DESC:Field of the Invention:
The present invention provides novel polymorphic forms of Tedizolid Phosphate in crystalline and amorphous forms. The present invention also relates to a method for preparing the new polymorphic forms, a pharmaceutical composition thereof and the use thereof.

Background of the Invention:
Tedizolid, chemical name: (R) -3- (4- (2- (2- methyl-5-yl) pyridine-5-yl) -3-fluoro phenyl) -5-hydroxymethyl-oxazolidin-2-one, the chemical structure of the formula:

Tedizolid Phosphate is a phosphate prodrug of Tedizolid, chemical name is [(5R)-(3-{3-Fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl] phenyl}-2-oxooxazolidin-5-yl] methyl hydrogen phosphate, the chemical structure of the formula:

Tedizolid Phosphate is the first FDA-approved second-generation oxazolidinone antibiotic is marketed in USA and Europe under the trade name of Sivextro®. The drug was developed by the pharmaceutical company Cubist for the treatment of Staphylococcus aureus (including methicillin-resistant strains, methicillin-sensitive strains) and Streptococcus faecalis and various acute bacterial skin and skin structure enterococci and other gram-positive bacterial infections.
Tedizolid and its prodrug is generically and specifically described in US patent 7,816,379 B2.
The PCT application WO 2010/091131 A1 discloses crystalline form 1 of Tedizolid Phosphate and process for the preparation thereof.
Polymorphism is the ability of a compound to exist in two or more different crystalline phases that differ in arrangement of the molecules in crystal lattice. Although polymorphs have the same chemical composition, they differ in packing and geometrical arrangement and exhibit different physical properties such as melting point, X-ray diffraction patterns, density, stability, and solubility.

Polymorphs often improve physical and biological characteristics of mother compounds without modifying primary pharmacological activity, based on mechanism of action. Thus there is a continuing need to obtain new polymorphs of Tedizolid Phosphate having improved physical and/or chemical properties. The present invention satisfies this need by providing new polymorphs of Tedizolid Phosphate with enhanced bioavailability, stability and solubility in water or aqueous media as an essential property of active pharmaceutical ingredients determining the performance of pharmaceutical formulation.

Description of drawings:
Figure 1: illustrates X-ray powder diffraction pattern of anhydrous crystalline form of Tedizolid Phosphate designated as Form L1.
Figure 2: Differential Scanning Calorimetry thermogram of Form L1.
Figure 3: Thermogravimetric analysis curve of Form L1.
Figure 4: illustrates X-ray powder diffraction pattern of crystalline hydrated form of Tedizolid Phosphate designated as Form L2.
Figure 5: Differential Scanning Calorimetry thermogram of Form L2.
Figure 6: Thermogravimetric analysis curve of Form L2.
Figure 7: illustrates X-ray powder diffraction pattern of semi crystalline form of Tedizolid Phosphate designated as Form L3.
Figure 8: Differential Scanning Calorimetry thermogram of Form L3.
Figure 9: Thermogravimetric analysis curve of Form L3.
Figure 10: illustrates X-ray powder diffraction pattern of amorphous form of Tedizolid Phosphate designated as Form L4.
Figure 11: Differential Scanning Calorimetry thermogram of Form L4.
Figure 12: Thermogravimetric analysis curve of Form L4.

Summary of the Invention:
In one aspect, the invention provides an anhydrous crystalline form of Tedizolid Phosphate (Form L1).
In another aspect, the invention provides a process for the preparation of the above-mentioned anhydrous crystalline form of Tedizolid Phosphate (Form L1).
In another aspect, the invention provides a crystalline hydrate form of Tedizolid Phosphate (Form L2).
In another aspect, the invention provides a process for the preparation of the above-mentioned crystalline hydrated form of Tedizolid Phosphate (Form L2).
In another aspect, the invention provides semi crystalline form of Tedizolid Phosphate (Form L3).
In another aspect, the invention provides a process for the preparation of the above-mentioned semi crystalline form of Tedizolid Phosphate (Form L3).
In another aspect, the invention provides an amorphous form of Tedizolid Phosphate (Form L4).
In another aspect, the invention provides a process for the preparation of the above-mentioned amorphous form of Tedizolid Phosphate (Form L4).
In another aspect, the present invention provides a stable amorphous Tedizolid Phosphate (Form L5) premix having enhanced stability and dissolution properties.
In another aspect, the invention provides pharmaceutical compositions comprising the above-mentioned polymorphic forms viz., Form L1, Form L2, Form L3 Form L4 and Form L5 of Tedizolid Phosphate and uses thereof.

