KR20060025167A - Pharmaceutical compositions of atorvastatin - Google Patents

Abstract

A dry-granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof, as well as a dry-granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one other active drug, methods for preparing said compositions, kits for containing such compositions, and a method of treating hypercholesterolemia and/or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease using a therapeutically effective amount of the pharmaceutical composition.

Description

Pharmaceutical composition of atorvastatin {PHARMACEUTICAL COMPOSITIONS OF ATORVASTATIN}

Cross-Reference to the Related Application

This application claims priority to US Provisional Patent Application No. 60 / 477,917, filed June 12, 2003.

Field of invention

The present invention relates to pharmaceutical compositions comprising atorvastatin and pharmaceutically acceptable salts thereof, and methods of making the same, kits containing such compositions, and hypercholesterolemia and / or hyperlipidemia using such compositions, And a method for treating a subject suffering from 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 initial rate-determining step in the cholesterol biosynthetic pathway. This step is facilitated by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from promoting this conversion. As such, statins are collectively potent lipid lowering agents.

The atorvastatin calcium described in US Pat. No. 5,273,995, incorporated herein by reference, has the chemical name [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5 -(1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptano acid calcium salt (2: 1) trihydrate and the following formula: Lipitor Currently sold under (registered trademark)):

Atorvastatin and its pharmaceutically acceptable salts are selective and competitive inhibitors of HMG-CoA reductase. Atorvastatin calcium per se is a potent lipid-lowering compound and is therefore useful as a hyperlipidemic and / or hypercholesterolemic agent and in the treatment of osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease.

Numerous patents have been issued describing atorvastatin, preparations of atorvastatin and methods of making atorvastatin and key intermediates for the preparation. These include US Pat. No. 4,681,893; 5,273,995; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,686,104; 5,998,633; 6,087,511; 6,126,971; 6,433,213; And 6,476,235, which are incorporated herein by reference.

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

Crystalline forms of atorvastatin calcium are described in US Pat. Nos. 5,969,156 and 6,121,461, which are incorporated herein by reference. Additional crystalline forms of atorvastatin are described in US Pat. No. 6,605,729, which is incorporated herein by reference.

In addition, many published international patent applications describe crystalline forms of atorvastatin and methods for preparing 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.

Amorphousities of many drugs have been shown to show different dissolution properties compared to crystalline forms and in some cases different bioavailability patterns (Konno, T., Chem. Pharm. Bull., 1990; 38: 2003-2007) . For some therapeutic indications, one bioavailability pattern may be more desirable than another.

Changes in dissolution rate can make it advantageous to prepare the atorvastatin formulation in crystalline or amorphous form. For example, potential uses of some of the atorvastatin (e.g., Takemoto, M .; Node, K .; Nakagami, H .; Liao, Y .; Grimm, M .; Takemoto, Y .; Kitakaze, M For Liao, JK, Journal of Clinical Investigation, 2001; 108 (10): 1429-1437), rapid expression of activity can be very beneficial in improving the efficacy of the drug.

Methods of preparing solid formulations of atorvastatin are described in US Pat. Nos. 5,686,104 and 6,126,971. The methods described in these patents combine atorvastatin with stabilizing additives and excipients, such as alkaline earth metal salts, and apply to wet granulation using a combination of water and surfactant (Tween 80). Since alkaline earth metal salts can sometimes affect atorvastatin bioavailability, there remains a need to provide atorvastatin as an agent that minimizes the level of alkaline earth metal salts.

In preparing and storing unit dosage forms of atorvastatin, it is important to provide the active drug in pure form. Moreover, it may be desirable to obtain such high purity and stability using as simple a formulation as possible. There is still a need to provide a simple preparation of atorvastatin and a process for preparing unit dosage forms thereof that have low levels of impurities and provide adequate stability to allow the dosage forms to have a commercially viable shelf life.

Because atorvastatin is a very potent drug, the formulation of this drug is generally diluted to provide a dosage form of the appropriate size for ease of manufacture and handling by the patient. If the drug is used in diluted form, there is a risk that the separation between the drug and excipient during the process before the drug is made into its final dosage form induces part of the unit dosage form to be over or under effective. . Modulation of potency of a unit dosage form is essential to prevent individual patients from receiving inaccurate doses of the drug, sub-therapeutic doses, or doses that cause side effects. Granulation is one way to prevent separation. While excipients may be selected to produce unit dosage forms without a granulation step, as described in concurrently filed and co-owned US Patent Application _________ (Agent Case No. PC25684), granulation does not occur and granules do not occur. The particle size of can ensure that the drug and excipients are bound together to allow good flow. Wet granulation is unlikely to cause separation and represents one alternative method of providing atorvastatin in a form with good flow (see, simultaneously filed and co-owned, U.S. Patent Application No. _______, Representative Event No. PC25685). However, wet granulation requires exposing the formulation to water and / or solvent. Such exposure increases the risk of changing the solid-state form of atorvastatin (crystallizing or changing the polymorphic form) or of chemical degradation. The amount and the rate of liquid addition may depend on factors such as the volume and surface area of the wet granulation vessel and on the exact particle size of the drug and excipients used in the particular manufacturing process, so that the wet granulation process is There may be difficulties in increasing (ie variability in performance). Accordingly, it is an object of the present invention to dry granules of atorvastatin such that drug separation is minimized, the flow of the composition is allowed for commercial unit dosage forms, the drug is not exposed to solvents, and the robust method is used. To provide a formulation and method.

In dry granulation methods, the drug and at least some excipients are generally pressed together to form a ribbon or slug. Thereafter, these compacted materials are milled to an appropriate size to prevent drug separation and to ensure good flow during production of the unit dosage form. The inventors have found that when compacting the drug itself to form slugs, the material again remarkably returns to a fine powder with poor flow characteristics. Thus, there is still a need to provide a composition suitable for dry granulation of atorvastatin that provides an adequate flow of drug so that unit dosage forms can be made with good weight control.

It is an object of the present invention to provide compositions and methods for producing dosage forms of atorvastatin having good dose-to-dose potency uniformity, dissolution rate and bioavailability. It is a further object of the present invention to provide a stable and pure composition of crystalline or amorphous atorvastatin with minimal addition of alkali metal salts.

Summary of the Invention

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

The second aspect of the invention

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

(b) blending the mixture together in a mixer;

(c) compacting the mixture;

(d) grinding, grinding or sieving the compressed material;

(e) optionally adding additional excipients and mixing the blend to form a composition

A method of making a dry-granulated pharmaceutical composition of atorvastatin, comprising.

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

The fourth aspect of the invention

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

(b) blending the mixture in a mixer;

(c) compacting the mixture;

(d) milling, milling or sieving the compressed material;

(e) optionally adding additional excipients and mixing the blend to form a composition

It comprises a, a method for producing a dry-granulated pharmaceutical composition of atorvastatin.

A fifth aspect of the invention is a therapeutic package or kit suitable for commercial sale, which includes a container and a therapeutically effective amount of dry-granulated atorvastatin or a pharmaceutically acceptable salt thereof.

