WO2014013498A1

WO2014013498A1 - Amorphous coprecipitates of linezolid

Info

Publication number: WO2014013498A1
Application number: PCT/IN2012/000501
Authority: WO
Inventors: Dodda Mohan Rao; Buthukuri Venkat Reddy
Original assignee: Symed Labs Limited
Priority date: 2012-07-17
Filing date: 2012-07-17
Publication date: 2014-01-23

Abstract

Disclosed herein are stable amorphous coprecipitates of linezolid and a pharmaceutically acceptable excipient, methods for the preparation, pharmaceutical compositions, and method of treating thereof. The amorphous coprecipitates of linezolid disclosed herein are consistently reproducible, do not have the tendency to convert to crystalline forms, and are found to be more stable. The amorphou coprecipitates of linezolid disclosed herein exhibit properties making them suitable for formulating linezolid. More particularly, disclosed herein are amorphous coprecipitates of linezolid with improved physiochemical characteristics which help in the effective bioavailability of linezolid. 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 LINEZOLID

FIELD OF THE INVENTION

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

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,688,792 (hereinafter referred to as the '792 patent), assigned to Pharmacia & Upjohn Company, discloses a variety of oxazine and thiazine oxazolidinone derivatives and their stereochemically isomeric forms, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms and acid-fast organisms. Among them, Linezolid, a member of the oxazolidinone class of drugs and chemically named as N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide, is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicill in- resistant Staphylococcus aureus (MRSA). Linezolid is represented by the following structural formula:

The main indications of linezolid are infections of the skin and soft tissues and pneumonia (particularly hospital-acquired pneumonia). Linezolid is marketed by Pfizer under the trade names Zyvox (in the United States, United Kingdom, Australia, and several other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada and Mexico).

The synthesis of linezolid was first described in the '792 patent. Similar processes for the preparation of linezolid are also described in U.S. Patent No. 5,837,870, PCT Publication No. WO 99/24393, J. Med. Chem. 39(3), 673-679, 1996 (hereinafter referred to as the 'JMC Article'), and Tetrahedron Lett., 40(26), 4855, 1999.

Linezolid is known to exhibit polymorphism and three crystalline forms (Forms I, II & III) and an amorphous form of linezolid are so far known.

Amorphous form of linezolid is apparently disclosed in U.S. Patent Application Publication No. 2006/01 1 1350 A l and PCT Publication No. WO 2007/026369 A l .

U.S. Patent No. 6,559,305 (hereinafter referred to as the '305 patent), assigned to Pharmacia & Upjohn Company, discloses two crystal forms (Form I & Form II) of linezolid. According to the '305 patent, the crystalline Form II of linezolid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 17.69, 19.41 , 19.69, 19.93, 21 .61 , 22.39, 22.84, 23.52, 24.16, 25.28, 26.66, 27.01 and 27.77 degrees; and an IR spectrum having bands at 3364, 1 748, 1675, 1537, 15 17, 1445, 1410, 1401 , 1358, 1329, 1287, 1274, 1253, 1237, 1221 , 1 145, 1 130, 1 123, 1 1 16, 1078, 1066, 1049, 907, 852 and 758 cm^'1.

The '305 patent further states that when linezolid was originally produced, for example, as per the processes exemplified in the '792 patent (example 5) and J. Med. Chem. 39 (3), 673-679, 1996, the crystal form was Form I, which is characterized by having melting point of 181.5- 1 82.5°C, and an IR spectrum having bands at 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435 cm^{" 1}. Crystal Form II differs from Form I in its IR spectrum, X-ray powder diffraction spectrum (XRPD) and melting point.

U.S. Patent No. 7,714, 128 B2 (hereinafter referred to as the ' 128 patent), assigned to Symed Labs Limited (the present applicant), discloses a novel, stable and enantiomerically pure crystalline form (Form III) of linezolid, process for the preparation and pharmaceutical compositions thereof. According to the Ί 28 patent, the crystalline Form III of linezolid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at about 7.6, 9.6, 13.6, 14.9, 1 8.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 ± 0.2 degrees; and an IR spectrum having main bands at about 3338, 1741 , 1662, 1544, 1517, 1471 , 1452, 1425, 1400, 1381 , 1334, 1273, 1255, 1228, 1213, 1 197, 1 1 76, 1 1 16, 1082, 105 1 , 937, 923, 904, 869, 825 and 756 cm^'1.

