Field of the Invention

The present invention relates to a production method of amorphous apixaban using the method of encapsulation in a porous carrier and the hot-melt extrusion method.

Background Art

Apixaban, or l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl-4 ,5,6,7- tetrahydro-lH-pyrazolo-[3,4-c]pyridine-3-carboxamide is a strong and highly selective inhibitor of the active site of factor Xa and is therefore used for the treatment and prophylaxis of diseases related to blood coagulation. Currently, its use is approved for the prevention of thromboembolic events in patients who have undergone hip or knee joint replacement, for the prevention of venous brain events and systemic embolism in atrial fibrillation patients and for the treatment of deep vein thrombosis and lung embolism.

The molecule of apixaban, which was first described in the international patent application WO 03/026652, has the following structural formula:

Depending on the preparation conditions, apixaban may create various types of crystalline forms or an amorphous form. These forms differ from each other with their crystal arrangement and their physical properties, especially solubility and biological availability. The first mention of crystalline forms of apixaban can be found in the patent application WO 2006/078331, which describes preparation of the H2-2 dihydrate and the non-solvated form N-l. These forms were subsequently characterized in WO 2007/001385. Later, a great number of other polymorphs of apixaban were described, see e.g. WO 2013/119328 or WO 2014/173377. The original preparation sold under the trade name Eliquis contains crystalline apixaban in the form N-l. Eliquis is commercially available in a drug form with the total strength of 2.5 and 5.0 mg of the active substance with the recommended dosage twice a day. The drug form is represented by coated tablets with immediate release of the active substance, whose particles exhibit D(0.9) < 30 μηι, measured using the light diffusion method. It is the particle size that is the critical factor for the dissolution rate of apixaban in spite of the fact that according to the biopharmaceutical classification system apixaban is classified in the BCS III group of substances, i.e. substances that show good solubility, but poor permeability. Concerning such substances, an expert would not expect their particle size to have a principal influence on their bioavailability. However, the solubility and thus bioavailability of crystalline apixaban strongly depends on the particle size as proved in WO 2011/106478. Therefore, during the preparation of drug forms containing crystalline apixaban the particle size must be carefully checked, because any deviation may strongly influence the dissolution characteristics of the final preparation.

Solubility of apixaban can be improved by using an amorphous form instead of a crystalline form. WO 2010/147978 described a drug form for controlled releasing of apixaban containing the active substance in the form of a solid amorphous dispersion. Amorphous apixaban was prepared by means of a spray drying process with the use of a polymer as e.g. hydroxypropyl methylcellulose (HPMC) and tetrahydrofuran (THF) as the solvent. In this document, controlled release of apixaban is understood in such a sense that during an hour less than 70% by weight of the active substance is released. However, spray drying is a process with very high demands for energy and the technology, which is often very economically inconvenient in the industrial scale. Also, tetrahydrofuran is a highly flammable substance with suspected carcinogenicity. In addition, during its storage its contact with oxygen must be avoided, otherwise explosive peroxides are formed.

The patent applications WO 2013/164839, WO 2014/203275 and WO 2015/103230 describe amorphous apixaban prepared using the solvent evaporation method with the use of various polymers as e.g. hydroxypropyl methylcellulose acetate succinate, HPMC, copolymers of methacrylic acid, polyvinyl pyrrolidone or PVP-K30. A disadvantage of this method is that prepared amorphous apixaban may revert to the energetically more convenient crystalline state with time, especially if it is exposed to an environment with an elevated temperature or humidity. Similarly to the previous case, a disadvantage of this method is the necessity to use organic solvents, which are harmful both to human health and the used devices. Residual solvent can be virtually always detected in the final drug form, which is considerably problematic in the case of preparations intended for medical use.

Therefore, there is a continuing need of an easy, economically feasible preparation method of amorphous apixaban with good solubility and stability.

Disclosure of the Invention

An object of the invention is a preparation method of apixaban in an amorphous form that comprises the following steps:

a) dissolving apixaban or its pharmaceutically acceptable salt in an organic solvent, b) mixing the obtained solution of apixaban with a porous carrier and

c) removing the solvent.

After the removal of the solvent, apixaban remains encapsulated in the porous carrier in an amorphous form.

In one embodiment of the invention, the solution of apixaban and the porous carrier are mixed in one container and incubated for at least 1 h, preferably for 12 to 24 h and then the solvent is removed. The incubation time determines the quantity of the active substance encapsulated in the porous carrier. The equilibrium quantity is achieved after approx. 24 hours of incubation.

