DESC:
The following specification describes particularly describes the invention and the manner in which it is to be performed.
AMORPHOUS AND AMORPHOUS SOLID DISPERSIONS OF TEDIZOLID PHOSPHATE

INTRODUCTION
The present application relates to the amorphous and amorphous solid dispersion of tedizolid phosphate and the processes for the preparation thereof.
The drug compound having the adopted name tedizolid phosphate, has a chemical name (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl) pyridin-3-yl] phenyl}-5-(phosphonooxymethyl)-1,3-oxazolidin-2-one, and is represented by structure of formula (I).

(I)
Tedizolid is used to treat patients with acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including Staphylococcus aureus (including methicillin-resistant strains (MRSA) and methicillin-susceptible strains), various Streptococcus species, and Enterococcus faecalis.
U.S. Patent No. 7,816,379 generically and specifically discloses tedizolid and pharmaceutically acceptable salts thereof. Further, it discloses process for preparation of tedizolid and its intermediates.
U.S. Patent No. 8,426,389 discloses crystalline tedizolid phosphate having purity of at least 96% by weight and process for its preparation.
It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konne T., Chem pharm Bull., 38, 2003(1990)]. For some therapeutic indications one bioavailability pattern may be favored over another. An amorphous form of Cefuroxime axetil is a good example for exhibiting higher bioavailability than the crystalline form.
There remains a need to provide stable, commercially viable advantageous amorphous and amorphous solid dispersion of tedizolid phosphate.

SUMMARY
In the first embodiment, the present application provides an amorphous form of tedizolid phosphate.
In the second embodiment, the present application provides an amorphous form of tedizolid phosphate characterized by powder X-ray diffraction (PXRD) pattern substantially as illustrated by Figure 1 or Figure 2.
In the third embodiment the present application provides a process for preparing amorphous form of tedizolid phosphate, which comprises;
a) providing a solution of tedizolid phosphate in a solvent;
b) removing solvent from a solution of tedizolid phosphate obtained in step a); and
c) recovering amorphous form of tedizolid phosphate.
In the fourth embodiment the present application provides a process for preparing amorphous form of tedizolid phosphate by ball milling the tedizolid phosphate.
In the fifth embodiment, the present application provides a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers.
In the sixth embodiment, the present application provides a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure 3 or Figure 4 or Figure 5 or Figure 6 or Figure 7 or Figure 8.
In the seventh embodiment, the present application provides a process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution of tedizolid phosphate and pharmaceutically acceptable carrier in a solution,
b) removing solvent from a solution obtained in step (a) and
c) recovering a solid dispersion comprising an amorphous form of tedizolid
phosphate and one or more pharmaceutically acceptable carrier.

In the eighth embodiment the present application provides a process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers by ball milling the tedizolid phosphate and one or more pharmaceutically acceptable carriers.
In the ninth embodiment the present application provides a process for preparing amorphous form of tedizolid phosphate by hot melt extrusion of the tedizolid phosphate
In the tenth embodiment the present application provides a process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers by hot melt extrusion of the tedizolid phosphate and one or more pharmaceutically acceptable carriers.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction ("PXRD") pattern of amorphous form of tedizolid phosphate prepared according to Example 1.
Figure 2 is powder X-ray power diffraction ("PXRD") pattern of amorphous form of tedizolid phosphate prepared according to Example 2.
Figure 3 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of tedizolid phosphate and PVP-K30 prepared according to Example 3.
Figure 4 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of tedizolid phosphate and HPMC-AS prepared according to Example 4.
Figure 5 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of tedizolid phosphate and PVP-VA prepared according to Example 5 before adding syloid
Figure 6 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of tedizolid phosphate and PVP-VA prepared according to Example 5 after adding syloid.
Figure 7 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of tedizolid phosphate and HPMC prepared according to Example 6.
Figure 8 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of tedizolid phosphate and PVP-K90 prepared according to Example 7.