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 ( 1990)]. 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 linezolid 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 linezolid, a process for the preparation and a pharmaceutical composition thereof. SUMMARY OF THE INVENTION

The present inventors have carried out extensive experimentation to prepare amorphous coprecipitates of Iinezolid 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) and copovidone. It has been surprisingly and unexpectedly found that the Iinezolid forms amorphous coprecipitates with povidone, copovidone and hypromellose phthalate when employed in a specific ratio, whereas the Iinezolid does not form amorphous coprecipitates with hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC). The products obtained after removal of solvent from the solvent solution containing Iinezolid and the excipients such as 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 nature.

The present inventors have now surprisingly and unexpectedly found amorphous coprecipitates of Iinezolid with a pharmaceutically acceptable excipient selected from the group consisting of povidone, copovidone and hypromellose phthalate, which have high purity, adequate stability and good dissolution properties.

The amorphous coprecipitates of Iinezolid disclosed herein are consistently reproducible, do not have the tendency to convert to crystalline forms, and are found to be more stable. The amorphous coprecipitates of Iinezolid disclosed herein exhibit properties making them suitable for formulating Iinezolid. More particularly, disclosed herein are amorphous coprecipitates of Iinezolid with improved physiochemical characteristics which help in the effective bioavailability of Iinezolid. 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.

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

The amorphous coprecipitate of Iinezolid 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 linezolid 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 linezolid with one or more pharmaceutically acceptable excipients.

In another aspect, the amorphous coprecipitate of linezolid 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.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Coprecipitate of Linezolid with Hypromellose phthalate (1.5 : 1).

Figure 2 is a characteristic infra red (IR) spectrum of Amorphous Coprecipitate of Linezolid with Hypromellose phthalate ( 1.5 : 1 ).

Figure 3 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Coprecipitate of Linezolid with Hypromellose phthalate (1 : 1).

Figure 4 is a characteristic infra red (IR) spectrum of Amorphous Coprecipitate of Linezolid with Hypromellose phthalate (1 : I).

Figure 5 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Coprecipitate of Linezolid with povidone 30 (1 : 10).

Figure 6 is a characteristic infra red (IR) spectrum of Amorphous Coprecipitate of Linezolid with povidone K30 (1 : 10).

Figure 7 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Coprecipitate of Linezolid with copovidone (1 : 10).

Figure 8 is a characteristic infra red (IR) spectrum of Amorphous Coprecipitate of Linezolid with copovidone (1 : 10). DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there are provided amorphous coprecipitates comprising linezolid and a pharmaceutically acceptable excipient selected from the group consisting of povidone, copovidone and hypromellose phthalate, having improved physiochemical characteristics that assist in the effective bioavailability of linezolid.

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

The amorphous coprecipitates of linezolid 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 linezolid with hypromellose phthalate (1 .5 : 1 ) is characterized by a powder XRD pattern substantially in accordance with Figure 1. The X-ray powder diffraction pattern shows a plain halo with no well- defined peaks, thus demonstrating the amorphous nature of the product.

The amorphous coprecipitate of linezolid with hypromellose phthalate (1.5 : 1) is further characterized by an infra red (FT-IR) spectrum having main bands at about 3364, 3074, 2959, 2858, 2834, 1751 , 1675, 1653, 1628, 1600, 1576, 1558, 1539, 1520, 1516, 1487, 1447, 1418, 1378, 1328, 1273, 1256, 1237, 1222, 1 195, 1 173, 1 1 16, 1067, 935, 920, 894, 851 , 802, 746, 704 and 659 ± 2 cm^"1 substantially in accordance with Figure 2.

In another embodiment, the amorphous coprecipitate of linezolid with hypromellose phthalate ( 1 : 1 ) is characterized by a powder XRD pattern substantially in accordance with Figure 3. The X-ray powder diffraction pattern shows a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

The amorphous coprecipitate of linezolid with hypromellose phthalate (1 : 1 ) is further characterized by an infra red (FT-IR) spectrum having main bands at about 3365, 3073, 2959, 2859, 2835, 1756, 1734, 1718, 1679, 1669, 1653, 1646, 1635, 1628, 1601 , 1575, 1569, 1539, 1520, 1517, 1487, 1448, 141 8, 1379, 1328, 1289, 1273, 1239, 1225, 1 196, 1 174, 1 143, 1 1 18, 1067, 1050, 1033, 938, 922, 891 , 863, 843, 802, 747, 707 and 659 ± 2 cm^"1 substantially in accordance with Figure 4. In another embodiment, the amorphous coprecipitate of linezolid with povidone K30 (1 : 10) is characterized by a powder XRD pattern substantially in accordance with Figure 5. The X-ray powder diffraction pattern shows a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

The amorphous coprecipitate of linezolid with povidone K30 (1 : 10) is further characterized by an infra red (FT-IR) spectrum having main bands at about 3472, 2963, 2925, 2857, 1750, 1 739, 1733, 1699, 1683, 1668, 1653, 1646, 1569, 1540, 15 16, 1506, 1495, 1464, 1436, 1423, 1419, 1374, 1317, 1291 , 1263, 1217, 1 168, 1 101 , 1050, 1017, 935, 897, 846, 801 , 741 , 731 and 654 ± 2 cm^"1 substantially in accordance with Figure 6.