The solvent is best removed by evaporation, which is preferably conducted at a temperature from 20 to 150°C for at least one minute, more preferably at a temperature from 40 to 90°C for 20 to 120 minutes. A vacuum evaporator is advantageously used for the evaporation of the solvent. Particles of the porous carrier are especially advantageously separated by filtration before the evaporation. Most advantageously, after the filtration, particles of the porous carrier are at least once washed with the solvent to remove the crystalline active substance from its surface.

In another embodiment of the invention, step b) comprises spraying of the solution of apixaban onto the porous carrier and step c) comprises evaporation of the solvent. If this method is used, capillary forces virtually immediately cause retraction of the sprayed solution of apixaban into the pores of the carrier. Then, the solvent is evaporated and new spraying of the solution of apixaban can follow. Steps b) and c) may repeat alternately with the total number of cycles from 2 to 100, more preferably from 10 to 35. Especially advantageously, after the last step c), particles of the porous carrier are at least once washed with the solvent to wash crystalline apixaban off the carrier surface. Excessive solvent is removed by evaporation again.

As the porous carrier virtually any inorganic carrier approved for pharmaceutical use with the pore size smaller than 10 nm can be used. Pores of the carrier should not be larger than 10 nm, otherwise after the evaporation of the solvent the active substance might crystallize into a crystalline form. The porous carrier preferably has the average inner volume of pores from 0.4 to 5 c Vg. The size of the pores and their inner volume can be determined using a BET analysis.

Examples of carriers comprise porous oxides of metals, semi-metals, alkaline earth metals and their mixtures. The carrier is preferably selected from the group consisting of porous AI2O3, CaC0 ₃ , MgO, Ti0 ₂ , Si0 ₂₍ ZnO and their mixtures. Most preferably, porous Si0 ₂ is used as the carrier, especially porous silicon dioxide sold under the brand name Syloid 63 FP, Syloid 72 FP, Syloid 244 FP, Syloid XDP 3050 and Syloid XDP 3150.

As the source of apixaban, virtually any polymorphic form of apixaban or its pharmaceutically acceptable salt can be used. Preferably, the crystalline form N-l is used. This form was first prepared and characterized in WO 2006/078331 and is well-known to experts in the art.

For the dissolution of apixaban virtually any organic solvent that apixaban is soluble in can be used. Suitable solvents are well-known to experts in the art. They mainly comprise alcohols as methanol, ethanol, isopropanol, 1-butanol, t-butylalcohol, ethylene glycol or propylene glycol, ketones as acetone, butanone, methyl isobutyl ketone or N-methyl-2- pyrrolidone, esters as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate or isobutyl acetate, ethers as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol or cyclopentyl methyl ether, amides as N,N- dimethylformamide or N,N-dimethylacetamide, nitriles as acetonitrile, propionitrile or butyronitrile, organic acids as acetic acid, aliphatic and aromatic hydrocarbons as hexanes, heptanes, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons as dichloromethane, dichloroethane, chloroform, tetrachloromethane or chlorobenzene, sulfoxides as dimethylsulfoxide and their mixtures and mixtures with water. The solvent for apixaban is preferably selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethylene glycol, propylene glycol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dichloromethane, chloroform or dimethyl sulfoxide and their mixtures and mixtures with water. Most preferably, the solvent is ethanol or dichloromethane. Another object of the invention is amorphous apixaban encapsulated in a porous carrier. Amorphous apixaban prepared this way is suitable for the treatment or prophylaxis of thromboembolic events. They mainly include a stroke, systemic embolism, deep vein thrombosis and lung embolism.

Another object of the invention is a preparation method of apixaban in an amorphous form wherein apixaban or its pharmaceutically acceptable salt is mixed with a

pharmaceutically acceptable polymer and the resulting mixture is subjected to hot-melt extrusion (HME). This method is based on pushing of material at an elevated temperature and pressure through a nozzle, which guarantees obtaining of a product with uniform density and shape. HME is carried out in an extruder that consists of a filling device, shaft (worm) that ensures movement of the material through the heated space and an extruding head. The dwell time of the mixture of the pharmaceutically acceptable polymer with apixaban or its pharmaceutically acceptable salt in the extruder is preferably less than 10 minutes, especially preferably 1 to 5 minutes. The extrusion is preferably carried out at a temperature of 145 to 235°C, more preferably at a temperature of 165 to 215°C and most preferably at a temperature of l95 ± 10°C.