A sixth aspect of the invention is a method of using a dry-granulated atorvastatin composition to treat a subject 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 US Pat. Nos. 4,681,893, 5,273,995 and 5,969,156, which are incorporated herein by reference. Hemicalcium salts of atorvastatin are currently sold under 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 still have some structure, such as exhibited by the powder x-ray diffraction pattern. For the purposes of the present invention, all forms of atorvastatin are beneficial according to the invention and are included within the scope of the invention. Particularly advantageous is the atorvastatin in partially or fully disordered form. Partially or fully disordered forms of atorvastatin that are amorphous or significantly amorphous lead to maximum benefits in accordance with the present invention. Such forms can be prepared from crystalline atorvastatin using, for example, the methods described in US Pat. No. 6,087,511, which is incorporated herein by reference. Alternatively, the amorphous material may be prepared according to the method described in co-owned US patent application Ser. No. _______ (representative case number PC25825). For the practice of the present invention, non-crystalline and crystalline atorvastatin can be prepared by any method known in the art. Preferred forms of atorvastatin are described in US Pat. Nos. 5,969,156, 6,121,461 and 6,605,729, which are incorporated herein by reference; And 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.

Atorvastatin can be used in the form in which it is prepared, or can be applied to methods of changing the physical properties of a particle. For example, the material can be milled using any method known in the art. Non-limiting examples of such methods include mechanical grinding and jet grinding. The particles produced directly from the method of forming atorvastatin or after the grinding operation preferably give an average particle diameter in the range of 1-200 μm, more preferably 5 to 150 μm.

Pharmaceutically acceptable base addition salts of atorvastatin are formed using 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, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, eg, Berge, SM et. al., "Pharmaceutical Salts", J. Pharm. Sci., 1977; 66: 1).

Base addition salts of atorvastatin are prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to produce a salt. The free acid form can be regenerated by contacting the salt form with an acid and separating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but in other ways the salts correspond to their respective free acids according to the purposes of the present invention. In addition, atorvastatin can exist in solvated forms, including hydrated forms, as well as in unsolvated forms. In general, solvated forms, including hydrated forms, are intended to be included within the scope of the present invention.

The most significant benefit according to the invention is at least a somewhat disordered form of atorvastatin or a mixture of crystalline and disordered forms of atorvastatin. Somewhat disordered means that the line width (peak width at half the peak height) of any peak, measured using powder x-ray diffraction (PXRD), has a 2 theta value greater than about 2 °. Means that. Particularly advantageous amorphous or markedly amorphous forms of atorvastatin according to the invention are characterized by having very broad and uncharacteristic peaks. It should be noted that the combination of the crystalline and at least somewhat disordered form of atorvastatin will be both sharp (ie less than 2 ° for 2 theta) and broad peaks (ie greater than 2 °). Formulations in form are also advantageous according to the invention.

Atorvastatin has been shown to be an effective drug even at relatively low doses. Indeed, by keeping the dose low for a given patient, side effects can be minimized while still maintaining the efficacy of the drug. Thus, atorvastatin is preferably provided in a form that can provide a low dose to the patient. For the purposes of the present invention, the dose provided by the final dosage form of atorvastatin is preferably from 0.5 to 120 mgA (wherein mgA means milligrams of active drug based on the free acid), more preferably Preferably between 5 and 80 mgA.

For convenience and ease of patient compliance, most drugs are delivered in unit dosage form. In the case of solid drug substances, these unit dosage forms are generally in the form of tablets, capsules, sachets, chewable tablets and fast dissolving dosage forms. In the present invention, the dosage form is preferably in the form of a capsule or tablet; Most preferably in the form of a tablet. Preparation of these forms involves the necessary steps of several types of powder filling by volume or weight. For example, in the production of tablets and capsules, the powders are volume filled in molds or capsules, respectively. Equivalent effect within the unit dosage form within allowable margins (relative standard deviation (RSD) of less than 6% meets Stage I of the USP Directive and less than 7.8% meets Stage II) Ie, amount of drug, per unit dosage form), without significant separation of active drug from excipients. This is especially important when in highly diluted form. The present invention describes compositions that provide reproducible efficacy for the combination of a fixed amount of active atorvastatin and excipients. In addition, such potency control is maintained through methods of producing unit dosage forms. Such compositions provide atorvastatin with potency (mgA per gram of blend) variability of less than 7.8%, more preferably less than 6.0%, RSD prior to processing in unit dosage forms. In addition, the compositions of the present invention provide good powder fluidity such that weight control is maintained between unit dosage forms produced by such compositions (ie, variability in weight of unit dosage forms produced from such compositions is minimal). . Preferably, such compositions provide unit dosage forms with a weight control of RSD within 6%, more preferably within 5%, even more preferably within 4%. The combination of weight control and potency control can provide a unit dosage form with the efficacy of atorvastatin with an RSD per unit dosage form, preferably less than 7.8%, more preferably less than 6.0%.

Measurement of the potency of unit dosage forms of atorvastatin is necessary to determine the variability of activity between unit dosage forms. Extraction methods against standards using independently known drug levels best measure this potency. Potency assays are best performed using reverse phase high performance liquid chromatography (HPLC) as known in the art against standard. For the purposes of the present invention, RSD measurements are best performed using sampling in the method of forming unit dosage forms. More specifically, unit dosage forms can be sampled from the manufacturing process at various time points (start, middle and end of the run). In measuring RSD values, at least three unit dosage forms must be determined from each section. Alternative techniques for measuring the efficacy of a sample drug include the use of ultraviolet-visible absorption spectroscopy. In this technique, the absorbance corresponding to atorvastatin, as known in the art, is used to quantify the concentration of atorvastatin in the sample (with care to avoid excipients from inhibiting absorption).

The present invention describes methods and compositions for providing atorvastatin in pure and stable form. The term “impurity” refers to all drug-based substances formed in the preparation of unit dosage forms and substances in drug components present from synthesis and purification. The term "degradant" refers to all drug-based substances produced after the preparation of unit dosage forms. Analysis of impurities and degradation products is performed using reverse phase HPLC techniques on extracted samples as is known in the art. The calculation of the amount of impurities and degradation products is expressed as the cumulative area percent of degradation products or impurity peak (s) divided by the cumulative area percent of all drug-related peaks.

Particle sizes of atorvastatin and excipients play an important role in the effectiveness of dry granulation methods in preventing separation. As such, the average particle size can be measured using a laser diffraction particle size device such as manufactured by Sympatec GmbH, Goslar, Germany. For the purposes of the present invention, the average particle size can be regarded as a size in which 50% of the particles have a diameter smaller than the indicated number. Alternatively, particle size can be assessed using sieve analysis. The average particle size is determined using the percentage of the total weight of material remaining on the sieve of a particular size. The average particle size is the sieve size that allows about 50% of the weight of the material to pass through (50% remaining).

In the preparation of the composition of atorvastatin by dry granulation, a combination of diluents, binders, disintegrants, fragrances and lubricants is used to provide the necessary properties for the unit dosage form as is known in the art. For example, when preparing tablets, the formulation provides adequate tablet hardness upon compression while providing rapid disintegration in vivo. Although there is a wide range of tolerances in formulating atorvastatin to meet these conditions, these formulations generally have about 1-40% by weight drug, about 5-10% disintegrant, about 0-10% binder, and about 0.5-2 It contains% lubricant, the remaining percentage includes the diluent of the invention. Preferred disintegrants include carboxymethylcellulose, hydroxypropyl cellulose (low-substituted), microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium aluminum silicate, methylcellulose, polaracryl Chlorine potassium, povidone, sodium alginate, sodium starch glycolate and starch. Preferred binders include acacia, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polyethylene oxide, polymethacrylate, Povidone, sodium alginate, starch and zein. 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 Latex and magnesium stearate.