In another embodiment, the amorphous coprecipitate of linezolid with copovidone

( l : 10) is characterized by a powder XRD pattern substantially in accordance with Figure 7. The X-ray powder diffraction pattern shows a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

The amorphous coprecipitate of linezolid with copovidone ( 1 : 10) is further characterized by an infra red (FT-IR) spectrum having main bands at about 3448, 2959, 2924, 2854, 1741 , 1648, 1637, 1522, 1497, 1491 , 1466, 1458, 1438, 1425, 1420, 1375, 1320, 1295, 1261 , 1217, 1 1 18, 1019, 937, 896, 873, 846, 734 and 659 ± 2 cm^-1, substantially in accordance with Figure 8.

According to another aspect, there is provided a process for preparing an amorphous coprecipitate of linezolid and a pharmaceutically acceptable excipient selected from the group consisting of povidone, copovidone and hypromellose phthalate, comprising:

a) providing a solution of linezolid and a pharmaceutically acceptable excipient in a solvent, wherein the solvent is selected from the group consisting of an alcohol, water, acetone, ethyl acetate, dichloromethane, dichloroethane, chloroform and mixtures thereof, and wherein the pharmaceutically acceptable excipient is selected from the group consisting of povidone, copovidone and hypromellose phthalate;

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 linezolid with the pharmaceutically acceptable excipient. The process can produce amorphous coprecipitates of linezolid with the pharmaceutically acceptable excipient in substantially pure form.

The amorphous coprecipitates of linezolid 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 linezolid.

The use of mixtures of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, mixtures are all within the scope of this invention without limitation.

The povidone may be chosen from one or more of the grades such as PVP K-15, K- 25, K-30, K29/32, -60 and K-90.

In one embodiment, the solvent used in step-(a) is an alcohol solvent. Specifically, the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, and mixtures thereof; and more specifically, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, and mixtures thereof. A most specific alcohol solvent used in step-(a) is methanol.

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

Alternatively, a solution containing linezolid 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, linezolid should be completely soluble in the solvents used and should provide a clear solution. The presence of undissolved 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 60°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 linezolid 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 40°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 linezolid 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 1 10°C, and most specifically at a temperature of about 60°C to about 70°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.

Linezolid 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 Nos. 5,688,792; 6,559,305; and 7,714, 128.

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 linezolid with the pharmaceutically acceptable excipients obtained by the process disclosed herein are a random distribution of the linezolid 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 linezolid and/or only pharmaceutically acceptable excipient can be observed.

Further encompassed herein is the use of the amorphous coprecipitates of linezolid 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 linezolid is selected from a solid dosage form and an oral suspension.

In one embodiment, the amorphous coprecipitate of linezolid 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 150 microns.

In another embodiment, the amorphous coprecipitate of linezolid 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 linezolid 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 bacterial infections or diseases caused by Gram-positive bacteria including pneumonia, streptococci, vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), comprising administering a therapeutically effective amount of the amorphous coprecipitate of linezolid, or a pharmaceutical composition that comprises a therapeutically effective amount of amorphous coprecipitate of linezolid along with pharmaceutically acceptable excipients. According to another aspect, there are provided pharmaceutical compositions comprising amorphous coprecipitate of linezolid 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 linezolid 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 linezolid. 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 linezolid 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 linezolid 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 BRU ER AXS D8 FOCUS X- ray powder diffractometer equipped with a Cu-anode (copper-Κα 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 KV 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. 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 Coprecipitate of Linezolid with hypromellose phthalate (1.5 : 1)

Linezolid (3 g) and hydroxypropyl methyl cellulose phthalate (2 g) were dissolved in methanol (600 ml) at 25-30°C and then stirred for 30 minutes at the same temperature. The resulting solution filtered to remove un-dissolved particles, followed by removal of solvent by distillation under reduced pressure at 60-65°C to produce 5 g of amorphous coprecipitate of linezolid with hypromellose phthalate (1.5 : 1 ).