As the source of apixaban, virtually any polymorphic form of apixaban or its pharmaceutically acceptable salt can be used. Preferably, the crystalline form N-l is used. This form was first prepared and characterized in WO 2006/078331 and is well-known to experts in the art.

Any polymer approved for pharmaceutical use and exhibiting thermoplastic properties can be used to create the polymeric matrix. Suitable pharmaceutically acceptable polymers are well-known to experts in the art. With respect to the properties of the active pharmaceutical substance and/or the resulting extrudate some polymers may be more suitable than other ones in certain cases. The factors influencing the polymer selection include e.g. the chemical purity of the active substance, its temperature stability, hygroscopicity etc. Thus, the selection of a suitable polymer or group of polymers may differ in particular cases.

Suitable pharmaceutically acceptable polymers comprise especially homopolymers and copolymers of polyalkylene oxides, especially polyethylene glycol and polypropylene glycol, homopolymers and copolymers of N-vinyl lactams, especially N-vinylpyrrolidone, as polyvinylpyrrolidone (PVP), and N-vinylcaprolactam, homopolymers and copolymers of acrylic acid and its derivatives, homopolymers and copolymers of methacrylic acid and its derivatives, especially methylmethacrylate, further derivatives of cellulose as methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose, starch derivatives etc.

The pharmaceutically acceptable polymers preferably have their glass transition temperature (Tg) lower than 180°C, especially preferably their Tg is in the range of 50 to 150°C.

In a preferred embodiment of the invention, the pharmaceutically acceptable polymer is selected from the group consisting of Soluplus, which is chemically a polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, and Eudragits, which belong to copolymers of methacrylic acid. Out of Eudragits, Eudragit SI 00 and LI 00 are especially convenient, which are chemically copolymers of methacrylic acid with methylmethacrylate in the ratio of 1:2 (SI 00) or 1:1 (LI 00).

The weight ratio of apixaban and the pharmaceutically acceptable polymer is preferably 1:1 to 1:15, more preferably 1:2 to 1:10 and even more preferably 1:5.

Another object of the invention is amorphous apixaban prepared using the hot-melt extrusion method. In one embodiment, apixaban is in the form of an amorphous dispersion in a pharmaceutically acceptable polymer, which is preferably Soluplus. In another embodiment, amorphous apixaban is in the form of a solid solution with a pharmaceutically acceptable polymer, which is preferably Eudragit LI 00 or SI 00.

Amorphous apixaban prepared with the use of hot-melt extrusion is suitable for the treatment or prophylaxis of thromboembolic events. They mainly include a stroke, systemic embolism, deep vein thrombosis and lung embolism.

An object of the invention is also a pharmaceutical composition containing amorphous apixaban encapsulated in a porous carrier and a pharmaceutical composition containing amorphous apixaban prepared using the hot-melt extrusion method. The content of apixaban in both pharmaceutical compositions amounts to 1 to 10 mg, which advantageously represents 1 to 10% of the total weight of the composition. Especially advantageously the content of apixaban is 2.5 or 5 mg.

Both compositions may also contain one or more pharmaceutically acceptable auxiliary substances that serve especially as fillers, binders, lubricants, surfactants, disintegrants, dyes, solvents, antimicrobial substances or as taste and smell correctors. The composition preferably contains at least one excipient selected from the group consisting of microcrystalline cellulose, lactose, sodium lauryl sulphate, sodium croscarmellose and magnesium stearate. The pharmaceutical composition may be prepared in virtually any solid drug form, e.g. in the form of tablets, capsules, powder, pellets, or granules. A preferred drug form is a capsule, tablet or coated tablet. It can be advantageously prepared in such a manner that the porous carrier containing amorphous apixaban obtained in the above mentioned way is mixed with pharmaceutically acceptable auxiliary substances and subjected to tableting, which is possibly followed by coating. The other embodiment can be preferably prepared in such a way that the extrudate obtained in the above mentioned way is ground to particles with D(0.9) > 100 μηι, preferably to particles with D(0.9) = 0.5 mm, or D(0.9) = 1.0 mm (measured by means of image analysis), mixed with pharmaceutically acceptable auxiliary substances and subjected to tableting, which is possibly followed by coating.

