 31.7 2,281 67.2 0.06 6th 4,651 44.8 1,653 32,7 3,308 45.0 4g 0,052 15.0 5,174 6.8 4,783 78.7 0.50 6g 2,404 42.7 4,187 22.4 3,028 53.6 4z 0,048 44.1 0.119 40.3 9,814 47.4 0.65 6h 4,937 47.2 1,214 35,2 3,491 42,2 4i 0,029 - 2,420 5.5 7,524 52,2 0.37 6i 2,221 41.1 2,440 19.2 5,009 43.0 4k 0.206 8.8 7,910 6.2 1,860 204.6 0.53 6k 4,214 41.5 3,231 24.9 2,390 75.6

Table 5 Comparison of simple mixtures and dry granules with atorvastatin and a number of diluents (with atorvastatin in an amount of 40% (wt.)), Showing the beneficial effects on segregation of certain diluents Example 60 mesh screen material 200 mesh screen material Fine particles Granulation factor Mass (g) Activity (mgA / g) Mass (g) Activity (mgA / g) Mass (g) Activity (mgA / g) 5a 5,881 24.1 0.248 101.8 3,799 893.2 0.84 6a 6,462 325.7 1,930 333,4 0.970 522.9 5 B 5,260 33.0 1.011 83,4 3,681 824.0 0.73 6b 5,283 303.3 1,577 367.2 1,361 518.2 5c 3,367 13.3 2,541 8.4 4,005 881.9 0.62 6c 5,063 284.0 2,624 233.7 1,851 672.7 5g 0.205 54.3 6,064 191.0 3,678 627.1 0.64 6g 4,992 361.1 2,764 251.3 1,565 499.5 5d 1,129 29.1 3,869 66.8 4,955 633.0 0.79 6d 5,807 348.5 2,454 292.7 1,319 490.6 5th 0.059 146.0 7,224 245.5 2,634 650.5 0.62 6th 6,224 364.6 1,666 315.3 1,691 376.0 5g 0,112 114.7 5,413 184.0 4,426 558.8 0.24 6g 2,295 359.1 3,425 180,4 3,506 483.3 5h 0,071 235.0 0.106 518.4 9,788 384.6 0.69 6h 5,213 383.1 1,195 360,0 3,024 350.7 5i 0,087 - 4,920 269.2 4,917 397.8 0.02 6i 2,263 351.4 2,502 202.9 4,575 404.9 5k 0.206 67.1 5,011 15.1 4,739 708.7 0.68 6k 5,300 346.1 2,499 251.1 2,000 550.7

Claims (6)

1. A dry granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt and diluent thereof, wherein the diluent contains more than about 50 wt.% Microcrystalline cellulose, lactose, sucrose, xylitol or dibasic calcium phosphate. 2. The pharmaceutical composition according to claim 1, containing less than about 5 wt.% Additives, representing a salt of an alkaline earth metal. 3. The pharmaceutical composition according to claim 1, used in the preparation of a solid unit dosage form. 4. The pharmaceutical composition according to claim 3, where the standard dosage form is selected from the group consisting of tablets and capsules. 5. The pharmaceutical composition according to claim 1, where atorvastatin contains at least partially disordered or completely disordered form of atorvastatin or its pharmaceutically acceptable salt. 6. A method of obtaining a granular dry method of the pharmaceutical composition of atorvastatin, including a) combining atorvastatin or its pharmaceutically acceptable salt and one or more diluents, where the diluent contains more than about 50 wt.% microcrystalline cellulose, lactose, sucrose, xylitol or dibasic calcium phosphate; b) mixing the mixture in a mixer; c) pressing the mixture; d) grinding, grinding or sieving the pressed material; d) the possible addition of additional excipients and mixing the combination to obtain a composition.