Characterization Data:

The resulting amorphous coprecipitate of linezolid with hypromellose phthalate (1.5 : 1) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no well- defined peaks, as shown in Figure l ; and further characterized by an infra red (FT-IR) spectrum having main bands at about 3364, 3074, 2959, 2858, 2834, 1 751 , 1675, 1653, 1628, 1600, 1576, 1558, 1539, 1520, 1516, 1487, 1447, 1418, 1378, 1328, 1273, 1256, 1237, 1222, 1 195, 1 173, 1 1 16, 1067, 935, 920, 894, 851 , 802, 746, 704 and 659 ± 2 cm^"1 as shown in Figure 2.

Example 2

Preparation of Amorphous Coprecipitate of Linezolid with hypromellose phthalate (1 : 1)

Linezolid (2.5 g) and hydroxypropyl methyl cellulose phthalate (2.5 g) were dissolved in methanol (500 ml) at 25-30°C and then stirred for 30 minutes at the same temperature. The resulting solution filtered to remove un-dissolved particles, followed by removal of solvent by distillation under reduced pressure at 60-65°C to produce 5 g of amorphous coprecipitate of linezolid with hypromellose phthalate (1 : 1).

Characterization Data: The resulting amorphous coprecipitate of linezolid with hypromellose phthalate (1 .5 : 1) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no well- defined peaks, as shown in Figure 3; and further characterized by an infra red (FT-IR) spectrum having main bands at about 3365, 3073, 2959, 2859, 2835, 1756, 1734, 1718, 1679, 1669, 1653, 1646, 1635, 1628, 1601 , 1575, 1569, 1539, 1520, 1517, 1487, 1448, 1418, 1379, 1328, 1289, 1273, 1239, 1225, 1 196, 1 174, 1 143, 1 1 18, 1067, 1050, 1033, 938, 922, 891 , 863, 843, 802, 747, 707 and 659 ± 2 cm^{" 1} as shown in Figure 4.

Example 3

Preparation of Amorphous Coprecipitate of Linezolid with Povidone K30 (1 : 10)

Linezolid (0.5 g) and povidone K30 (5 g) were dissolved in methanol (250 ml) at 25-30°C and then stirred for 30 minutes at the same temperature. The resulting solution filtered to remove un-dissolved particles, followed by removal of solvent by distillation under reduced pressure at 60-65°C to produce 5.5 g of amorphous coprecipitate of linezolid with povidone K30 (l : 10).

Characterization Data:

The resulting amorphous coprecipitate of linezolid with povidone K30 (1 : 10) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no well- defined peaks, as shown in Figure 5; and further characterized by an infra red (FT-IR) spectrum having main bands at about 3472, 2963, 2925, 2857, 1750, 1739, 1733, 1699, 1683, 1668, 1653, 1646, 1569, 1540, 1516, 1506, 1495, 1464, 1436, 1423, 1419, 1374, 1317, 1291 , 1263, 121 7, 1 168, 1 101 , 1050, 1017, 935, 897, 846, 801 , 741 , 731 and 654 ± 2 cm^"1 as shown in Figure 6. Example 4

Preparation of Amorphous Coprecipitate of Linezolid with Copovidone (1 : 10)

Linezolid (0.5 g) and copovidone (5 g) were dissolved in methanol (250 ml) at 25-30°C and then stirred for 30 minutes at the same temperature. The resulting solution filtered to remove un-dissolved particles, followed by removal of solvent by distillation under reduced pressure at 60-65°C to produce 5.5 g of amorphous coprecipitate of linezolid with copovidone (1 : 10). Characterization Data:

The resulting amorphous coprecipitate of linezolid with copovidone ( 1 : 10) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no well- defined peaks, as shown in Figure 7; and further characterized by an infra red (FT-IR) spectrum having main bands at about 3448, 2959, 2924, 2854, 1741 , 1648, 1637, 1522, 1497, 1491 , 1466, 1458, 1438, 1425, 1420, 1375, 1320, 1295, 1261 , 1217, 1 1 18, 1019, 937, 896, 873, 846, 734 and 659 ± 2 cm^{" 1} as shown in Figure 8.

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 "μιη" both are equivalent and refer to "micrometer" which is 1 x l O^"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 (D90), 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 Dg₀ 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 linezolid 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 silicate, 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 linezolid and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group consisting of povidone, copovidone and hypromellose phthalate.