In improving the flow of the atorvastatin composition and minimizing the separation from the excipient, the compression of the drug and the excipient can be carried out in a dry granulation process. In the case of atorvastatin, however, we form dry granules in which only some excipients are acceptable with the drug due to the brittle nature of the drug. Acceptable excipients can be defined as providing a significant reduction in the amount of fine drug particles remaining in the blend without binding to the excipient when dry granulated (ie compressed and comminuted) in the presence of atorvastatin. For the purposes of the present invention, fine drug particles (or “fines”) may be defined as particles passing through a 200 mesh sieve. We can also define the granulation factor as follows: granulation factor (GF) = 1-[(percentage of atorvastatin as fines during granulation) / (in nongranulation blends) Percentage of atorvastatin as fines in To determine the granulation coefficient for a given excipient or excipient combination, a blend of the drug and the selected excipient is first prepared. This blend is passed through a sieve using a sifting device such as Sonic Sifter ™ (Allen Bradley Sonic Sifter, Advantech Manufacturing, New Berlin, WI). The percentage of atorvastatin as a fine is determined by multiplying the weight of the fine by the weight of the fine divided by the total weight of the drug in the blend. The same analysis can be performed on the dry granulated material with atorvastatin. The overall ability of a given excipient or set of excipients to form a formulation with low tendency to separate from these assays can be measured. The inventors have found that atorvastatin and excipients or excipient combinations that provide a minimal tendency to separate during unit dosage form preparations have granulation coefficients between 0.4 and 1.0, more preferably between 0.5 and 1.0, even more preferably between 0.6 and 1.0. It was found that it can be characterized.

The inventors have found that in determining excipients suitable for dry granulation with atorvastatin, compression of the blend under conditions that can be converted to commercial dry granulation is important for determining the true tendency of atorvastatin to separate. One of the important criteria to consider when granulating atorvastatin is the compact fraction of the blend or ribbon of the blend, especially when the granulation is subjected to further compression steps such as appearing during the formation of the tablet. The solid fraction is an indicator of the amount of compaction remaining in the material. As such, the first step involves measuring the true density of the blend, i.e. the density of the material without air space between the particles. This density can be measured using techniques such as helium gravimetry or similar techniques as is known in the art. This value can also be judged by the weighted average of the true density values for each component. The solid fraction of dry granulation represents the ratio of the density of the compact (or ribbon) to the true density of the material from which the compact is made. Control of the solid fraction is achieved by adjusting the compaction force during compression. In order to obtain good binding of the atorvastatin while still providing sufficient compressibility for subsequent tableting, the granulation preferably produces a solid fraction between about 0.55 and 0.85, more preferably between about 0.60 and 0.80 after granulation. It was found to have.

Another criterion for obtaining acceptable dry granulation of atorvastatin is the tensile strength of the compact or ribbon. The tensile strength of the compact (or ribbon) can be measured using a suitable device well known in the art, such as a CT5 tensile strength tester (Engineering System (NOTTM), Nottinghan, England). Preferably, a rectangular compact having dimensions of 10 × 22 × 2 mm is used for this measurement. The inventors have found that the preferred tensile strength is 0.5 to 7.0 megapascals (Mpa), more preferably 0.8 to 6.0 MPa, ultimately to produce acceptable granulation of atorvastatin. Preference is given to a combination of atorvastatin and the material which can achieve the desired tensile strength within the range of the preferred solid fraction. Examples of such materials include lactose and microcrystalline cellulose. An example of a material that cannot achieve the desired tensile strength is mannitol.

By plotting solid fraction versus tensile strength, one can find a range of solid fractions suitable to provide the desired tensile strength by the desired blend of atorvastatin with an excipient or excipient combination. We have found that it is possible to estimate exponential least squares fitting using interpolation between measured values.

Preferred excipients are diluents which preferably occupy at least 40%, more preferably at least 50%, even more preferably at least 60% by weight of the total composition in the formulation containing atorvastatin. Preferred diluents when tested in a two component blend with atorvastatin preferably provide granulation coefficients between 0.4 and 1.0, more preferably between 0.5 and 1.0 and even more preferably between 0.6 and 1.0. Potential diluents have been identified per se 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, carboxymethylcellulose calcium, cellulose, cellulose acetate, dextrates, dextrins, dextrose, fructose, glyceryl palmitostearate, hydrogenated vegetable oils , Kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, polymethacrylate, pregelatinized starch, silicified microcrystalline cellulose, sodium chloride, sorbitol, starch, sucrose And talc.

In determining excipients suitable for use in dry granulation with atorvastatin, it is important to use the particular form and particle size of atorvastatin desired in the final dosage form. Likewise, the excipient or excipient formulation used may have properties that depend on the particle size and the method of preparation. Preferred excipients are generally smaller than desirable in the absence of granulation, since the compression of excipients with atorvastatin in the dry granulation process is generally facilitated by excipients of smaller particle size. As such, the excipient preferably has an average particle size between 20 and 200 μm, more preferably between 40 and 150 μm. These particle size ranges correspond to 50% by weight of the blend passing through the sieve between 635 mesh sieve (ASTM number) to 70 mesh, more preferably between 325 mesh and 100 mesh. The preferred size for a given excipient depends on the specific properties of the atorvastatin form used and in each case should be determined experimentally.

Thus, more preferred excipients in combination with atorvastatin can provide high values of granulation coefficients, obtain high tensile strength, and have a preferred average particle size, preferably 20 to 200 μm, more preferably 40 to 150 Diluent having an average particle size of μm. Particularly preferred diluents include microcrystalline cellulose having an average particle size of 20 to 40 μm (for example available from Avicel ™ PH105, FMC Biopolymer (FMC Biopolymer, Philadelphia, PA)), 80 to Lactose having a particle size range of 150 μm (eg, available from spray dried monohydrate material or Fast Flo ™ 316, Foremost Farms, Rothschild, WI); Or directly refined grade anhydrides, available from Quest International, Flavors & Food Ingredients CCL, Norwich, NY), xylitol (e.g., C granule grade, Danisco Sweeteners, Thomson , IL)), mannitol (e.g., Mannogem ™ 2080 granular, available from SPI Polyols, New Castle, DE), sucrose (e.g. For example, Di-Pac ™, available from Tate & Lyle Co. American Sugars Inc., Brooklyn, NY), and dibasic calcium phosphate Anhydrides (eg, available from A-Tab ™, Rhodia, Chicago Heights, IL). Preferably, the preferred diluent comprises more than 50% by weight, more preferably 60% by weight, even more preferably 70% by weight of the diluent content of the dry-granulated composition of atorvastatin.

Unit dosage forms of atorvastatin formed by the dry granulation step with preferred excipients exhibit low levels of drug-related impurities and degradation products. Surprisingly, these low levels of impurities and degradation products have been found in the absence of added alkalizers or alkaline earth metal salts. Even more surprisingly, these low levels of impurities and degradation products were maintained even when the atorvastatin used was at least somewhat disordered form of the drug. In particular, while wet granulated controlled unit dosage forms of atorvastatin exhibited high levels of drug degradation, unit dosage forms of atorvastatin prepared by dry granulation were found to have greater stability. Measured by HPLC, prepared by dry granulation containing up to about 2% total drug related impurities and / or degradation products based on the area percent of impurities / degradates relative to the cumulative area of all drug related peaks. Preferred are these unit dosage forms of atorvastatin; More preferably they contain less than 1%, even more preferably less than 0.7%. In addition, the unit dosage form was measured by HPLC at storage at 40 ° C. and 75% relative humidity (RH) for 4 weeks, based on the area percent of impurities / degradants relative to the cumulative area of all drug related peaks Those of atorvastatin prepared by dry granulation that provide stability up to% total drug related impurities and / or degradation products, more preferably less than 1%, even more preferably less than 0.7% Unit dosage forms are preferred.

