WO2014016842A1

WO2014016842A1 - Amorphous coprecipitates of rivaroxaban

Info

Publication number: WO2014016842A1
Application number: PCT/IN2012/000512
Authority: WO
Inventors: Dodda Mohan Rao; Buthukuri Venkat Reddy
Original assignee: Symed Labs Limited
Priority date: 2012-07-23
Filing date: 2012-07-23
Publication date: 2014-01-30

Abstract

Disclosed herein are stable amorphous coprecipitates of rivaroxaban and a pharmaceutically acceptable excipient, methods for the preparation, pharmaceutical compositions, and method of treating thereof. The amorphous co-precipitates of rivaroxaban disclosed herein are essentially free of crystalline forms, consistently reproducible, do not have the tendency to convert to crystalline forms, and are found to be more stable. The amorphous coprecipitates of rivaroxaban disclosed herein exhibit properties making them suitable for formulating rivaraxaban. More particularly, disclosed herein are amorphous coprecipitates of rivaroxaban with improved physiochemical characteristics which help in the effective bioavailability of rivaroxaban. Such pharmaceutical compositions may be administered easily to a mammalian patient in a dosage form, e.g., liquid, powder, elixir, injectable solution, with a high rate of bioavailability.

Description

AMORPHOUS COPRECIPITATES OF RIVAROXABAN

FIELD OF THE INVENTION

The present invention relates to stable amorphous coprecipitates of rivaroxaban with pharmaceutically acceptable excipients, methods for the preparation, pharmaceutical compositions, and method of treating thereof.

BACKGROUND OF THE INVENTION PCT Publication No. WO01/47919A 1 (corresponding US equivalent patent No. US 7,585,860) discloses a variety of substituted oxazolidinone derivatives and their salts processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are anticoagulants which inhibit the blood coagulation factor Xa with increased selectivity. Among them, Rivaroxaban, 5-chloro-N- [[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yI)phenyl]oxazolidin-5-yl]methyl]thiophene-2- carboxamide, acts as inhibitor of clotting factor Xa and which is used as agent for the prophylaxis and/or treatment of thromboembolic disorders, in particular myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses. Rivaroxaban is represented by the following structural formula I:

Rivaroxaban is sold by Bayer under the brand name Xarelto® and it is orally administered as tablets containing 10 mg of rivaroxaban.

Various processes for the preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.S. Patent Nos. 7,585,860; 7,35 1 ,823 and 7,816,355; PCT Publication Nos. WO201 1 /012321 , WO201 1/080341 and WO201 1/098501 ; and J. Med. Chem. 2005, 48, 5900-5908. According to U.S. Patent No. 7,585,860 (hereinafter referred to as the '860 patent), rivaroxaban is prepared by reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l ,3-oxazolidin-3- yl]phenyl]morpholine-3-one with 5-chlorothiophene-2-carbonyl chloride in the presence of excess amounts of pyridine. As per the process exemplified in example 44 of the '860 patent, rivaroxaban is prepared by drop-wise addition of 5-chlorothiophene-2-carbonyl chloride to a solution of 4-[4-[(5S)-5-(aminomethyl)-2-oxo- l ,3-oxazolidin-3- yl]phenyl]morpholine-3-one in pyridine at 0°C under argon, followed by removal of ice- cooling and stirring the reaction mixture at room temperature for 1 hour and then admixing with water. After addition of dichloromethane and phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried, filtered, and evaporated in vacuo. The residue was purified by Flash chromatography (dichloromethane/methanol mixtures) to produce rivaroxaban.

Rivaroxaban is known to exhibit polymorphism and various solid state forms including crystalline modifications (I, II & III), amorphous form, hydrate, dihydrate, solvates and co-crystals of rivaroxaban are apparently disclosed in U.S. Patent No. 8, 188,270; and PCT Publication Nos. WO20091/049851 , WO2010/075631 and WO2012/004245.