2. The amorphous coprecipitate of linezolid of claim 1 , wherein:

a) the amorphous coprecipitate of linezolid with hypromellose phthalate (1.5 : 1) is characterized by a powder XRD pattern, showing no well-defined peaks, substantially in accordance with Figure 1 ;

b) the amorphous coprecipitate of linezolid with hypromellose phthalate (1 : 1) is characterized by a powder XRD pattern, showing no well-defined peaks, substantially in accordance with Figure 3;

c) the amorphous coprecipitate of linezolid with povidone K30 (1 : 10) is characterized by a powder XRD pattern, showing no well-defined peaks, substantially in accordance with Figure 5; and

d) the amorphous coprecipitate of linezolid with copovidone ( 1 : 10) is characterized by a powder XRD pattern, showing no well-defined peaks, substantially in accordance with Figure 7.

3. The amorphous coprecipitate of claim 2, wherein:

a) the amorphous coprecipitate of linezolid with hypromellose phthalate ( 1.5 : 1) is further characterized by an infra red (FT-IR) spectrum having main bands at about

3364, 3074, 2959, 2858, 2834, 1751 , 1675, 1653, 1628, 1600, 1576, 1558, 1539, 1520, 1516, 1487, 1447, 1418, 1378, 1328, 1273, 1256, 1237, 1222, 1 195, 1 173, 1 1 16, 1067, 935, 920, 894, 851 , 802, 746, 704 and 659 ± 2 cm^"1 substantially in accordance with Figure 2;

b) the amorphous coprecipitate of linezolid with hypromellose phthalate (1 : 1) is further characterized by an infra red (FT-IR) spectrum having main bands at about

3365, 3073, 2959, 2859, 2835, 1756, 1734, 1718, 1679, 1669, 1653, 1646, 1635, 1628, 1601 , 1575, 1569, 1539, 1520, 1517, 1487, 1448, 1418, 1379, 1328, 1289, 1273, 1239, 1225, 1 196, 1 174, 1 143, 1 1 1 8, 1067, 1050, 1033, 938, 922, 891 , 863, 843, 802, 747, 707 and 659 ± 2 cm^"1 substantially in accordance with Figure 4; c) the amorphous coprecipitate of linezolid with povidone 30 (1 : 10) is further characterized by an infra red (FT-IR) spectrum having main bands at about 3472, 2963, 2925, 2857, 1750, 1739, 1733, 1699, 1683, 1668, 1653, 1646, 1569, 1540, 1516, 1506, 1495, 1464, 1436, 1423, 1419, 1374, 1317, 1291 , 1263, 1217, 1 168, 1 101 , 1050, 1017, 935, 897, 846, 801 , 741 , 731 and 654 ± 2 cm^"1 substantially in accordance with Figure 6; and

d) the amorphous coprecipitate of linezolid with povidone 30 (1 : 10) is further characterized by an infra red (FT-IR) spectrum having main bands at about 3448, 2959, 2924, 2854, 1741 , 1648, 1637, 1522, 1497, 1491 , 1466, 1458, 1438, 1425, 1420, 1375, 1320, 1295, 1261 , 1217, 1 1 1 8, 1019, 937, 896, 873, 846, 734 and 659 ± 2 cm^"1 substantially in accordance with Figure 8.

A process for the preparation of the amorphous coprecipitate of linezolid of claim 1 , comprising:

a) providing a solution of linezolid and a pharmaceutically acceptable excipient in a solvent, wherein the solvent is selected from the group consisting of an alcohol, water, acetone, ethyl acetate, dichloromethane, dichloroethane, chloroform and mixtures thereof, and wherein the pharmaceutically acceptable excipient is selected: from the group consisting of povidone, copovidone and hypromellose phthalate; 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 linezolid with the pharmaceutically acceptable excipient.

The process of claim 4, wherein the solvent used in step-(a) is an alcohol solvent; 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.

The process of claim 5, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, and mixtures thereof; and wherein the removal of the solvent in step-(c) is accomplished by distillation.

7. The process of claim 6, wherein the alcohol solvent is methanol; and wherein the distillation process is performed under reduced pressure at a temperature of about 50°C to about 1 10°C.

8. The process of claim 7, wherein the distillation process is performed under reduced pressure at a temperature of about 60°C to about 70°C.

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

10. A method for treating a patient suffering from bacterial infections or diseases caused by Gram-positive bacteria including pneumonia, streptococci, vancomycin-resistant enterococci (VRE) and methicill in-resistarit Staphylococcus aureus (MRSA), comprising administering a therapeutically effective amount of the amorphous coprecipitate of linezolid of claim 1 , or a pharmaceutical composition that comprises a therapeutically effective amount of the amorphous coprecipitate of linezolid along with pharmaceutically acceptable excipients.