Atorvastatin undergoes two major degradation pathways, lactonization and oxidation. Lactones are formed by forming six-membered rings by internal condensation of alcohols and carboxylic acids (loss of water). This is the main degradation product of amorphous atorvastatin, which appears during wet granulation and tablet formation, as described in US Pat. Nos. 6,126,971 and 5,686,104, especially in the absence of alkaline earth metal salts. We unexpectedly find that the level of lactone in a unit dosage form combines the excipients of the invention both in the initial and upon storage under accelerated aging conditions of elevated temperature and humidity, and uses a dry granulation method to produce the unit dosage form. It has been found that by production can be significantly reduced. Preferably, the level of atorvastatin lactone in the unit dosage form is 2% (when using HPLC, after storage for 4 weeks at 40 ° C./75% RH where RH represents relative humidity). Based on the ratio of the accumulation of lactone peaks to the peak accumulation area), more preferably less than 1%.

In order to minimize bioavailability issues and potential interactions with other drugs in combination dosage forms, the levels of alkaline earth metal salts in the formulations when practicing the present invention are preferably about 0-5% by weight; More preferably about 0-3%; Most preferably about 0-2%. In addition, the level of other alkalizing agents in the formulation is about 0-5% by weight; More preferably about 0-3%; Most preferably about 0-2%.

Dry granulation of atorvastatin with excipients is preferably carried out by first blending atorvastatin with at least some of the preferred excipients. Preferably, the excipients in this blend comprise 50 to 95% by weight of the blend. This blending method is preferably a high shear mixer, V-blender (or other twin-shell blender), bin blender or Turbula ™ mixer-shaker (Willy A. Bachofen AG Maschinenfabrik, available from Basel, Switzerland). Blending is generally performed without first adding lubricant for a time sufficient to ensure complete mixture. At that point, the lubricant is generally added and then mixed further for a short period of time (about 1-10 minutes). This blend is then compressed into slugs or ribbons using a tablet press (eg, a single-station press or a rotary tablet press) or a roller compressor. In the former case, compacts (slugs) are produced using flat-surface mold and punch combinations. In both cases, the density of the compact or ribbon is preferably from about 0.5 to 7.0 MPa; More preferably, it is selected to provide a compact or ribbon having a tensile strength of about 0.8 to 6.0 MPa. The compact or ribbon is then preferably ground, milled or sieved. Particle size reduction is known in the art and is performed in an optimal manner designed to provide good throughput while providing a suitable particle size distribution. Preferably, less than 30% by weight of the ground material may pass through the 200-mesh sieve and at least 70% by weight may pass through the 60-mesh sieve. Once the material is ground, other excipients can be added extragranularly to provide the final blend for unit dosage form preparation. These additives are preferably mixed using a high shear mixer, V-blend (or other twin-shell blender), empty blender or Turbula ™ shake-shaker. Blending is generally first performed without the addition of lubricant for a time sufficient to ensure complete mixing. At that point, lubricant is generally added and then further mixed for a short time (about 1-10 minutes). At this point the granulated material can be used for the preparation of unit dosage forms. Such unit dosage forms include sachets, tablets, fast-release 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 with a film designed to provide ease of swallowing, the exclusive or identifiable appearance and / or protection of the dosage form. The final dosage form is then packaged using methods known in the art. In the case of the invention, the package is preferably in the form of a foil-foil cold form blister, a plastic blister or a sealed bottle containing a desiccant. Optionally, the package may contain active oxygen absorbers such as those described in EP1243524A2, which is incorporated herein by reference.

In the production of unit dosage forms of atorvastatin by dry granulation, it is possible to produce such unit dosage forms without the formulation of the present invention using methods unsuitable for commercial production. For example, granulated material that tends to separate may also be weighed directly into the capsule. Thus, the present invention is preferably used with a high speed production apparatus. More specifically, preferred formulations are used with a single device-unit dosage form at a rate of more than 10,000 unit dosages per hour, more preferably more than 25,000 unit dosages per hour, most preferably more than 50,000 unit dosages per hour. In the case, dry granulation is provided which allows for potency control of less than 7.8% RSD (more preferably less than 6.0% RSD) during unit dosage form production. Non-limiting examples of commercial rotary tablet presses include Niro Pharma Systems, Columbia, MD, Kilian and Company, Horsham, PA, Korsch, Berline, Germany, and Elizabeth. Produced by Hatta International (Elizabet-Hata International, North Huntingdon, PA). Non-limiting examples of commercial capsule filling devices include those made by Capsugel (Morris Plains, NJ) and CapPlus Technologies (PPlusenix, AZ).

Since granulation does not potentially require solubilization and / or other destabilizing solvents and still maintains atorvastatin content uniformity, the present invention provides compositions of atorvastatin that are particularly well suited for combination products with other drug components. do. This is particularly the case when the second drug (with its associated excipient) can destabilize atorvastatin. Non-limiting examples of drugs that may be beneficial in combination with the atorvastatin compositions and methods of the present invention include torcetrapib and amlodipine and pharmaceutically acceptable salts thereof.

The composition of atorvastatin according to the present invention may be combined with one or more other active drugs to form a unit dosage form. Preferred unit dosage forms include tablets and capsules. In combinations of atorvastatin compositions with one or more other active drugs to form unit dosage forms, the following non-limiting list describes the options for such unit dosage forms: (a) excipients, formed from tablets or capsules Atorvastatin granulation as a blend with (ie, extragranular addition of other drugs and excipients to the dry granulated composition of atorvastatin), or as granules (ie, a granulation mixture of dry granulated composition of atorvastatin with other drugs) Blends with other active drugs themselves (ie, extragranular addition of other drugs to the dry granulating composition of atorvastatin); (b) single dry granulation of atorvastatin with other drugs formed as tablets or capsules; (c) a bilayer tablet comprising dry granulated atorvastatin in one layer and other drugs and optional excipients in the other layer.

The present invention is directed to subjects to diseases and conditions such as hyperlipidemia and / or hypercholesterolemia, osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease, low levels of degradation products and / or impurities contained in therapeutic packages or kits. A method of treating with atorvastatin or a pharmaceutically acceptable salt thereof as described above, which may be administered in a unit dosage form having. The kit includes unit dosage forms and containers. In general, the kit includes instructions for the administration of the unit dosage form. The container may be in any conventional shape or form known in the art, for example a blister pack having a paper box, a glass or plastic bottle, or an individual dosage form pushed back according to a therapeutic schedule. Can be.

The following non-limiting examples illustrate the preferred method of the present inventors for preparing and using the pharmaceutical composition of the present invention.

Example  One

Spray-dried amorphous Atorvastatin  General method for manufacturing

A spray dried amorphous atorvastatin, an example of disordered atorvastatin as already described in the detailed description of the invention and used in the examples below, is in accordance with concurrently filed and co-owned U.S. Patent Application _________ (Agent Case No. PC-25825) It was prepared by first dissolving atorvastatin calcium (US Pat. No. 5,273,995) in methanol to form a 5% by weight solution. This solution was sprayed in a Niro PSD-1 spray dryer at a rate of 170 g / min using nitrogen as the atomizing gas. The inlet temperature was 195 ° C and the outlet temperature was 60 ° C. After spray drying, the powder was tray-dried in an oven at 40 ° C. for 12 hours.