U.S. Patent No. 8, 1 88,270 (hereinafter referred to as the '270 patent), assigned to Bayer Schering Pharma, discloses three crystalline modifications (modifications I, II & III) and four solid state forms (an amorphous form, a hydrate, an NMP solvate and an inclusion compound with THF) of rivaroxaban, processes for their preparation, and characterizes the modifications and the solid state forms by powder X-ray diffraction (XRPD), Infra Red spectrum (IR), Raman spectrum, Far Infra Red spectrum (FIR), Near Infra Red spectrum (NIR) and Differential Scanning Calorimetric thermogram (DSC).

The '270 patent teaches that when rivaroxaban was originally produced, for example, as per the process described in the ' 860 patent, the crystal form was crystal modification I, which is characterized by having melting point of 230°C; a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 8.9, 12.0, 14.3, 16.5, 17.4, 18.1 , 19.5, 19.9, 21 .7, 22.5, 23.4, 24.1 , 24.5, 24.7, 25.6, 26.4, 26.7, 30.0, 30. 1 and 31 .8 degrees; and an IR spectrum having bands at 564, 686, 708, 746, 757, 830, 846, 920, 991 , 101 1 , 1056, 1077, 1 120, 1 146, 1 163, 1219, 1286, 1307, 1323, 1341 , 1374, 141 1 , 1429, 1470, 1486, 1517, 1546, 1605, 1646, 1669, 1737, 2867, 2895, 2936, 2976 and 3354 cm^"1. The '270 patent further teaches that the modification 1 has a solubility lower by the factor 4 in comparison to the modification II.

As per the process exemplified in the '270 patent, the amorphous form of rivaroxaban is prepared by fusing rivaroxaban in a crystalline form at a temperature of at least 230°C, preferably at a temperature of 240°C to 250°C, and subsequently rapidly cooling it to produce amorphous form of rivaroxaban. The amorphous form of rivaroxaban is characterized by an IR^' spectrum having bands at 467, 5 12, 550, 595, 613, 643, 689, 709, 725, 750, 810, 834, 864, 921 , 995, 1015, 1026, 1058, 1083, 1 126, 1 161, 1222, 1288, 1312, 1325, 1380, 1407, 1428, 1480, 1516, 1549, 1607, 1647, 1753, 2126, 2869, 2933, 2967, 3084 and 33 17 cm^"' .

However, the amorphous form of rivaroxaban obtained according to the process described in the '270 patent suffers from several disadvantages since the resulting amorphous form is a black-brownish colored solid, which is found to be decomposed, and has a very low purity (i.e., about 50% purity as measured by HPLC).

Based on the aforementioned drawbacks, the amorphous form of rivaroxaban obtained according to the prior art is an impure form and therefore it is not suitable for pharmaceutical formulations and therapeutic use thereof.

Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Amorphous solids consist of disordered arrangement of molecules and do not possess a distinguishable crystal lattice. The amorphous form is generally more soluble than the crystalline form and thus contributes more in the bioavailability.

An important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered pharmaceutical compound may reach the patient's bloodstream. The rate of dissolution is a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability. It has been disclosed in the art that the amorphous forms of a number of pharmaceutical compounds exhibit superior dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [ onno T., Chem. Pharm. Bull., 38, 2003 ( 1 990)]. For some therapeutic indications, one bioavailability pattern may be favored over another.

The discovery of new solid state forms of a pharmaceutical compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a pharmaceutical compound with a targeted release profile or other desired characteristics.

Amorphous coprecipitates of rivaroxaban have not been prepared, isolated, or characterized in the literature.

Hence, there is a need in the art for highly pure and stable amorphous coprecipitates of rivaroxaban, a process for the preparation and a pharmaceutical composition thereof.