Detailed description of the Invention

During the development of the solid drug form of amorphous apixaban it was necessary to solve inconvenient technological properties of apixaban. Attempts with spray drying of a mixture of apixaban with a polymer in a solvent showed that the principal factor influencing the quality of the final product was homogeneity of the mixture. Since the content of apixaban in the drug form only amounts to 2.5 or 5 mg, any slightest inhomogeneity causes fluctuation of the content of the active substance in the final amorphous dispersion. Besides, apixaban exhibits high adhesion to commonly used surfaces. Thus, during spray drying problems occurred with adhesion of the resulting particles inside the cyclone of the spray drier. In addition, the spray drying technology is difficult to translate into the industrial scale.

Further investigation showed that the technology of encapsulation into a porous carrier could be used. Within this method, pores of the carrier are first filled with a prepared solution of apixaban, which is followed by removal of the solvent. Under normal circumstances, recrystallization of apixaban would occur, but due to a limited space inside the pore the transformation to a crystalline form is prevented and apixaban remains in the amorphous form. The reason is the fact that the molecules of apixaban do not have enough space to create a crystalline lattice. Crystalline active ingredients exhibit a long-distance arrangement (over 100 A), a sharp melting point and they can be described by the respective parameters of the internal structure (lattice parameters, interplanar distances, positions of atoms, spatial symmetry group etc.). Amorphous active ingredients exhibit a short-distance arrangement (under 100 A), a glass transition temperature and their structure cannot be described by any structural parameters. Similar attempts can be found in the literature, e.g. the patent application WO 2014/177491 described amorphization of vortioxetine hydrobromide with the use of porous adsorbents. The technological procedure used by the authors consisted in placing an adsorbent into a solution of the solvent and active substance, incubation of the mixture for a certain time, filtering and drying. However, it is by far not a rule that any active substance encapsulated in any porous carrier will be in an amorphous state after evaporation of the solvent. Whether this will happen is influenced by the size of the molecules of the active substance, the size and shape of the pores of the porous carrier and the way of encapsulation in the porous carrier. The authors of the invention have managed to find a suitable combination of the above mentioned factors and prepare an amorphous form of apixaban inside a porous carrier.

In the case of apixaban, water cannot be used as the solvent, but organic solvents must be used. This poses higher demands for the process safety and ensuring evaporation of residues of organic solvents in the final product. The solvent evaporation method also brings similar problems. In addition, this technology is not commonly used in the industrial scale, but it is rather used for laboratory purposes and experiments.

Thus, none of the procedures known from the prior art was suitable for industrial production of amorphous apixaban. However, when looking for a new preparation method of amorphous apixaban the authors of the invention surprisingly found out that hot-melt extrusion could be used for its preparation.

Literature usually says that to obtain an amorphous form of an active pharmaceutical ingredient the hot-melt extrusion should be carried out at a temperature that is at least 30°C higher than its glass transition temperature (Tg). However, at the same time in a non-aqueous medium work at temperatures to 140°C is recommended for five minutes at the most due to excessive thermal loading of the active pharmaceutical ingredient, which leads to its chemical degradation and formation of impurities. However, in the case of apixaban, which has Tg of approx. 120°C, the amorphous form could not be obtained at temperatures lower than 140°C. Since at higher temperatures degradation of the active ingredient should occur, this method was not considered as suitable for the preparation of the amorphous form. However, it was surprisingly found out that in combination with certain pharmaceutically acceptable polymers apixaban could be protected up to temperatures exceeding 200°C. Thus, the authors of the invention managed to obtain an amorphous form of apixaban without undesired degradation of the active ingredient occurring. Compared to spray drying, hot-melt extrusion and encapsulation in a porous carrier are faster, require less energy, and also eliminate the need to handle organic solvents. Both methods are generally more economical and technologically less demanding. Moreover, the final extrudate has better technological properties than particles produced by spray drying or solvent evaporation. Apixaban is encapsulated in the porous carrier in an amorphous form, or, in the other embodiment, is enclosed in the polymeric matrix in the form of an amorphous dispersion or solid solution form which reduces its undesired adhesive properties. At the same time, dust formation and possible exposure to apixaban during tableting, encapsulating or packing of powder in bags is also reduced. This is very important because it is a substance classified as OEB 4 (Occupational Exposure Band). This classification expresses the exposure band during work and for apixaban the preliminary value has been particularly determined to be 5 μξ/να3 (OEL, Occupational Exposure Limit).