DETAILED DESCRIPTION
The present invention provides amorphous and amorphous solid dispersions of tedizolid phosphate and the processes for the preparation thereof. Tedizolid phosphate which may be used in the present application can be prepared by any process known in the art such as processes disclosed in U.S. Patent No. 7,816,379 or U.S. Patent No. 8,426,389.
In the first embodiment, the present application provides an amorphous form of tedizolid phosphate.
In the second embodiment, the present application provides an amorphous form of tedizolid phosphate characterized by powder X-ray diffraction (PXRD) pattern substantially as illustrated by Figure 1 or Figure 2.
In the third embodiment, the present application provides a process for preparing an amorphous form of tedizolid phosphate, which comprises;
a) providing a solution of tedizolid phosphate in a solvent;
b) removing solvent from a solution of tedizolid phosphate; and
c) recovering an amorphous form of tedizolid phosphate.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing tedizolid phosphate that is obtained in the course of its synthesis; or
ii) dissolving tedizolid phosphate in a solvent.
Any physical form of tedizolid phosphate may be utilized for providing the solution of tedizolid phosphate in step a).
Suitable solvent which can be used for dissolving the tedizolid phosphate is formic acid and the like; dimethyl sulphoxide, dimethyl fumarate and dimethyl acetamide and mixtures thereof or any other suitable solvent.
After dissolution in step (a), the obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves removing solvent from a solution of tedizolid phosphate.
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.
Step (c) involves recovering an amorphous form of tedizolid phosphate. The said recovery can be by using the processes known in the art.
The resulting compound in step (c) may be optionally further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the tedizolid phosphate is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In the fourth embodiment the present application provides a process for preparing amorphous form of tedizolid phosphate by ball milling the tedizolid phosphate.
A ball mill used in the present invention consists of a cylindrical vessel and grinding media composed typically of spherical ceramic or steel balls. Ball milling was performed using a Retsch planetary ball-mill PM-100 equipped with a 50 ml stainless steel milling jar and stainless steel balls as milling media .The milling speed was 500 rpm.
Any physical form of tedizolid phosphate may be utilized for by ball milling.
In the fifth embodiment, the present application provides a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers.
Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or matrix (carrier), where the active ingredients could exist in, solubilized or amorphous state (Sareen et al., 2012 and Kapoor et al., 2012). Solid dispersion consists of two or more than two components, generally a carrier polymer and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it required very less external energy to dissolve.
In the sixth embodiment, the present application provides a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure 3 or Figure 4 or Figure 5 or Figure 6 or Figure 7 or Figure 8.
In the seventh embodiment, the present application provides a process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution of tedizolid phosphate and pharmaceutically acceptable carrier in a solution,
b) removing solvent from a solution obtained in step (a); and
c) recovering a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carrier.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing tedizolid phosphate that is obtained in the course of its synthesis; or
ii) dissolving tedizolid phosphate and pharmaceutically acceptable carrier in a solvent.
Any physical form of tedizolid phosphate may be utilized for providing the solution of tedizolid phosphate in step (a).
Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones(PVP K-30 ,K-90), poly (vinyl pyrrolidone-co-vinyl acetate) (PVP-VA), hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS), hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, , colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Suitable solvent which may be used for dissolving the tedizolid phosphate formic acid and the like; dimethyl sulphoxide, dimethyl fumarate and dimethyl acetamide and mixtures thereof or any other suitable solvent.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from a solution obtained in step (a);
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other technique known in the art.
Step (c) involves recovering a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers. The said recovery can be by using the processes known in the art.
The resulting compound obtained in step (c) may be optionally further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Tedizolid phosphate is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In the eighth embodiment the present application provides a process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers by ball milling the tedizolid phosphate and one or more pharmaceutically acceptable carriers.
A ball mill used in the present invention consists of a cylindrical vessel and grinding media composed typically of spherical ceramic or steel balls. Ball milling was performed using a Retsch planetary ball-mill PM-100 equipped with a 50 ml stainless steel milling jar and stainless steel balls as milling media. The milling speed was 500 rpm.
Any physical form of tedizolid phosphate may be utilized for by ball milling.
Suitable pharmaceutically acceptable carriers which can be used in ball milling include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones(PVP K-30, K-90), poly (vinyl pyrrolidone-co-vinyl acetate) (PVP-VA), hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS), hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
In the ninth embodiment the present application provides a process for preparing amorphous form of tedizolid phosphate by hot melt extrusion of the tedizolid phosphate
In the tenth embodiment the present application provides a process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers by hot melt extrusion of the tedizolid phosphate and one or more pharmaceutically acceptable carriers.
Amorphous and amorphous solid dispersions of tedizolid phosphate of the present application are characterized by its PXRD pattern. All PXRD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 A, and were obtained using a PANalytical, Powder X-ray Diffractometer.
Although the exemplified procedures herein illustrate the practice of the present invention in some of its embodiments, the procedures should not be construed as limiting the scope of the invention. Modifications from consideration of the specification and examples within the ambit of current scientific knowledge will be apparent to one skilled in the art.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
“Amorphous form” as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES

Example 1: Preparation of amorphous form of tedizolid phosphate
Tedizolid phosphate (500 mg) was taken in to a ball miller and milled at 25 °C for 16 hours to afford title compound.