SUMMARY OF THE INVENTION

We have carried out extensive experimentation to prepare amorphous coprecipitates of rivaroxaban with various pharmaceutically acceptable excipients, in different ratios, such as polyvinylpyrrolidone (also called as povidone or PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hypromellose phthalate (also called as hydroxypropyl methylcellulose phthalate or HPMCP), maltodextrin, cyclodextrin, copovidone, and the like. It has been surprisingly and unexpectedly found that the rivaroxaban forms amorphous coprecipitates with hypromellose phthalate when a specific solvent or a solvent medium is employed, whereas the rivaroxaban does not form amorphous coprecipitates with povidone, copovidone, hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC). The products obtained after removal of solvent from the solvent solution containing rivaroxaban and the excipients such as povidone, copovidone, hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) are found to be in the form of a crystalline solid or in the form of a solid state form that contains crystalline forms. We have now surprisingly and unexpectedly found amorphous coprecipitates of rivaroxaban with a pharmaceutically acceptable excipient, for example, hypromellose phthalate, which have high purity, adequate stability and good dissolution properties.

The amorphous co-precipitates of rivaroxaban disclosed herein are essentially free of crystalline forms, consistently reproducible, do not have the tendency to convert to crystalline forms, and are found to be more stable. The amorphous coprecipitates of • rivaroxaban disclosed herein exhibit properties making them suitable for formulating rivaroxaban. More particularly, disclosed herein are amorphous coprecipitates of rivaroxaban with improved physiochemica! characteristics which help in the effective bioavailability of rivaroxaban. Such pharmaceutical compositions may be administered easily to a mammalian patient in a dosage form, e.g., liquid, powder, elixir, injectable solution, with a high rate of bioavailability.

The term "amorphous co-precipitates of rivaroxaban essentially free of crystalline forms" means that no crystalline forms of rivaroxaban or the excipient can be detected within the limits of a powder X-ray diffractometer.

In yet another aspect, encompassed herein is a process for preparing the novel and stable amorphous coprecipitates of rivaroxaban with pharmaceutically acceptable excipients.

The amorphous coprecipitate of rivaroxaban obtained by the processes described herein has improved solubility properties and hence also has improved bioavailability.

In another aspect, provided herein are pharmaceutical compositions comprising the amorphous coprecipitates of rivaroxaban and one or more pharmaceutically acceptable excipients.

In still further aspect, encompassed herein is a process for preparing pharmaceutical formulations comprising combining the amorphous coprecipitates of rivaroxaban with one or more pharmaceutically acceptable excipients.

In another aspect, the amorphous coprecipitate of rivaroxaban disclosed herein for use in the pharmaceutical compositions has a D90 particle size of less than or equal to about 400 microns, specifically about l micron to about 300 microns, and most specifically about 10 microns to about 150 microns. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Coprecipitate of Rivaroxaban with Hypromellose phthalate obtained according to the example 1 .

Figure 2 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Coprecipitate of Rivaroxaban with Hypromellose phthalate obtained according to the example 2.

Figure 3 is a characteristic Infra red (IR) spectrum of Amorphous Coprecipitate of Rivaroxaban with Hypromellose phthalate obtained according to example 2.

Figure 4 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Form of Rivaroxaban obtained according to the comparative example.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there are provided amorphous coprecipitates comprising rivaroxaban and a pharmaceutically acceptable excipient having improved physiochemical characteristics that assist in the effective bioavailability of rivaroxaban. In one embodiment, the pharmaceutically acceptable excipient is hypromellose phthalate.

According to another aspect, there are provided pharmaceutical compositions comprising amorphous coprecipitates of rivaroxaban, and one or more pharmaceutically acceptable excipients.

The amorphous coprecipitates of rivaroxaban with a pharmaceutically acceptable carrier obtained by the processes disclosed herein may be characterized by one or more of their powder X-ray diffraction (XRD) pattern, infrared absorption (IR) spectrum, and SEM images of the morphological analysis.