Amorphous apixaban encapsulated in a porous carrier, or apixaban in the form of an amorphous dispersion or solid solution, can be easily formulated with auxiliary substances into a pharmaceutical composition. The formulation prepared this way is highly stable, no subsequent recrystallization or degradation of apixaban occurs, which means that no special storage conditions of the drug are required.

Brief description of the Drawings

Fig. 1 represents XRPD characterization of a) crystalline apixaban of form N-1 (bottom curve), b) amorphous apixaban encapsulated in the porous carrier Syloid 72 FP (top curve).

Fig. 2 represents DSC characterization of amorphous apixaban encapsulated in the porous carrier Syloid 72 FP. Fig. 3 represents TGA characterization of amorphous apixaban encapsulated in the porous carrier Syloid 72 FP.

Fig. 4 represents the dissolution profile of amorphous apixaban encapsulated in the porous carrier Syloid 72 FP. For comparison, it also contains the dissolution profile of crystalline apixaban with the particle size of d(0.9) < 50 μιη, measured with the use of light diffusion. Fig. 5 represents XRPD characterization of a) crystalline apixaban of form N-l (bottom curve), b) extrudate prepared using the procedure in accordance with Example 1 at the HME temperature of 135°C (top curve). Fig. 6 represents XRPD characterization of a) crystalline apixaban of form N-l (bottom curve), b) extrudate prepared using the procedure in accordance with Example 1 at the HME temperature of 195°C (top curve).

Fig. 7 represents DSC characterization of extrudate obtained using the procedure in accordance with Example 1 at the HME temperature of 195°C.

Fig. 8 represents the dissolution profile of extrudate prepared using the procedure in accordance with Example 1 at the HME temperature of 195°C milled to the size of 1.0 mm (amorphous formulation I) and 0.5 mm (amorphous formulation Π). For comparison, it also contains the dissolution profile of crystalline apixaban with the particle size of d(0.9) < 50 μιη, measured with the use of light diffusion.

Fig. 9 represents DSC characterization of extrudate obtained using the procedure in accordance with Example 2 at the HME temperature of 185°C.

Examples

The examples below are only provided to illustrate and to explain the invention and are not in any case intended to restrict the protection scope, which is only delimited by the wording of the patent claims.

Example 1

1 g of apixaban in the polymorphic form N-l was dissolved in 100 ml of dichloromethane and the obtained solution was stirred in an enclosed container for 10 minutes. Subsequently, 5 g of porous particles of Syloid 72 FP (highly porous micronized Si0 ₂ ) were added to the solution. The solution was stirred in an enclosed vessel for 24 hours and then the particles were filtered off and washed with pure dichloromethane. The particles were dried on a rotary vacuum evaporator at the temperature of 40°C and the pressure of 15 mBar for 60 minutes. During the optimization of this procedure was further found out, that the solution of apixaban with porous particles doesn't require stirring for 24 hours, but that stirring for only 2 hours is sufficient.

With the use of this method it was managed to encapsulate the amount of amorphous apixaban corresponding to 12.3% of weight of the porous carrier alone, see Fig. 3.

The porous carrier with encapsulated apixaban was characterized using the X-ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC) methods. The results summarized in Fig. 1 and 2 show that encapsulated apixaban is in an amorphous form.

Particles of the carrier were further subjected to dissolution tests. As shown in Fig. 4, in the case of encapsulation of the amorphous form of apixaban in the porous carrier considerable acceleration of solubility of apixaban as compared to crystalline form N-l occurred.

Example 2

1 g of apixaban in the polymorphic form N-l was dissolved in 100 ml of

dichloromethane and the obtained solution was stirred in the enclosed container A for 10 minutes. 5 g of porous particles of Syloid 72 FP were put in the stirred enclosed container B fitted with an atomizing nozzle with a supply for spraying the solution. In this case, the inner volume of the pores of the porous carrier was 1.2 ml / 1 g. The solution was directed via a plastic tube from the enclosed stirred container A to the container B. The solution was dosed from the container A to the container B in the quantity corresponding to the volume of the inner pores of the porous carrier. This way, 6 ml of the solution was sprayed in each cycle. After each spraying cycle, the container B was heated up to 60°C for 10 minutes to ensure evaporation of the solvent. The spraying was repeated seventeen times. After the last spraying cycle and heating up, the particles were washed with pure dichloromethane to wash off apixaban that crystallized on the carrier surface after the evaporation of the solvent. The particles were dried on a rotary vacuum evaporator at the temperature of 40°C and the pressure of 15 mBar for 60 minutes.