Detail Description of the Invention:
In one embodiment of the invention, the present invention provides an anhydrous crystalline Form L1 of Tedizolid Phosphate having enhanced stability and dissolution properties that can be easily formulated into pharmaceutical compositions.
In another embodiment, the present invention provides an anhydrous crystalline Form L1 of Tedizolid Phosphate, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 5.2, 10.0, 10.4, 12.4, 12.6, 15.6, 15.9, 16.4, 17.1, 17.8, 19.5, 20.1, 20.5, 20.8, 22.8, 24.7, 25.6, 26.2 ± 0.2 degrees. The XRPD of the anhydrous crystalline Form L1 of Tedizolid Phosphate is depicted in figure 1.
In another embodiment, the present invention provides a process for the preparation of the anhydrous crystalline Form L1 of Tedizolid Phosphate, which comprises the steps of:
i) dissolving Tedizolid phosphate in water and liquor ammonia to form a solution of Tedizolid Phosphate;
ii) heating the solution of Tedizolid Phosphate from step i);
iii) cooling the solution from step ii); and
iv) isolating the anhydrous crystalline Form L1 of Tedizolid Phosphate.
The reaction of step (i) can be carried out at room temperature.
The reaction of step (ii) can be carried out at a temperature of about 50 to about 90°C, most preferably at about 70 - 80°C.
The isolation of the anhydrous crystalline Form L1 of Tedizolid Phosphate of step (iv) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation etc.
In another embodiment of the invention, the present invention provides a crystalline Form L2 of Tedizolid Phosphate having enhanced stability and dissolution properties that can be easily formulated into pharmaceutical compositions.
In another embodiment, the present invention provides a crystalline Form L2 of Tedizolid Phosphate, which is characterized by XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2? at 4.9, 7.3, 9.7, 12.9, 15.3, 17.6, 24.0, 29.8, 30.9, 34.1, 35.4 ± 0.2 degrees. The XRPD of crystalline Form L2 of Tedizolid Phosphate is depicted in figure 4.