In one embodiment, the amorphous coprecipitate of rivaroxaban with hypromellose phthalate is characterized by a powder XRD pattern substantially in accordance with Figure 1 or Figure 2. The X-ray powder diffraction patterns show a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

In another embodiment, the amorphous coprecipitate of rivaroxaban with hypromellose phthalate is further characterized by an infra red (FT-IR) spectrum having main bands at about 3448, 2925, 2853, 1735, 1664, 1648, 1637, 1629, 1602, 1560, 1518, 1290, 1216, 798, 742, 705, 680 and 665 cm^"1 substantially in accordance with Figure 3.

According to another aspect, there is provided a process for preparing an amorphous coprecipitate of rivaroxaban and a pharmaceutically acceptable excipient, comprising:

a) providing a solution of rivaroxaban and a pharmaceutically acceptable excipient in a solvent wherein the solvent is water, an organic solvent, or a solvent medium comprising water and an organic solvent, wherein the organic solvent is selected from the group consisting of an alcohol, a ketone, a nitrile, an ester, an organic water- miscible solvent, and mixtures thereof;

b) optionally, filtering the solvent solution to remove insoluble matter; and

c) substantially removing the solvent from the solution to produce the amorphous coprecipitate of rivaroxaban with the pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutically acceptable excipient used in step-(a) is hypromellose phthalate.

The use of other pharmaceutically acceptable excipients and mixtures of more than one of the pharmaceutical carriers for preparing amorphous coprecipitates of rivaroxaban to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Exemplary pharmaceutically acceptable excipients include, but are not limited to, polyvinylpyrrolidone (also called povidone), polyvinyl alcohol, hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, maltodextrins, cyclodextrins, gelatins, hypromellose phthalate, sugars, and combinations comprising one or more of the foregoing hydrophilic carriers. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, mixtures are all within the scope of this invention without limitation.

The process can produce amorphous co-precipitates of rivaroxaban with the pharmaceutically acceptable excipient in substantially pure form.

The term "substantially pure amorphous co-precipitate of rivaroxaban with the pharmaceutically acceptable excipient" refers to the amorphous co-precipitate of rivaroxaban having total purity, which includes both chemical and enantiomeric purity, greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.95% (measured by HPLC). For example, the total purity of the amorphous co-precipitate of rivaroxaban obtained by the process disclosed herein can be about 99.5% to about 99.99% as measured by HPLC.

The amorphous coprecipitates of rivaroxaban obtained by the process disclosed herein are stable, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling. The novel coprecipitates obtained by the process disclosed herein are suitable for formulating rivaroxaban.

In one embodiment, the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethoxyethane, dimethylsulfoxide, 1 ,4- dioxane, acetic acid, formic acid, and mixtures thereof.

In another embodiment, the solvent used in step-(a) is a solvent medium comprising water and an organic solvent wherein the organic solvent is selected from the group consisting of an alcohol, a ketone, a nitrile, an ester, an organic water-miscible solvent, and mixtures thereof.

Specifically, the solvent used in step-(a) is a solvent medium comprising water and an organic solvent wherein the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, acetonitrile, and mixtures thereof; and most specifically, the solvent used in step-(a) is a solvent medium comprising water and an organic solvent wherein the organic solvent is ethanol or acetonitrile.

Step-(a) of providing a solution of rivaroxaban includes dissolving rivaroxaban in the solvent, or such a solution may be obtained directly from a reaction in which rivaroxaban is formed. The pharmaceutical excipient can be dissolved in a solution containing rivaroxaban, or, rivaroxaban can be dissolved in a solution containing a pharmaceutical excipient.

Alternatively, a solution containing rivaroxaban can be combined with a solution containing a pharmaceutically acceptable excipient, and the solvents used for preparing the different solutions need not be the same as long as the solvents have mutual solubility and form a single phase. In any event, rivaroxaban should be completely soluble in the solvents used and should provide a clear solution. The presence of insoluble crystals could lead to the formation of a material that is not completely amorphous.