With the use of this method it was managed to encapsulate the amount of amorphous apixaban corresponding to 15% of weight of the porous carrier alone. Example 3

1 g of apixaban in the polymorphic form N-l was dissolved in 100 ml of dichloromethane and the obtained solution was stirred in the enclosed container A for 10 minutes. 5 g of porous particles of Syloid 244 FP were put in the stirred enclosed container B fitted with an atomizing nozzle with a supply for spraying the solution. In this case, the inner volume of the pores of the porous carrier was 1.5 ml / 1 g. The solution was directed via a plastic tube from the enclosed stirred container A to the container B. The solution was dosed from the container A to the container B in the quantity corresponding to the volume of the inner pores of the porous carrier. This way, 7.5 ml of the solution was sprayed in each cycle. After each spraying cycle, the container B was heated up to 60°C for 10 minutes to ensure evaporation of the solvent. The spraying was repeated thirteen times. After the last spraying cycle and heating up, the particles were washed with pure dichloromethane to wash off apixaban that crystallized on the carrier surface after the evaporation of the solvent. The particles were dried on a rotary vacuum evaporator at the temperature of 40°C and the pressure of 15 mBar for 60 minutes. Using this method, it was managed to encapsulate the quantity of amorphous apixaban corresponding to 17% of the weight of the porous carrier alone.

Example 4

1 g of apixaban in the polymorphic form N-l was dissolved in 1000 ml of ethanol and the obtained solution was stirred in the enclosed container A for 10 minutes. 2.5 g of porous particles of Syloid 72 FP were put in the stirred enclosed container B fitted with an atomizing nozzle with a supply for spraying the solution. The solution was directed via a plastic tube from the enclosed stirred container A to the container B. The solution was dosed from the container A to the container B in the quantity corresponding to the volume of the inner pores of the porous carrier. This way, 3 ml of the solution was sprayed in each cycle. After each spraying cycle, the container B was heated up to 90°C for 10 minutes to ensure evaporation of the solvent. The spraying was repeated thirty-three times. After the last spraying cycle and heating up, the particles were washed with pure ethanol to wash off apixaban that crystallized on the carrier surface after the evaporation of the solvent. The particles were dried on a rotary vacuum evaporator at the temperature of 40°C and the pressure of 15 mBar for 60 minutes. Using this method, it was managed to encapsulate the quantity of amorphous apixaban corresponding to 10% of the weight of the porous carrier alone. Example 5

The porous carrier prepared using the procedure in accordance with Example 1 was mixed with microcrystalline cellulose, lactose, sodium lauryl sulphate, sodium croscarmellose and magnesium stearate. The mixture was homogenized and tableted into tablets with the strength of 2.5 mg or 5 mg of apixaban. The composition of individual tablets is presented in Tables 1 and 2.

Table 1 - strength 2.5 mg

Example 6

1 g of apixaban in the polymorphic form N-l was dissolved in 65 ml of dichloromethane under the reflux. Subsequently, 5 g of porous particles of Syloid 72 FP (highly porous micronized Si0 ₂ ). The solution was stirred in the enclosed container for 24 hours, after that the particles were filtered and washed with pure dichloromethane. The particles were dried on a rotary vacuum evaporator at the temperature of 40°C and the pressure of 15 mBar for 60 minutes.

Using this method, it was managed to encapsulate the quantity of amorphous apixaban corresponding to 15-20% of the weight of the porous carrier alone.

The porous carrier with encapsulated apixaban was characterized using the X-ray

Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC). The results show that encapsulated apixaban is in an amorphous form.

Example 7

1 g of apixaban in the polymorphic form N-l was dissolved in 50 ml of chloroform at room temperature. Subsequently, 5 g of porous particles of Syloid 72 FP (highly porous micronized Si0 ₂ ). The solution was stirred in the enclosed container for 24 hours, after that the particles were filtered and washed with pure dichloromethane. The particles were dried on a rotary vacuum evaporator at the temperature of 40°C and the pressure of 15 mBar for 60 minutes.

Using this method, it was managed to encapsulate the quantity of amorphous apixaban corresponding to 15-20% of the weight of the porous carrier alone.

The porous carrier with encapsulated apixaban was characterized using the X-ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC). The results show that encapsulated apixaban is in an amorphous form.