In another embodiment, the present invention provides a process for the preparation of crystalline hydrate Form L2 of Tedizolid Phosphate, which comprises the steps of:
i) dissolving Tedizolid Phosphate in a phosphate buffer to form a solution of Tedizolid Phosphate in phosphate buffer;
ii) adding alcoholic solvent to the solution from step i); and
iii) isolating the crystalline Form L2 of Tedizolid Phosphate.
The reaction of step (i) can be carried out at a temperature of about 40 to about 70°C, most preferably at about 50 - 60°C.
The alcoholic solvent used in step-(ii) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butanol, tert-butanol.
The reaction of step (ii) can be carried out at ambient temperature.
The isolation of crystalline hydrate Form L2 of Tedizolid Phosphate of step (iii) could be done by conventional techniques known to a person skilled in the art such as filtration, centrifugation etc.
In another embodiment of the invention, the present invention provides semi crystalline Form L3 of Tedizolid Phosphate having enhanced stability and dissolution properties that can be easily formulated into pharmaceutical compositions.
In another embodiment, the present invention provides a semi crystalline Form L3 of Tedizolid Phosphate, which is characterized by XRPD (X-ray powder diffractogram) which comprises of two broad peaks expressed as 2? at 14.8, 25.4 ± 0.2 degrees. The XRPD of semi crystalline Form L3 of Tedizolid Phosphate is depicted in figure 7.
In another embodiment, the present invention provides a process for the preparation of semi crystalline Form L3 of Tedizolid Phosphate, which comprises the steps of:
i) dissolving Tedizolid Phosphate in water and liquor ammonia to form a solution of Tedizolid Phosphate;
ii) freeze-drying the solution from step i); and
iii) isolating the semi crystalline Form L3 of Tedizolid Phosphate.
The reaction of step (i) can be carried out at ambient temperature.
The reaction of step (ii) can be carried out at a temperature of about -25°C to about -50°C.
The isolation of semi crystalline Form L3 of Tedizolid Phosphate of step (iii) could be done by conventional techniques known to a person skilled in the art, such as filtration, centrifugation, etc.
In another embodiment of the invention, the present invention provides an amorphous Form L4 of Tedizolid Phosphate having enhanced stability and dissolution properties that can be easily formulated into pharmaceutical compositions.
In another embodiment, the present invention provides an amorphous Form L4 of Tedizolid Phosphate, which is characterized by XRPD (X-ray powder diffractogram). The XRPD of amorphous Form L4 of Tedizolid Phosphate is depicted in figure 10.
In another embodiment, the present invention provides a process for the preparation of amorphous Form L4 of Tedizolid Phosphate, which comprises the steps of:
i) dissolving Tedizolid Phosphate in phosphate buffer to form a solution of Tedizolid Phosphate;
ii) freeze-drying the solution from step i); and
iii) isolating the amorphous Form L4 of Tedizolid Phosphate.
The reaction of step (i) can be carried out at a temperature of about 40 to about 70°C, most preferably at about 50 - 60°C.
The reaction of step (ii) can be carried out at a temperature of about -25°C to about -50°C.
The isolation of amorphous Form L4 of Tedizolid Phosphate of step (iii) could be done by conventional techniques known to a person skilled in the art, such as filtration, centrifugation, etc..
In another embodiment of the invention, the present invention provides a stable amorphous premix Form L5 of Tedizolid Phosphate having enhanced stability and dissolution properties that can be easily formulated into pharmaceutical compositions.
In another embodiment, the present invention provides a process for the preparation of stable amorphous premix Form L5 of Tedizolid Phosphate, which comprises the steps of:
(i) providing a solution of Tedizolid Phosphate in a solvent;
(ii) adding suitable premixing agent(s); and
(iii) substantially removing the solvents from the solution to afford stable amorphous Form L5 of Tedizolid Phosphate.

The suitable premixing agent of step (ii) can be any pharmaceutically acceptable excipient(s) discussed in the specification includes but not limited to diluents, Bulking agents, lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising said polymorphic forms viz., Form L1, Form L2, Form L3, Form L4 and Form L5 of Tedizolid Phosphate with pharmaceutically acceptable excipients.
Said polymorphic forms viz., Form L1, Form L2, Form L3, Form L4 and Form L5 of Tedizolid Phosphate can be formulated into various pharmaceutical compositions, may be in solid, semi-solid or liquid, may be prepared as suitable dosage form such as a solid dosage form, including tablets, granules, powders, pills, powders and capsules; liquid dosage forms, including solutions, syrups, suspensions, dispersions and emulsions; injectable formulations including solutions, dispersions, suitable for injection prior to dissolving or suspending a solid in a liquid form such as a lyophilized preparation. Formulations may be adapted for quick release of the active ingredient, sustained release, or modified release. It may be conventional, dispersible, chewable, mouth dissolving or fast melt formulations. Routes of administration include oral, by gastric feeding tube, duodenal feeding tube through, intravenous, intraarterial, intramuscular, subcutaneous, bone, skin, intravaginal, intrarectal, intraperitoneal, transdermal, intranasal, eye drops, ear drops and the like.
The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. The composition or formulation may be coated or uncoated. Coating of compositions such as tablets and caplets is well known in the art.
Although for many pharmaceutical compounds oral administration in the form of a tablet or capsule is preferred, some patients, for example elderly and paediatric patients, may have difficulties in swallowing such formulations. Therefore, liquid formulations such as oral solutions may offer a suitable alternative, avoiding the need of swallowing tablets or capsules. An oral solution further provides the possibility of a more flexible dosing regimen. In order to limit the volume of an oral solution it is necessary to have a high concentration of the active ingredient in the solution, which again requires a high solubility of the active ingredient. Hence the superior solubility of polymorphic forms viz., Form L1, Form L2, Form L3, Form L4 and Form L5 of the present invention makes this particular solid state form especially suitable for the preparation of liquid pharmaceutical formulations such as oral solutions
Pharmaceutically acceptable excipients may be utilized as required for conversion of the polymorphic forms viz., Form L1, Form L2, Form L3, Form L4 and Form L5 of Tedizolid Phosphate into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations.
The present invention includes administration of an effective amount of polymorphic forms viz., Form L1, Form L2, Form L3, Form L4 and Form L5 of Tedizolid Phosphate (either alone or as the active component of a pharmaceutical composition), in particular for use in the treatment of various acute bacterial skin and skin structure enterococci and other gram-positive bacterial infections.
In a further embodiment, the present invention provides a method for the treatment of Staphylococcus aureus (including methicillin-resistant strains, methicillin-sensitive strains) and Streptococcus faecalis and various acute bacterial skin and skin structure enterococci and other gram-positive bacterial infections, in a subject in need of such treatment, which method comprises administering to such subject a therapeutically effective amount of Form L1, Form L2, Form L3, Form L4 and Form L5 of Tedizolid Phosphate.
The diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations includes