In one embodiment, the dissolution is carried out at a temperature of about 20°C to about 100°C, specifically at about 25°C to about 80°C, and more specifically at about 25°C to about 65°C.

In another embodiment, the solution obtained in step-(a) is optionally be subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment may be carried out by methods known in the art, for example by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 5 minutes, specifically at a temperature of about 40°C to about 70°C for at least 30 minutes; and filtering the resulting mixture through hyflo bed to obtain a filtrate containing rivaroxaban by removing charcoal or silica gel. Preferably, a finely powdered carbon is an active carbon. In one embodiment, a specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

The solution obtained in step-(a) is stirred at a temperature of about 20°C to the reflux temperature of the solvent used for at least 10 minutes, and specifically at a temperature of about 20°C to about 60°C for about 20 minutes to about 2 hours.

Removal of solvent in step-(c) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere to obtain amorphous coprecipitate comprising rivaroxaban and the pharmaceutically acceptable excipient.

In one embodiment, the removal of solvent in step-(c) is carried out by distillation. The distillation process can be performed at atmospheric pressure or at reduced pressure.

Specifically the distillation process is performed at reduced pressure. In one embodiment, the solvent is removed at a pressure of about 760 mm Hg or less, specifically at about 400 mm Hg or less, more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.

In a preferred embodiment, the distillation process is performed under reduced pressure and at a temperature of about 50°C to about 120°C, and most specifically at a temperature of about 60°C to about 90°C. In another embodiment, the solvent is removed by evaporation. Evaporation can be achieved at sub-zero temperatures by lyophilisation or freeze-drying techniques. The solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer ("ATFD").

In another embodiment, the removal of solvent in step-(c) may also be accomplished by spray-drying. The air inlet temperature to the spray drier used may range from about 50°C to about 150°C, specifically from about 60°C to about 120°C and most specifically from about 70°C to about 100°C; and the outlet air temperature used may range from about 30°C to about 90°C.

Another suitable method is vertical agitated thin-film drying (or evaporation). Agitated thin film evaporation technology involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled conditions. In vertical agitated thin-film drying (or evaporation) (ATFD-V), the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside-flowing solution while the heating jacket heats it.

The dried product obtained by the process disclosed herein above can optionally be milled to get desired particle sizes. Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles. Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling will frequently be performed prior to the drying operation.

Rivaroxaban as used herein as starting materials can be obtained by the processes described in the prior art, for example, the processes described in the U.S. Patent No. 7,585,860.

Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.

The resulting amorphous powder compositions disclosed herein have improved solubility properties and hence also have improved bioavailability. The amorphous coprecipitates of rivaroxaban with the pharmaceutically acceptable excipients obtained by the process disclosed herein are a random distribution of the rivaroxaban and the pharmaceutically acceptable excipient in a particle matrix. Without being held to any particular theory, the coprecipitates have the characteristics of solid dispersions at a molecular level, being in the nature of solid solutions. The solid solutions, or molecular dispersions, provide homogeneous particles in which substantially no discrete areas of only amorphous rivaroxaban and/or only pharmaceutically acceptable excipient can be observed.

Further encompassed herein is the use of the amorphous coprecipitates of rivaroxaban and the pharmaceutically acceptable excipients for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of the amorphous coprecipitates of rivaroxaban is selected from a solid dosage form and an oral suspension.

In one embodiment, the amorphous coprecipitate of rivaroxaban and the pharmaceutically acceptable excipient, has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 1 50 microns.

In another embodiment, the amorphous coprecipitate of rivaroxaban and the pharmaceutically acceptable excipient, disclosed herein for use in the pharmaceutical compositions has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.

In another embodiment, the particle sizes of the amorphous coprecipitate of rivaroxaban and the pharmaceutically acceptable excipient, can be achieved by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.