Example 8

10 g of apixaban in the polymorphic form N-l was mixed with 100 g of silicone particles of Syloid 72 FP (highly porous micronized Si0 ₂ ). The obtained mixture was homogenized on the homogenization device. Subsequently, the mixture of silicone particles and apixaban was brought into the hot-melt extruder. The extruder was equipped with five heating segments, out of which was set to the temperature of 90°C and four to the temperature of 200°C. The amount of the mixture brought to the extruder was calculated in such a way that the dwell time of the mixture in the extruder should not exceed five minutes and hot-melt extrusion could be accomplished.

Using this method, it was managed to encapsulate the quantity of amorphous apixaban corresponding to 10% of the weight of the porous carrier alone. The porous carrier with encapsulated apixaban was characterized using the X-ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC). The results show that encapsulated apixaban is in an amorphous form. Example 9

90 g of apixaban in the polymorphic form N-l was mixed with 450 g of Soluplus and the resulting mixture was homogenized in a homogenizing device. Then, the mixture of the polymer and apixaban was brought to a hot-melt extruder. The extruder was equipped with five heating segments out of which two were set to the temperature of 90°C and three to a higher temperature (see Table 3). The amount of the mixture brought to the extruder was calculated in such a way that the dwell time of the mixture in the extruder should not exceed five minutes and hot-melt extrusion could be accomplished. The resulting extrudate was pushed through a nozzle with the diameter of 0.5 mm, 1.0 mm or 1.5 mm and directly cut into particles with the size of 0.5 mm, 1.0 mm or 1.5 mm.

Extrudates prepared at different temperatures were characterized using the X-ray powder diffraction (XRPD) method, see Fig. 5 and 6. The results summarized in Table 3 show that the amorphous form of apixaban only starts to be formed from the temperature of approx. 165°C. At lower temperatures, apixaban remains in the crystalline form. Thus, the temperature used in the hot-melt extruder represents one of the principal factor influencing the production and quality of the amorphous form of apixaban.

Table 3

To find out whether a solid solution of amorphous apixaban with the polymer or amorphous dispersion of apixaban in the polymer was obtained, the differential scanning calorimetry (DSC) method was used with the heating rate of 5°C/min (amplitude = 0.8°C, period = 60 s). The results in Fig. 7 show that the extrudate prepared at 195°C showed two different glass transition temperatures (Tgl=57.1°C and Tg2=106.2°C). Thus, this is the case of apixaban in the amorphous dispersion form.

Particles of the extrudate prepared at 195°C were subjected to dissolution tests. As shown in Fig. 8, the amorphous form showed considerable acceleration of dissolution of apixaban and an increase of dissolution reproducibility as compared to the crystalline form N-l.

The prepared extrudates were subjected to stability tests under the controlled conditions 25°C/65% relative humidity (RH) and 40°C/75% RH for 1, 3, 6 a 12 months. Results show that after the 3 months in the load 40°C/75% RH the recrystalUzation of apixaban occurs in some samples. Under the conditions 25 °C/65% apixaban remains in an amorphous form.

The recrystallization may occur for various reasons. Without wishing to bound to any theory, the cause of recrystallization may be the fact that the examined ratio active substance -.polymer 1:5 is too close to the solubility limit of apixaban in polymer.

Therefore, also other samples of extrudate with the ratio apixaban: Soluplus 1:7 and

1:10 were prepared the same way as described above. Simultaneously were prepared also extrudates with the ratio apixaban:Soluplus 1:1 and 1:2. The temperature of hot-melt extrusion was 195°C. The prepared extrudates were characterized using the X-ray powder diffraction (XRPD) method. Measurements revealed that in all cases apixaban was obtained in an amorphous form.

Example 10

90 g of apixaban was mixed with 450 g of Eudragit SI 00 and homogenized in a homogenizing device. Then, the mixture of the polymer and apixaban was brought to a hot- melt extruder. The extruder was equipped with five heating segments out of which two were set to the temperature of 90°C and three to a higher temperature (see Table 4). The amount of the mixture brought to the extruder was calculated in such a way that the dwell time of the mixture in the extruder should not exceed five minutes and hot-melt extrusion could be accomplished. The resulting extrudate was pushed through a nozzle with the diameter of 0.5 mm, 1.0 mm or 1.5 mm and directly cut into particles with the size of 0.5 mm, 1.0 mm or 1.5 mm.

Extrudates prepared at different temperatures were characterized using the XRPD method. The results summarized in Table 4 show that the amorphous form of apixaban starts to be formed from the temperature of approx. 145°C already. At lower temperatures, apixaban remains in the crystalline form.