Diluents:
Various useful fillers or diluents include but are not limited to starches, lactose, mannitol (PearlitolTM SD200), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, FlowlacTM, PharmatoseTM and others. Different starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch and others. Different cellulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include but are not limited to CEOLUSTM KG801, AvicelTM PH101, PH102, PH301, PH302 and PH-F20, PH112 microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol (PearlitolTM SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Binders:
Various useful binders include but are not limited to hydroxypropylcelluloses, also called HPC (KlucelTM LF, Klucel EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromelloses or HPMC (MethocelTM) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP-K30, and PVP-K90), PlasdoneTM S-630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (CarbopolTM), methylcelluloses, polymethacrylates, and starches.

Disintegrants:
Various useful disintegrants include but are not limited to carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, KollidonTM CL, PolyplasdoneTM XL, XI-10, and INF-10 and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33. Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

Stabilizers:
Various useful stabilizers include basic inorganic salts, such as but not limited to basic inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6Al2(OH)16.CO3.4H2O], aluminum hydroxide-magnesium [2.5MgO.Al2O3.xH2O], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like.

Surface-Active Agents:
Useful surface-active agents include non-ionic, cationic and anionic surface-active agents. Useful non-ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPANTM) and polyhydroxyethylenically treated sorbitan esters (TWEENTM), aliphatic alcohols and PEG ethers, phenol and PEG ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidyl glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yolk.

Lubricants:
An effective amount of any pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof.

Glidants:
One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variations can be used. Useful glidants include but are not limited to silicone dioxide, talc and combinations thereof.

Coloring Agents:
Coloring agents can be used to color code the compositions, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, combinations thereof, and the like.

Useful additives for coatings include but are not limited to plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

Various useful plasticizers include but are not limited to substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like titianium dioxide may also be present, typically in an amount ranging from about 10% to about 20% based on the total weight of the coating.

Examples:
Example 1:
Preparation of anhydrous crystalline form of Tedizolid Phosphate (Form L1):
2.0 g of Tedizolid Phosphate was dissolved in a mixture of 10 ml deionized water and 2 ml liquor ammonia at ambient temperature. (pH - 10.0). The solution was heated at 80°C to allow ammonia gas to come out from the solution for an hour. White precipitate appeared in the aqueous solution (pH-6.0). Cooled down the reaction mass and filtered under vacuum. The white cake was washed with deionized water and dried in vacuum oven at 50°C overnight to give 1.7 g of desired product.
Example 2:
Preparation of crystalline hydrate of Tedizolid Phosphate (Form L2):
1.0 g of Tedizolid Phosphate was heated in 20 ml of phosphate buffer solution (pH - 7) at 60°C for 15-20 minutes until the solid was dissolved. The solution was treated with excess MeOH and stirred. When no precipitation observed, the solution was left for slow evaporation at ambient temperature. After 48 hours, colorless crystals appeared which was filtered to give 0.59 g of desired product.
Example 3:
Preparation of semi crystalline form of Tedizolid Phosphate (Form L3):
2.0 g of Tedizolid Phosphate was dissolved in a mixture of 10 ml water and liquor ammonia at ambient temperature. The solution was freezed into solid ice at –45°C and then kept in a lyophilizer for 24h. The wet cake was dried in vacuum oven to give 1.02 g of desired product.