According to another aspect, there is provided a method for treating a patient suffering from myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses, comprising administering a therapeutically effective amount of the amorphous coprecipitate of rivaroxaban, or a pharmaceutical composition that comprises a therapeutically effective amount of amorphous coprecipitate of rivaroxaban along with pharmaceutically acceptable excipients.

According to another aspect, there are provided pharmaceutical compositions comprising amorphous coprecipitate of rivaroxaban prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining amorphous coprecipitate of rivaroxaban prepared according to the process disclosed herein, with one or more pharmaceutically acceptable excipients.

Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of the amorphous coprecipitate of rivaroxaban. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The amorphous coprecipitate of rivaroxaban may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.

The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinafter.

In one embodiment, capsule dosage forms contain the amorphous coprecipitate of rivaroxaban within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating agents include phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.

Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions described herein may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, micro fine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.

Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low- substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:

X-Ray Powder Diffraction (P-XRD):

The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X- ray powder diffractometer equipped with a Cu-anode (copper- α radiation). Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 V and current 35 mA. Infra-Red Spectroscopy (FT-IR):

FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm^"1 to 650 cm^"1.

HPLC Method for measuring Chemical Purity:

The chemical purity was measured by HPLC using Shimadzu LC-2010 CHT system with LC solutions software or its equivalent under the following conditions: Column = Develosil ODS HG-5, 150 mm x 4.6 mm, 5μιη or Equivalent; Detector wavelength = 270 nm; Flow Rate = 1 .0 ml/minute; Injection volume = Ι Ομί; Oven temperature = 30°C; Run time = 45 minutes; Diluent = 0. 1 % orthophosphoric acid : acetonitrile (40 : 60); Elution = Gradient; and Sample Concentration: 0.5 mg/ml.

Mobile Phase-A: 2.72 g of potassium dihydrogen phosphate + 1 ml of triethylamine in 1000 ml of water, pH was adjusted to 3.0 with dilute orthophosphoric acid (25%).

Mobile Phase-B: Acetonitrile.

HPLC Method for measuring Chiral Purity:

The chiral purity was measured by HPLC using Shimadzu LC-2010 CHT system with LC solutions software or its equivalent under the following conditions: Column = CHIRAL CEL OJ-3 column, 250 mm x 4.6 mm, 3μηι or Equivalent; Detector wavelength = 250 nm; Sample Concentration: 1 mg/ml; Run time = 30 minutes; Oven temperature: 35°C; Diluent = Mobile phase; Elution = Isocratic; Flow Rate: 1 ml/minute; Injection Volume: Ι Ομί; Mobile Phase = n-hexane (50 ml) : ethanol (50 ml) : trifluoro acetic acid (0.2 ml).

COMPARATIVE EXAMPLE

Preparation of Amorphous Form of Rivaroxaban as per the process exemplified in Example 7 of U.S. Patent No. 8,188,270 B2 (lines 52-67 of col-12 & lines 1-9 of col-13).

Rivaroxaban crystal modification I (2 g, a white crystalline solid having purity 99.6% as measured by HPLC) was placed in a reaction flask and then heated to 230-240°C under nitrogen atmosphere, the solid was maintained at the same temperature for 10 minutes (melting of the solid was observed) and subsequently brought to room temperature (25- 30°C) by sudden cooling while keeping the flask in an ice-water bath to yield amorphous form of rivaroxaban as a black-brownish colored solid (Purity by HPLC: 50.3%).