Example 2: Preparation of amorphous form of tedizolid phosphate
Tedizolid phosphate (3 g) was dissolved in formic acid (50 mL). The obtained solution was subjected to spray drying (Spray dryer conditions: Inlet temperature 100 °C, aspiration 70% and feed pump 5%).The resultant compound was dried under reduced pressure at 60 °C to afford title compound.

Example 3: Preparation of a solid dispersion comprising an amorphous form of tedizolid phosphate and PVP-K30.
Tedizolid phosphate (500 mg) and PVP-K30 (500 mg) were mixed homogeneously and the obtained compound was milled in a ball miller at 25 °C for 10 hours and 30 minutes to afford title compound.

Example 4: Preparation of a solid dispersion comprising an amorphous form of tedizolid phosphate and Hydroxypropyl Methylcellulose Acetate Succinate (HPMC-AS).
Tedizolid phosphate (600 mg) and HPMC-AS (600 mg) were dissolved in formic acid (25 mL) at 25 °C. The obtained solution solvent was evaporated under reduced pressure (2 torr) at 92 °C using rotavapor. Resultant compound was dried under reduced pressure at 60 °C to afford title compound. Syloid (0.6 g) was added to the dried compound and mixed homogeneously at 25 °C. The resultant compound was characterized by its PXRD and it shows amorphous form.

Example 5: Preparation of a solid dispersion comprising an amorphous form of tedizolid phosphate and poly vinyl pyrrolidone-vinyl acetate (PVP-VA).
Tedizolid phosphate (1 g) and PVP-VA (1 g) were dissolved in formic acid (30 mL) at 25 °C and the resultant solution was subjected to spray drying (spray dryer conditions: Inlet temperature 98 °C, aspiration 75% and feed pump 5%).The obtained compound was dried at 60 °C in air tray dryer for about 2 hours to afford title compound. Syloid (1 g) was added to the dried compound and mixed homogeneously at 25 °C. The resultant compound was characterized by its PXRD and it shows amorphous form.

Example 6: Preparation of a solid dispersion comprising an amorphous form of tedizolid phosphate and hydroxy propyl methyl cellulose (HPMC).
Tedizolid phosphate (1 g) and HPMC (1 g) were dissolved in formic acid (30 mL) at 25 °C and the resultant solution was subjected to spray drying (Spray dryer conditions: Inlet temperature 98 °C, aspiration 75% and feed pump 5%).The obtained compound was dried at 60 °C in air tray dryer for about 2 hours to afford title compound. Syloid (1 g) was added to the dried compound and mixed homogeneously at 25 °C. The resultant compound was characterized by its PXRD and it shows amorphous form.

Example 7: Preparation of a solid dispersion comprising an amorphous form of tedizolid phosphate and PVP-K90.
PVP-K90 (1 g) was dissolved in formic acid (40 mL) at 25 °C. Tedizolid phosphate (1 g) was added to the reaction mass and stirred for 10 minutes to get the clear solution. The resultant solution was subjected to spray drying (Spray dryer conditions: Inlet temperature 98 °C, aspiration 70% and feed pump 5%). The obtained compound was dried at 60 °C in air tray dryer for about 2 hours to afford title compound. Syloid (1 g) was added to the dried compound and mixed homogeneously at 25 °C. The resultant compound was characterized by its PXRD and it shows amorphous form.
,CLAIMS:We Claim:

1. An amorphous tedizolid phosphate.

2. An amorphous tedizolid phosphate according to claim 1 characterized by powder X-ray diffraction (PXRD) pattern substantially as illustrated by Figure 1.

3. A process for preparing amorphous form of tedizolid phosphate of claim 1, comprising:
a) providing a solution of tedizolid phosphate in a solvent,
b) removing solvent from a solution of tedizolid phosphate obtained in step a) and
c) recovering amorphous form of tedizolid phosphate.

4. Solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers.

5. Solid dispersion comprising an amorphous form of tedizolid phosphate according to claim 4 characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure 3.

6. A process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers comprising:
a) providing a solution of tedizolid phosphate and pharmaceutically acceptable carrier in a solution,
b) removing solvent from a solution obtained in step (a) and
c) recovering a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carrier.

7. A process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers by ball milling the tedizolid phosphate and one or more pharmaceutically acceptable carriers.

8. A process for preparing amorphous form of tedizolid phosphate by hot melt extrusion of the tedizolid phosphate.

9. a process for preparing a solid dispersion comprising an amorphous form of tedizolid phosphate and one or more pharmaceutically acceptable carriers by hot melt extrusion of the tedizolid phosphate and one or more pharmaceutically acceptable carriers.