Example 4:
Preparation of amorphous form of Tedizolid Phosphate (Form L4):
1.0 g of Tedizolid Phosphate was heated with 20 ml of phosphate buffer solution (pH - 7) at 60°C for 15-20 minutes until the solid was dissolved. The solution was cooled to make solid ice at –45°C and then kept in a lyophilizer for 24h. The wet cake was dried under vacuum to give 1.02 g of desired product.
,CLAIMS:1. A crystalline Form L1 of Tedizolid Phosphate.
2. A crystalline Form L1 of Tedizolid Phosphate, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ? at 5.2, 10.0, 10.4, 12.4, 12.6, 15.6, 15.9, 16.4, 17.1, 17.8, 19.5, 20.1, 20.5, 20.8, 22.8, 24.7, 25.6, 26.2 ± 0.2 degrees.
3. A process for preparation of crystalline form L1 Tedizolid Phosphate comprising the steps of:
i) dissolving Tedizolid phosphate in water and liquor ammonia to form a solution of Tedizolid Phosphate;
ii) heating the solution of Tedizolid Phosphate from step i);
iii) cooling the solution from step ii); and
iv) isolating the anhydrous crystalline Form L1 of Tedizolid Phosphate.
4. A crystalline Form L2 of Tedizolid Phosphate.
5. A crystalline Form L2 of Tedizolid Phosphate, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ? at 4.9, 7.3, 9.7, 12.9, 15.3, 17.6, 24.0, 29.8, 30.9, 34.1, 35.4 ± 0.2 degrees.
6. A process for preparation of crystalline form L2 Tedizolid Phosphate comprising the steps of:
i) dissolving Tedizolid Phosphate in a phosphate buffer to form a solution of Tedizolid Phosphate in phosphate buffer;
ii) adding alcoholic solvent to the solution from step i); and
iii) isolating the crystalline Form L2 of Tedizolid Phosphate.
7. A crystalline Form L3 of Tedizolid Phosphate.
8. A crystalline Form L3 of Tedizolid Phosphate, characterized by an x-ray powder diffraction pattern having two broad peaks expressed as 2? at 14.8, 25.4 ± 0.2 degrees.
9. A process for preparation of crystalline form L3 Tedizolid Phosphate comprising the steps of:
i) dissolving Tedizolid Phosphate in water and liquor ammonia to form a solution of Tedizolid Phosphate;
ii) freeze-drying the solution from step i); and
iii) isolating the semi crystalline Form L3 of Tedizolid Phosphate.
10. Amorphous Form L4 of Tedizolid Phosphate.
11. Amorphous Form L4 of Tedizolid Phosphate, characterized by an x-ray powder diffraction pattern as in figure 10.
12. A process for preparation of amorphous Form L4 of Tedizolid Phosphate comprising the steps of:
i) dissolving Tedizolid Phosphate in phosphate buffer to form a solution of Tedizolid Phosphate;
ii) freeze-drying the solution from step i); and
iii) isolating the amorphous Form L4 of Tedizolid Phosphate.
13. A stable amorphous premix Form L5 of Tedizolid Phosphate.
14. A process for preparation of stable amorphous premix Form L5 of Tedizolid Phosphate comprising the steps of:
i) providing a solution of Tedizolid Phosphate in a solvent;
ii) adding suitable premixing agent(s); and
iii) substantially removing the solvents from the solution to afford stable amorphous Form L5 of Tedizolid Phosphate.