Characterization Data:

The resulting amorphous form of rivaroxaban is characterized by an X-ray powder diffraction pattern as shown in Figure 4; and further characterized by an infra red (FT-IR) spectrum having bands at about 3328, 3080, 2933, 2867, 2743, 1752, 1701 , 1648, 161 1 , 1548, 1517, 1478, 1440, 1428, 1407, 1380, 1345, 1325, 131 1 , 1288, 1261 , 1238, 1221 , 1 161 , 1 124, 1 101 , 1072, 1033, 994, 965, 919, 863, 822, 808, 749, 725, 708, 690 and 667 cm^"1.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of Amorphous Co-precipitate of Rivaroxaban with Hydroxypropyl methylcellulose phthalate

Acetonitrile (200 ml) and water (20 ml) were added to rivaroxaban (0.5 g), followed by heating the mixture at 50-55°C to form a clear solution. Hydroxypropyl methylcellulose phthalate (5 g) was added to the above solution at 50-55°C and then stirred for 45 minutes at the same temperature. The resulting solution filtered to remove insoluble particles, followed by removal of solvent by distillation under reduced pressure at 80°C to produce 5.5 g of amorphous co-precipitate of rivaroxaban with hydroxypropyl methylcellulose phthalate (1 : 10) as a white colored powder (Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.99%).

Characterization Data:

The resulting amorphous co-precipitate of rivaroxaban with hydroxypropyl methylcellulose phthalate ( 1 : 10) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 1 . Example 2

Isopropyl alcohol (700 ml) and water (50 ml) were added to rivaroxaban (0.5 g), followed by heating the mixture at 60°C to form a clear solution. The resulting solution was cooled to 30-35°C, followed by the addition of hydroxypropyl methylcellulose phthalate (5 g) and then stirring the solution for 30 minutes at the same temperature. The resulting solution filtered to remove insoluble particles, followed by removal of solvent by distillation under reduced pressure at 80°C to produce 5.5 g of amorphous co-precipitate of rivaroxaban with hydroxypropyl methylcellulose phthalate (1 : 10) as a white colored powder (Purity by HPLC: 99.85%; and Chiral Purity by HPLC: 99.99%).

Characterization Data:

The resulting amorphous co-precipitate of rivaroxaban with hydroxypropyl methylcellulose phthalate (1 : 1 0) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 2; and further characterized by an infra red (FT-IR) spectrum having main bands at about 3448, 2925, 2853, 1735, 1664, 1648, 1637, 1629, 1602, 1560, 1518, 1290, 1216, 798, 742, 705, 680 and 665 cm^"1 as shown in Figure 3.

Example 3

Preparation of Amorphous Coprecipitate of Rivaroxaban with hydroxypropyl methyl cellulose phthalate

Ethanol (700 ml) and water (50 ml) were added to rivaroxaban (0.5 g), followed by heating the mixture at 60°C to form a clear solution. The resulting solution was cooled to 30-35°C, followed by the addition of hydroxypropyl methylcellulose phthalate (5 g) and then stirring the solution for 30 minutes at the same temperature. The resulting solution filtered to remove insoluble particles, followed by removal of solvent by distillation under reduced pressure at 80°C to produce 5.5 g of amorphous co-precipitate of rivaroxaban with hydroxypropyl methylcellulose phthalate (1 : 10) as a white colored powder. Example 4

Acetone (200 ml) and water (20 ml) were added to rivaroxaban (0.5 g), followed by heating the mixture at 50-55°C to form a clear solution. Hydroxypropyl methylcellulose phthalate (5 g) was added to the above solution at 50-55°C and then stirred for 45 minutes at the same temperature. The resulting solution filtered to remove insoluble particles, followed by removal of solvent by distillation under reduced pressure at 80°C to produce 5.5 g of amorphous co-precipitate of rivaroxaban with hydroxypropyl methylcellulose phthalate ( 1 : 10) as a white colored powder.

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The term "micronization" used herein means a process or method by which the size of a population of particles is reduced .

As used herein, the term "micron" or "μπι" both are equivalent and refer to "micrometer" which is 1 x 10^"6 meter.

As used herein, "Particle Size Distribution (P.S.D)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent.