Example  2

Wet Granulation  Used amorphous Atorvastatin  Manufacture of tablets

The following materials were added to a 950-mm amber bottle: 2.59 g of spray dried amorphous atorvastatin prepared as described in Example 1, 78.00 g of microcrystalline cellulose (Avicel ™ PH102, FMC Biopolymer , Philadelphia, PA), 101.41 g of lactose (hydrate, Foremost Farms USA, Rothschild, WI), 6.00 g of croscarmellose sodium (Ac-Di-Sol ™ FMC Biopolymer, Philadelphia, PA) And 4.000 g of hydroxypropyl cellulose (Klucel ™ EXF, Hercules Incorporated, Aqualon Division, Wilmington, DE). The materials are bottle blended for 10 minutes using a Turbula Shaker Mixer, Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland, then drained and sieved through a 30 mesh screen to remove lumps It was. Subsequently, the materials were introduced back into the bottle and turbula mixed for an additional 10 minutes. Bottle-blended material is added to a Procept Mi-Mi-Pro high shear wet granulator (Pro-CepT nv, B-9060 Zelzate, Belgium) using a 1.7 L bowl It was. The materials were dry mixed for 2 minutes at a chopper speed of 1000 revolutions per minute and an impeller speed of 400 rpm per minute, then raised to 600 rpm at the impeller speed while maintaining the chopper speed. At this point, 90 ml of water were added at a rate of 30 ml / min by three separate additions (60 ml, 15 ml, 15 ml) over a total of 5.5 minutes of wet mixing. Excellent granulation with minimal fines was formed. The materials were drained and wet sieved through a # 10 mesh sieve by hand. The sieved material was dried by placing it on a polyethylene lined tray in a Gruenberg ™ forced hot oven at 50 ° C. for 16 hours. The dried material was then ground at 500 rpm using a Fitzpatrick L1A grinder (The Fitzpatrick Co., Elmhurst, IL) with a 0.040 "Conidur rasping screen. 175.0 g of blend To this was added 5.469 g of liquid-di-sol and the mixture was bottle blended for 5 minutes using a turbula mixer (950-mm amber bottle), followed by 1.822 g of magnesium stearate (Mallinckrodt Inc., St. Louis, MO) and the mixture was turbula blended for an additional 3 minutes to complete the formulation. Tablets (˜250) were F-press with a 13/32 "standard round concave (SRC) tool. (Manesty F-Press, Liverpool, United Kingdom) was used to produce a target weight of 450 mg (± 3%) and a target hardness of 12 kP (range 10-14 kP). A total of 12 tablets were sealed with 30-mm high-density polyethylene (HDPE) using heat induction seal (HIS) closures sealed with a heat induction sealant (Enercon Industries Corp., Menomonee, WI). ) Into the bottle. Samples were stored for 4 weeks at 40 ° C. and 75% relative humidity (RH). Samples were analyzed for levels of atorvastatin lactone by adding one tablet to 50 ml 1: 1 (v: v) 0.05 M ammonium citrate buffer (pH 7.4): acetonitrile and shaking for 20 minutes. The material is then filtered using a Gelman Acrodisc polytetrafluoroethylene membrane (0.45 μm pore size) and high pressure liquid chromatography (HPLC) (Phenomenex, Ultremex C18 column, 25.0 cm × 4.6 mm, HPLC) HP 1100 series, Agilent Corp., Wilmington, DE, 20 μl injection volume, flow rate of 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). The lactone level was found to be 25.4% (based on the ratio of lactone peaks to total peak area of all peaks).

Example  3

deflation Granulation  Used amorphous Atorvastatin  Preparation of Calcium Tablets

The following materials were added to a 950-mm amber bottle: 2.59 g of spray dried amorphous atorvastatin calcium, 78.00 g of microcrystalline cellulose (Avisel PH102 ™, FMC Corp., prepared as described in Example 1). Philadelphia, PA), 101.41 g of lactose hydrate (REG 310; Foremost Farms USA, Rothschild, WI), 4.00 g of hydroxypropyl cellulose (Klucel EXF ™; Aqualon, Wilmington, DE), 6.00 g of Croscarmellose sodium (liquid-di-sol; FMC Corp., Philadelphia, PA) and 1.00 g of magnesium stearate (Mallinckrodt Co., St. Louis, MO). The combination of the ingredients was mixed for 10 minutes using a turbula blender (Glen Mills, Clifton, NJ). The blend was then passed through a stainless steel sieve (# 30 mesh) after an additional 10 minutes of mixing to remove lumps. The blend was then stiffened to 3.5 kP by a 1 "flat-surface tool using a single-site Manesty F-press (Manesty, Liverpool, UK) (the tablet hardness was Schleuniger Tablet hardness tester). Hardness Tester, Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland), was used to dry granulate by slugging with a 1.00 g compaction). The compacts were fitted with a Fitzpatrick L1A grinder with a 0.040 "Konidur lapping plate. (Fitzpatrick Co., Elmhurst, IL) was used to grind at 500 rpm. The recovered milled product was placed back into the glass jar, to which 6.00 g of croscarmellose sodium was added and the contents were blended for 5 minutes. Finally, 1.00 g of magnesium stearate was added to the amber glass jar and the contents were blended for 3 minutes using a turbula. Tablets were made using a single site Manesty F-press. Tablets weighing 450 mg each were produced using 13/32 "standard circular concave (SRC) punches and molds. Average tablet hardness was 13 kilopascals (kP), with a range of 12-14 kP. The tablet weight was 447.9 mg and had a 0.7% RSD The tablets were packaged, stored and analyzed as described in Example 2 and the level of atorvastatin lactone was found to be 0.17% (based on the area percent of the lactone peak). ).

Example  4

Amorphous Atorvastatin  Calcium and Excipients Blend  Manufacture and Analysis-5% Drug

To each of the 10 60-mm amber bottles was added 500 mg of amorphous atorvastatin prepared as described in Example 1 and one of the following excipients:

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

(b) mannitol (mannozem 2080 granular, SPI Polyols, New Castle, DE);

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

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

(e) lactose (anhydride, direct tabletting grade, Quest International, Flavors & Food Ingredients CCL, Norwich, NY);

(f) lactose (Fast Flo ™ 316, Foremost Farms, Rothschild, WI);

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

(h) microcrystalline cellulose (Avisel PH105, FMC Biopolymer, Philadelphia, PA);

(i) microcrystalline cellulose (Avisel PH101, FMC Biopolymer, Philadelphia, PA);

(j) Dibasic calcium phosphate anhydride (A-Tab ™, Rhodia, Chicago Heights, IL).

Each mixture was blended for 15 minutes using a Turbula Mix-Shaker (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). Then, 100 mg of magnesium stearate (plant origin, Mallinckrodt Inc., St Louis, Mo.) was added to each bottle and the mixture was turbula-blended for an additional 5 minutes. A sieve stack with five spacers (top to bottom), a 60-mesh sieve, a 200-mesh sieve and a pan at the bottom was prepared. Pieces of 6 "weighing paper were placed between the fourth and fifth spacers. Each blend was placed separately on a 60-mesh sieve and the sieve stack was placed on a Sonic Sifter ™ by Allen Bradley Sonic. Sifter, Advantech Manufacturing, New Berlin, WI) The blends were sieved for 6 minutes using a sieve and pulse amplitude of 6. The weight in each sieve compartment was measured and potency analysis was performed using a 1: 1 ( v: v) extraction with deionized water: acetonitrile and shaking for 30 minutes, after which the material was used with a Gelman Acrodisc ™ polytetrafluoroethylene membrane (0.45 μm pore size) Filtration and analysis using a UV-Vis spectrophotometer (Model 8453, Agilent Corp., Wilmington, DE) The atorvastatin content was quantified using an external standard curve. The exit volume is shown in Table 1. The results are reported in Table 4.