Table 4

To find out whether a solid solution of amorphous apixaban with the polymer or amorphous dispersion of apixaban in the polymer was obtained, the DSC method was used with the heating rate of 5°C/min (amplitude = 0.8°C, period = 60 s). The results in Fig. 9 show that the extrudate prepared at 165°C showed one glass transition temperature (Tg=146.0°C). Thus, this is the case of apixaban in the solid solution form.

Example 11

Extrudate prepared using the procedure in accordance with Example 9 or 10 was mixed with microcrystalline cellulose, lactose, sodium lauryl sulphate, sodium croscarmellose and magnesium stearate. The mixture was homogenized and tabletted into tablets with the strength of 2.5 mg or 5 mg of apixaban. The composition of individual tablets is presented in Tables 5 and 6.

Table 5 - strength 2.5 mg

Constituent Function Content

Polymeric matrix with the active

Extrudate 15 mg

ingredient

Microcrystalline cellulose Filler 24.3 mg

Lactose Filler 54.4 mg

Sodium lauryl sulphate Surfactant 0.5 mg

Sodium croscarmellose Disintegrant 4.3 mg

Magnesium stearate Lubricant 1.5 mg

Table 6 - strength 5 mg

Constituent Function Content

Extrudate Polymeric matrix with the active 30 mg ingredient

Microcrystalline cellulose Filler 48.6 mg

Lactose Filler 108.8 mg

Sodium lauryl sulphate Surfactant 1 mg

Sodium croscarmellose Disintegrant 8.6 mg

Magnesium stearate Lubricant 3 mg

Example 12

90 g of apixaban was mixed with 180 g of Eudragit SI 00 and homogenized in a homogenizing device. Then, the mixture of the polymer and apixaban was supplied to a hot- melt extruder. The extruder was equipped with five heating segments out of which two were set to the temperature of 90°C and three to the temperature of 185°C. The amount of the mixture brought to the extruder was calculated in such a way that the dwell time of the mixture in the extruder should not exceed five minutes and hot-melt extrusion could be accomplished. The resulting extrudate was pushed through a nozzle with the diameter of 0.5 mm, 1.0 mm or 1.5 mm and directly cut into particles with the size of 0.5 mm, 1.0 mm or 1.5 mm.

Example 13

Extrudate prepared using the procedure in accordance with Example 12 was mixed with microcrystalline cellulose, lactose, sodium lauryl sulphate, sodium croscarmellose and magnesium stearate. The mixture was homogenized and tableted into tablets with the strength of 2.5 mg of apixaban. The composition of the tablets is presented in Table 7.

Table 7 - strength 2.5 mg

Constituent Function Content

Polymeric matrix with the active

Extrudate 7.5 mg

ingredient

Microcrystalline cellulose Filler 31.8 mg

Lactose Filler 54.4 mg

Sodium lauryl sulphate Surfactant 0.5 mg

Sodium croscarmellose Disintegrant 4.3 mg

Magnesium stearate Lubricant 1.5 mg Example 14

90 g of apixaban was mixed with 900 g of Eudragit SI 00 and homogenized in a homogenizing device. Then, the mixture of the polymer and apixaban was brought to a hot- melt extruder. The extruder was equipped with five heating segments out of which two were set to the temperature of 90°C and three to the temperature of 185°C. The amount of the mixture brought to the extruder was calculated in such a way that the dwell time of the mixture in the extruder should not exceed five minutes and hot-melt extrusion could be accomplished. The resulting extrudate was pushed through a nozzle with the diameter of 0.5 mm, 1.0 mm or 1.5 mm and directly cut into particles with the size of 0.5 mm, 1.0 mm or 1.5 mm.

Example 15

Extrudate prepared using the procedure in accordance with Example 14 was mixed with microcrystalline cellulose, lactose, sodium lauryl sulphate, sodium croscarmellose and magnesium stearate. The mixture was homogenized and tabletted into tablets with the strength of 2.5 mg of apixaban. The composition of the tablets is presented in Table 8.

Table 8 - strength 2.5 mg

Constituent Function Content

Polymeric matrix with the active

Extrudate 27.5 mg

ingredient

Microcrystalline cellulose Filler 26.2 mg

Lactose Filler 40 mg

Sodium lauryl sulphate Surfactant 0.5 mg

Sodium croscarmellose Disintegrant 4.3 mg

Magnesium stearate Lubricant 1.5 mg