The important characteristics of the PSD are the (D₉o), which is the size, in microns, below which 90% of the particles by volume are found, and the (D₅₀), which is the size, in microns, below which 50% of the particles by volume are found. Thus, a D90 or d(0.9) of less than 300 microns means that 90 volume-percent of the particles in a composition have a diameter less than 300 microns.

The term "coprecipitate or co-precipitate" as used herein refers to compositions comprising amorphous rivaroxaban together with at least one pharmaceutically acceptable excipient, being prepared by removing solvent from a solution containing both of them.

The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use. The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.

The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.

The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.

The term "diluents" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "glidant" as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti- caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum sil icate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

We claim:

1. An amorphous coprecipitate comprising rivaroxaban and a pharmaceutically acceptable excipient.

2. The amorphous coprecipitate of rivaroxaban of claim 1 , wherein the pharmaceutically acceptable excipient is hypromellose phthalate.

3. The amorphous coprecipitate of rivaroxaban of claim 2, wherein the amorphous coprecipitate of rivaroxaban with hypromellose phthalate is characterized by a powder XRD pattern, showing no peaks, substantially in accordance with Figure 1 or Figure 2.

4. The amorphous coprecipitate of rivaroxaban of claim 2, wherein the amorphous coprecipitate of rivaroxaban with hypromellose phthalate is further characterized by an infra red (FT-IR) spectrum having main bands at about 3448, 2925, 2853, 1 735, 1664, 1648, 1637, 1629, 1602, 1560, 15 18, 1290, 121 6, 798, 742, 705, 680 and 665 cm^{- 1} substantially in accordance with Figure 3.

5. A process for the preparation of the amorphous coprecipitate of rivaroxaban of claim 1 , comprising:

a) providing a solution of rivaroxaban and a pharmaceutically acceptable excipient in a solvent wherein the solvent is water, an organic solvent, or a solvent medium comprising water and an organic solvent, wherein the organic solvent is selected from the group consisting of an alcohol, a ketone, a nitrile, an ester, an organic water-miscible solvent, and mixtures thereof;

b) optionally, filtering the solvent solution to remove insoluble matter; and

6. The process of claim 5, wherein the pharmaceutically acceptable excipient used in step-(a) is hypromellose phthalate.

7. The process of claim 5, wherein the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran, Ν,Ν-dimethylformamide, dimethoxyethane, dimethylsulfoxide, 1 ,4-dioxane, acetic acid, formic acid, and mixtures thereof. .

8. The process of claim 5, wherein the solvent used in step-(a) is a solvent medium comprising water and an organic solvent wherein the organic solvent is selected from the group consisting of an alcohol, a ketone, a nitrile, an ester, an organic water- miscible solvent, and mixtures thereof; and wherein the removal of the solvent in step- (c) is accomplished by distillation or complete evaporation of the solvent, spray drying, vacuum drying, lyophilization or freeze drying, agitated thin-film drying, or a combination thereof.

9. The process of claim 8, wherein the solvent used in step-(a) is a solvent medium comprising water and an organic solvent wherein the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, acetonitrile, and mixtures thereof; and wherein the removal of the solvent in step-(c) is accomplished by distillation.

10. The process of claim 9, wherein the solvent used in step-(a) is a solvent medium comprising water and an organic solvent wherein the organic solvent is ethanol or acetonitrile; and wherein the distillation process is performed under reduced pressure at a temperature of about 50°C to about 120°C.

1 1. The process of claim 10, wherein the distillation process is performed under reduced pressure at a temperature of about 60°C to about 90°C.

12. A pharmaceutical composition comprising the amorphous coprecipitate of rivaroxaban of claim 1 , and one or more pharmaceutically acceptable excipients.

13. A method for treating a patient suffering from myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses, comprising administering a therapeutically effective amount of the amorphous coprecipitate of rivaroxaban of claim 1 , or a pharmaceutical composition that comprises a therapeutically effective amount of the amorphous coprecipitate of rivaroxaban along with pharmaceutically acceptable excipients.

r