Sample Preparation Conditions for HPLC Analysis. Dilution involves adopting the initial solution formed by combining the analyzed amount with the extraction volume and diluting to an amount designated 1: 1 (v: v) acetonitrile: water. Example Substances remaining on 60 mesh sieve Substances remaining on 200 mesh sieve Fine water Analytical Volume (g) Extraction Volume (ml) Analytical Volume (g) Extraction Volume (ml) Analytical Volume (g) Extraction Volume (ml) 4a 8.9 1000 0.6 500 0.3 500 (dilution 5: 1) 4b 3.9 2000 0.7 500 0.5 1000 (dilution 5: 1) 4c 5.0 500 4.2 500 0.5 1000 (dilution 5: 1) 4d 0.2 100 7.2 1000 2.1 1000 4e 1.3 500 5.2 500 (dilution 5: 1) 3.1 500 (dilution 4: 1) 4f 0.038 25 7.2 500 (diluted 6.67: 1) 2.3 1000 4 g 0.017 10 5.0 500 4.8 500 (dilution 5: 1) 4h 0.007 10 0.070 25 9.8 1000 (dilution 5: 1) 4i 1.1 1000 1.9 1000 4j 0.2 50 7.8 500 (diluted 6.67: 1) 1.8 1000 (dilution 4: 1)

Example  5

Amorphous Atorvastatin  Calcium and Excipients Blend  Manufacture and Analysis-40% Drug

To each of the ten 60-mm amber bottles was added 4.0 g of amorphous atorvastatin and 5.8 g of one of the following excipients prepared as described in Example 1:

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

(b) mannitol (mannozem 2080 granular, SPI Polyols, New Castle, DE);

(c) sucrose (compressible sugar, white d-pack, Tate & Lyle Co. American Sugars Inc, Brooklyn, NY);

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

(e) lactose (anhydride, direct tabletting grade, Quest International, Flavors & Food Ingredients CCL, Norwich, NY);

(f) lactose (Fast Flow 316, Foremost Farms, Rothschild, WI);

(g) microcrystalline cellulose (Avisel PH102, FMC Biopolymer, Philadelphia, PA);

(h) microcrystalline cellulose (Avisel PH105, FMC Biopolymer, Philadelphia, PA);

(i) microcrystalline cellulose (Avisel PH101, FMC Biopolymer, Philadelphia, PA);

(j) Dibasic calcium phosphate anhydride (A-Top, Rhodia, Chicago Heights, IL).

Each mixture was blended for 15 minutes using a Turbula Mix-Shaker (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). Then, 200 mg of magnesium stearate (plant origin, Mallinckrodt Inc., St Louis, Mo.) was added to each bottle and the mixture was turbula-blended for an additional 5 minutes. Sieve and potency analyzes were performed as described in Example 4 using the extraction volumes reported in Table 2. The results of the analysis are reported in Table 4.

Sample Preparation Conditions for HPLC Analysis. Dilution involves adopting the initial solution formed by combining the analyzed amount with the extraction volume and diluting to an amount designated 1: 1 (v: v) acetonitrile: water. Example Substances remaining on 60 mesh sieve Substances remaining on 200 mesh sieve Fine water Analytical Volume (g) Extraction Volume (ml) Analytical Volume (g) Extraction Volume (ml) Analytical Volume (g) Extraction Volume (ml) 5a 5.7 1000 0.2 500 1.9 1000 (diluted 20: 1) 5b 1.7 1000 0.9 500 0.9 1000 (diluted 10: 1) 5c 3.3 500 2.5 500 2.0 1000 (diluted 20: 1) 5d 0.1 500 2.8 1000 (diluted 10: 1) 1.8 1000 (diluted 20: 1) 5e 1.1 500 3.5 1000 (diluted 14.3: 1) 2.5 1000 (diluted 20: 1) 5f 0.024 100 3.4 1000 (diluted 20: 1) 2.6 1000 (diluted 10: 1) 5 g 0.034 10 (dilution 10: 1) 5.0 1000 (diluted 20: 1) 2.2 1000 (diluted 10: 1) 5h 0.012 10 (dilution 10: 1) 0.018 1000 (diluted 25: 1) 4.9 1000 (diluted 20: 1) 5i 1.5 1000 (dilution 5: 1) 1.6 1000 (dilution 5: 1) 5j 0.2 500 4.9 500 (diluted 16.7: 1) 4.7 1000 (diluted 20: 1)

Example  6

Amorphous Atorvastatin  Calcium and Excipients Combination of  deflation Granulated  Manufacture and analysis

For the dry granulation process, the specific density of each excipient and atorvastatin was determined using a micro-ultrapycnometer 1000 (Quantachrome Corp., Boynton Beach, FL) with ultra high purity helium at 20 psig inlet pressure. It was measured at 25.1 ℃ ± 0.9 ℃. All density measurements are large cells with instruments programmed to operate in a multi-run mode (max drive 15, run with average 3, 0.1% deviation, purge mode flow, purge time 15 minutes). (Cup volume 4.5 cm 3). The reported value was derived from the average of one iteration or two iterations with a new sample at every iteration. Sample weight was at least 1 gram (weight in the range from 1.1 to 2.7 grams).

(a) The true density of the 5 wt% atorvastatin blend with xylitol is the cumulative average of the true density of xylitol (1.49 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1, i.e. 1.48 g / ㏄ was estimated. Compressions were made from blends prepared as described in Example 4a using an F-press with a rectangular tool of 10 × 22 mm. Thickness and weight were varied to obtain a range of densities and corresponding solid fractions (ie, density of compacts divided by 1.48 g / dL), in which case thickness, weight 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 on the compacts were measured using a CT5 tensile strength tester (Engineering System (NOTTM), Nottingham, England) and found to be 0.034, 0.042, 0.152 and 0.163 kg. These values were converted to tensile strengths corresponding to the following values by dividing the strain force by the square of the thickness (multiplied by 22.07 in megapascal MPa): 0.21, 0.20, 0.80 and 0.89 MPa. Since this sample could not achieve the desired 1.0 MPa tensile strength, a maximum solid fraction of 0.92 was used for the production of the compacts. Based on this, the compacts of the blends were made to have a thickness of 351 mg and 2.0 mm per compact using a 0.50 "circular flat-surface tool on an F-press. These compacts (10 g total) were 900 rpm Were ground using a Mini Comil 193 (Quadro Engineering Incorporated, Waterloo, Ontario, Canada) with a 0.040 "lapping screen. Samples of material were analyzed as described in Example 4 using the extraction volumes listed in Table 3, and the results of the analysis are described in Table 4.

(b) The true density of the 5 wt% atorvastatin blend with mannitol is the cumulative mean of the true density of mannitol (1.45 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1, i.e. 1.44 g / ㏄ was estimated. Compressions were made from blends prepared as described in Example 4b using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared as described in Example 6a were 1.98 mm, 460 mg, 0.73; 1.77 mm, 422 mg, 0.75; 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. Corresponding tensile strengths for the compacts were 0.19, 0.25, 0.39, 1.03, 0.98, 0.40 and 1.92 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.84. On this basis the compacts were prepared as described in Example 6a to have a thickness of 305 mg and 1.95 mm per compact. In addition, the compacts were made to have a tensile strength of 3.30 MPa using 320 mg / compression with a thickness of 1.90 mm. Both compacts were ground as described in Example 6a. Two samples of material were analyzed for particle size distribution by sieve analysis as described in Example 4. The latter sample was analyzed for potency as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(c) The true density of the 5 wt% atorvastatin blend with direct tableting grade sucrose was that of sucrose (1.52 g / dl) and that of atorvastatin (1.24 g / dl) prepared as described in Example 1. It was estimated to be a cumulative mean, that is 1.51 g / dL. Compressions were made from blends prepared as described in Example 4c using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.76, 2.06, 2.15, 0.34 and 1.15 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.78. On this basis, a blend of the blend (311 mg / compression, thickness of 2.00 mm) was prepared and milled as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(d) The true density of the 5 wt% atorvastatin blend with lactose monohydrate is the cumulative average of the true density of lactose (1.49 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1 It was estimated to be 1.48 g / dl. Compressions were made from blends prepared as described in Example 4d using an F-press with a 10 × 22 mm rectangular tool. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 1.55, 1.05, 0.74, 0.35, 0.60 and 1.83 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.78. On this basis, a blend of the blend (302 mg / compression, 2.02 mm thick) was prepared and milled as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(e) The true density of the 5 wt% atorvastatin blend with lactose anhydride is the cumulative mean of the true density of lactose (1.50 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1, i.e. 1.49 It was estimated to be g / dL. Compressions were made from blends prepared as described in Example 4e using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.68, 2.16, 2.52 and 1.80 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.75. On this basis, a blend of the blend (286 mg / compression, 2.02 mm thick) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(f) The true density of the 5% wt atorvastatin blend with lactose fast flow is the cumulative mean of the true density of lactose (1.54 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1 It was estimated to be 1.53 g / dl. Compressions were made from blends prepared as described in Example 4f using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 1.10, 1.27, 1.16, 0.13 and 2.61 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.70. Based on this, the blend of compacts (272 mg / compression, thickness of 2.01 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(g) The true density of the 5 wt.% atorvastatin blend with microcrystalline cellulose (avicel PH102) is determined by the microcrystalline cellulose (1.58 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1. It was estimated to be a cumulative mean of true density, i.e., 1.56 g / dl. Compressions were made from blends prepared as described in Example 4g using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.22, 3.36, 6.99, 0.64, 2.58 and 1.03 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.56. On this basis, a blend of the blend (226 mg / compression, 2.01 mm thick) was prepared and milled as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(h) The true density of the 5 wt% atorvastatin blend with microcrystalline cellulose (avicel PH105) was determined by the microcrystalline cellulose (1.55 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1. The cumulative mean of true density, i.e., 1.53 g / dl was estimated. Compressions were made from blends prepared as described in Example 4h using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fraction for the compacts prepared 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. Corresponding tensile strengths for the compacts were 4.17, 7.99, 1.29, 2.62, 0.27 and 2.31 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.51. On this basis, a blend of the blend (211 mg / compression, 2.03 mm thick) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(i) The true density of the 5 wt.% atorvastatin blend with microcrystalline cellulose (avicel PH101) was determined from the microcrystalline cellulose (1.56 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1. It was estimated to be a cumulative mean of true density, ie 1.54 g / dl. Compressions were made from blends prepared as described in Example 4i using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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; 2.20 mm, 432 mg, 0.57; And 1.84 mm, 450 mg, 0.72. Corresponding tensile strengths for the compacts were 7.25, 4.96, 5.11, 1.79 and 5.11 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.50. Based on this the compact of the blend (208 mg / compression, thickness of 2.06 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(j) The true density of the 5 wt% atorvastatin blend with dibasic calcium phosphate anhydride (A-Tab ™) was calculated as calcium phosphate (2.78 g / dl) and atorvastatin prepared as described in Example 1 (1.24 g / dl Cumulative mean of true density, i.e., 2.70 g / dl. Compressions were made from blends prepared as described in Example 4j using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight, and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.98, 1.55, 2.32 and 0.49 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.53. On this basis, a blend of the blend (357 mg / compression, thickness of 1.94 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 4.

(k) The true density of the 40 wt% atorvastatin blend with xylitol is the cumulative mean of the true density of xylitol (1.49 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1, i.e. 1.39 g / ㏄ was estimated. Compressions were made from blends prepared as described in Example 5a using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.62, 0.98, 1.19, 0.09, 1.31 and 0.71 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.86. On this basis, a compact of the blend (296 mg / compression, thickness of 1.92 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(l) The true density of the 40 wt% atorvastatin blend with mannitol is the cumulative mean of the true density of mannitol (1.45 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1, i.e., 1.37 g / ㏄ was estimated. Compressions were made from blends prepared as described in Example 5b using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.63, 0.84, 2.13, 1.74, 2.91 and 2.72 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.76. On this basis a compact with a thickness of 269 mg and 2.00 mm per compact was prepared as described in Example 6a. In addition, the compacts were prepared to have a tensile strength of 2.18 MPa using 300 mg / compression with a thickness of 1.98 mm. Both compacts were ground as described in Example 6a. Two samples of material were analyzed for particle size distribution by sieve analysis as described in Example 4. The latter sample was analyzed for potency as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(m) The true density of the 40 wt% atorvastatin blend with direct tableting grade sucrose is the true density of atorvastatin (1.24 g / dl) prepared as described in Example 1 and sucrose (1.52 g / dl). It was estimated to be a cumulative mean, i. Compressions were made from blends prepared as described in Example 5c using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.20, 0.74, 1.43, 2.07, 0.46, 2.31 and 1.98 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.77. On this basis, a blend of the blend (298 mg / compression, thickness of 2.13 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(n) The true density of the 40 wt% atorvastatin blend with lactose monohydrate is the cumulative mean of the true density of lactose (1.49 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1 It was estimated to be 1.39 g / dl. Compressions were made from blends prepared as described in Example 5d using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 1.79, 1.34, 0.73 and 2.62 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.74. Based on this the blend of compacts (265 mg / compress, 1.96 mm thick) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(o) The true density of the 40 wt% atorvastatin blend with lactose anhydride is the cumulative mean of the true density of lactose (1.50 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1, i.e. 1.40 It was estimated to be g / dL. Compressions were made from blends prepared as described in Example 5e using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.81, 1.58, 1.52, 2.80 and 0.37 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.72. Based on this the compact of the blend (278 mg / compress, 2.08 mm thick) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(p) The true density of the 40 wt% atorvastatin blend with Lactose (FastFlo ™) is the cumulative mean of the true density of lactose (1.54 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1, That is, 1.42 g / dl. Compressions were made from blends prepared as described in Example 5f using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.09, 0.44, 0.43, 1.15 and 2.02 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.70. On this basis, a compact of the blend (262 mg / compression, thickness of 1.99 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(q) The true density of the 40% by weight atorvastatin blend with microcrystalline cellulose (avicel PH102) was determined by microcrystalline cellulose (1.58 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1. The cumulative mean of true density, i.e., 1.44 g / mm 3, was estimated. Compressions were made from blends prepared as described in Example 5g using an F-press with a 10 × 22 mm rectangular tool. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.78, 2.28, 1.88 and 0.29 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.59. On this basis, a blend of the blend (223 mg / compression, 2.04 mm thick) was prepared and milled as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(r) The true density of the 40% by weight atorvastatin blend with microcrystalline cellulose (avicel PH105) was determined by microcrystalline cellulose (1.55 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1. It was estimated to be a cumulative mean of true density, i.e., 1.43 g / dl. Compressions were made from blends prepared as described in Example 5h using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 0.85, 0.66, 2.22, 0.76, 2.00 and 4.42 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.58. On this basis, a blend of the blend (228 mg / compression, thickness of 2.03 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(s) The true density of the 40% by weight atorvastatin blend with microcrystalline cellulose (avicel PH101) was determined by microcrystalline cellulose (1.56 g / dl) and atorvastatin (1.24 g / dl) prepared as described in Example 1. It was estimated to be a cumulative mean of true density, i.e., 1.43 g / dl. Compressions were made from blends prepared as described in Example 5i using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 3.66, 0.75, 3.90, 1.62, 3.72 and 1.50 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.58. On this basis, a compact of the blend (209 mg / compression, thickness of 2.00 mm) was prepared and ground as described in Example 6a. Samples of material were analyzed as described in Example 4 with the extraction volumes listed in Table 3, and the final results are listed in Table 5.

(t) The true density of the 40 wt% atorvastatin blend with dibasic calcium phosphate anhydride (A-Tab ™) was calculated as calcium phosphate (2.78 g / dl) and atorvastatin prepared as described in Example 1 (1.24 g / dl Cumulative mean of true density, i.e., 2.16 g / dl. Compressions were made from blends prepared as described in Example 5j using an F-press with a rectangular tool of 10 × 22 mm. The thickness, weight and solid fractions for the compacts prepared 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. Corresponding tensile strengths for the compacts were 1.56, 1.31, 1.13, 1.95 and 0.45 MPa. The optimum solid fraction for 1.0 MPa tensile strength was found to be 0.54. Based on this the compact of the blend (294 mg / compression, thickness of 1.97 mm) was prepared and milled as described in Example 4 with the extraction volume described in Table 3 and the final results are listed in Table 5. It was.

Sample Preparation Conditions for HPLC Analysis. Dilution involves adopting the initial solution formed by combining the analyzed amount with the extraction volume and diluting to an amount designated 1: 1 (v: v) acetonitrile: water. Example Substances remaining on 60 mesh sieve Substances remaining on 200 mesh sieve Fine water Analytical Volume (g) Extraction Volume (ml) Analytical Volume (g) Extraction Volume (ml) Analytical Volume (g) Extraction Volume (ml) 6a 4.9 500 (dilution 5: 1) 2.8 1000 1.7 1000 6b 1.5 1000 1.4 1000 0.5 1000 6c 4.3 500 (dilution 4: 1) 2.9 500 (dilution 4: 1) 1.8 1000 6d 3.5 1000 3.0 1000 2.4 1000 6e 4.0 500 (dilution 4: 1) 3.1 1000 2.2 1000 6f 4.6 500 (dilution 4: 1) 1.5 500 3.3 1000 6 g 2.3 1000 4.0 500 (dilution 5: 1) 3.0 1000 6h 4.9 500 (dilution 5: 1) 1.2 500 3.5 500 (dilution 5: 1) 6i 2.2 1000 2.3 1000 5.0 500 (dilution 5: 1) 6j 4.2 500 (dilution 4: 1) 3.2 500 (dilution 4: 1) 2.4 1000 6k 3.2 1000 (diluted 10: 1) 1.8 500 (diluted 14.3: 1) 1.0 500 (dilution 10: 1) 6l 1.7 1000 (dilution 5: 1) 1.5 1000 (dilution 5: 1) 0.5 1000 (dilution 4: 1) 6m 4.9 1000 (diluted 20: 1) 2.5 1000 (diluted 10: 1) 1.8 1000 (diluted 6.67: 1) 6n 4.9 1000 (diluted 20: 1) 2.6 1000 (diluted 10: 1) 1.5 1000 (diluted 6.67: 1) 6o 2.8 1000 (diluted 10: 1) 2.3 1000 (diluted 10: 1) 1.3 500 (dilution 10: 1) 6p 3.0 1000 (diluted 10: 1) 1.5 500 (dilution 10: 1) 1.7 500 (dilution 10: 1) 6q 2.2 1000 (diluted 10: 1) 3.1 1000 (diluted 10: 1) 1.7 1000 (diluted 10: 1) 6r 2.5 1000 (diluted 10: 1) 1.0 500 (dilution 10: 1) 3.0 1000 (diluted 10: 1) 6s 2.2 1000 (diluted 10: 1) 2.2 500 (dilution 10: 1) 2.2 1000 (diluted 10: 1) 6t 2.5 1000 (diluted 10: 1) 2.4 500 (diluted 20: 1) 2.0 500 (diluted 20: 1)

Comparison of dry granulation versus a simple blend of atorvastatin (containing 40% by weight of atorvastatin) with a series of diluents that have a beneficial effect on the separation of certain diluents. Example Substances remaining on 60 mesh sieve Substances remaining on 200 mesh sieve Fine water  Granulation factor Weight (g) Effect (mgA / g) Weight (g) Effect (mgA / g) Weight (g) Effect (mgA / g) 5a 5.881 24.1 0.248 101.8 3.799 893.2 0.84 6k 6.462 325.7 1.930 333.4 0.970 522.9 5b 5.260 33.0 1.011 83.4 3.681 824.0 0.73 6l 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 6m 5.063 284.0 2.624 233.7 1.851 672.7 5d 0.205 54.3 6.064 191.0 3.678 627.1 0.64 6n 4.992 361.1 2.764 251.3 1.565 499.5 5e 1.129 29.1 3.869 66.8 4.955 633.0 0.79 6o 5.807 348.5 2.454 292.7 1.319 490.6 5f 0.059 146.0 7.224 245.5 2.634 650.5 0.62 6p 6.224 364.6 1.666 315.3 1.691 376.0 5 g 0.112 114.7 5.413 184.0 4.426 558.8 0.24 6q 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 6r 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 6s 2.263 351.4 2.502 202.9 4.575 404.9 5j 0.206 67.1 5.011 15.1 4.739 708.7 0.68 6t 5.300 346.1 2.499 251.1 2.000 550.7

Claims (15)

A dry-granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 1, comprising less than about 5% by weight alkaline earth metal salt additive. The dry granulated composition of claim 1, wherein the dry-granulated composition after storage for 4 weeks at 40 ° C. and 75% relative humidity has no greater than about 2% total impurities and / or degradation products based on the area percent of drug related HPLC peaks. A pharmaceutical composition containing. The pharmaceutical composition of claim 1, which is used for the formation of a solid unit dosage form. The pharmaceutical composition of claim 4, wherein the unit dosage form is selected from the group consisting of tablets and capsules. The pharmaceutical composition of claim 1, wherein the atorvastatin contains at least a portion of the atorvastatin or a pharmaceutically acceptable salt thereof in a partially or completely disordered form. The method of claim 4, wherein after four weeks of storage at 40 ° C. and 75% relative humidity, the unit dosage form contains up to about 1% total impurities and / or degradation products based on the area percent of drug related HPLC peaks. Pharmaceutical composition. The pharmaceutical composition of claim 1 comprising a diluent. The pharmaceutical composition of claim 8, wherein the diluent comprises more than about 50% by weight microcrystalline cellulose, lactose, sucrose, xylitol, or dibasic calcium phosphate. The unit dosage form of claim 4, wherein the dosage form also contains at least one active drug in addition to atorvastatin. The unit dosage form of claim 10, wherein the active drug other than atorvastatin comprises torcetrapib or amlodipine and a pharmaceutically acceptable salt thereof. (a) combining atorvastatin or a pharmaceutically acceptable salt thereof and one or more excipients suitable for use in the dry granulation step; (b) blending the mixture together in a mixer; (c) compacting the mixture; (d) milling, milling or sieving the compressed material; (e) optionally adding additional excipients and mixing the blend to form a composition A method of making a dry-granulated pharmaceutical composition of atorvastatin, comprising. A method for preparing a unit dosage form containing atorvastatin and at least one other active drug by combining the composition prepared according to the method of claim 12 with at least one other drug, and optionally further excipients. A method of treating hypercholesterolemia and / or hyperlipidemia, osteoporosis, benign prostatic hyperplasia and Alzheimer's disease comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 1. A kit for obtaining a therapeutic effect in a mammal, comprising a therapeutically effective amount of dry-granulated atorvastatin or a pharmaceutically acceptable salt thereof, and a container containing the dosage form prepared in a unit dosage form.