FIELD OF INVENTION:
The present invention is a novel solid pharmaceutical composition which permits high drug load. The present invention relates to directly compressed solid pharmaceutical composition which permits high drug load.
The present invention particularly relates to directly compressed solid pharmaceutical composition which permits high content of linezolid form I.
BACKGROUND OF INVENTION:
Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria.
Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the SOS subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process.
Linezolid, chemically, N- [[(5 S)-3 - [3 -fluoro-4-(4-morpholinyl)phenyl] -2-oxo-5-oxazolidinyl] methyl]acetamide has the chemical structure:

Linezolid is used in the treatment of vancomycin-resistant enterococcus faecium infections; nosocomial pneumonia; complicated skin and skin structure infections including diabetic foot infections, without concomitant osteomyelitis; uncomplicated skin and skin structure infections and community acquired pneumonia.
Linezolid Tablets are sold in the U. S. market under the brand name of ZYVOX® Tablets. Tablets are given two to three times a day.
ZYVOX I.V. Injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each ml contains 2 mg of linezolid. ZYVOX for Oral Suspension is supplied as an orange-flavored granule/powder for constitution into a suspension for oral administration. Following constitution, each 5 mL contains 100 mg of linezolid.
U.S. 6,514,529 patent discloses compressed tablets of linezolid, which provides high drug load and excellent bioavailability. It discloses a method for providing blood levels of an antibacterial oxazolidinone by oral administration medically equivalent to the blood levels produced by IV administration of the same antibacterial oxazolidinone which comprises administration of compressed tablet of the antibacterial oxazolidinone.

US 20070020329 application discloses a method of manufacturing linezolid Form IV composition using wet granulation, dry granulation and direct compression. It discloses method of manufacturing a pharmaceutical composition comprising linezolid Form IV comprising admixing linezolid form IV with a pharmaceutically acceptable excipient to provide a mixture and direct compressing the mixture.
WO/2012/029074 PCT application covers process for preparing stable pharmaceutical composition comprising linezolid form III, polacrilin potassium as disintegrant and at least one pharmaceutically acceptable excipient, using wet granulation, dry granulation, spray granulation or direct compression to develop a solid dosage form.
US 20070104785 application discloses process for the preparation of solid dosage form of linezolid Form III, wherein the process comprises contacting linezolid Form III with one or more of gelling reducing means and optionally one or more of diluent(s), binders), disintegrant(s), glidant(s), lubricant(s) and processing the mixture into a solid dosage form.
U.S. patent application no. 20070104785 discloses a manufacture of the solid oral dosage form of linezolid Form III. It describes a gelling potential of linezolid Form HI which affects the reproducibility of dissolution. The manufacturing of the dosage form with reproducible dissolution profile was achieved by using effervescent couple (or) by incorporating water insoluble polymers (or) by adding clays in the dosage form (or) combinations thereof.

U.S. patent application no. 20130274262 discloses process for preparing stable pharmaceutical composition comprising linezolid form III, polacrilin potassium as disintegrant and at least one pharmaceutically acceptable excipient, using wet granulation, dry granulation, spray granulation or direct compression to develop a solid dosage form.
WO2007/102082 discloses compositions of Linezolid crystalline Form II containing lactose-based water soluble excipient. The tablets of the present invention can be prepared using dry granulation and wet granulation.
SUMMARY OF INVENTION:
In one general aspect, the invention is provided a high drug content solid pharmaceutical composition comprising about 200 mg to about 700 mg linezolid crystalline form-I by direct compression technique.
In another general aspect there is provided a process for preparing high drug content solid pharmaceutical composition comprising about 200 mg to about 700 mg linezolid crystalline form I.
In another general aspect, a high drug content tablet is provided comprising about 200 mg to about 700 mg linezolid form I having a particle size d90 is less than or equal to about 100 microns.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
DETAILED DESCRIPTION OF INVENTION:
The "composition" or "formulation" as used herein refers to solid dosage forms such as tablets, capsules, sachets, powder, granules etc.
The term "direct compression" as used herein refers process by which tablets are compressed directly from powder mixture of API and suitable excipients. No pretreatment of the powder blend by wet or dry granulation procedure is required.
The term "wet granulation" as used herein refers to granules are formed by the addition of a granulation liquid onto a powder bed which is under the influence of an impeller or air (in a fluidized bed granulator).
The term "dry granulation" as used herein refers to granules are formed without using a liquid solution because the product to be granulated may be sensitive to moisture and heat. Forming granules without moisture requires compacting and densifying the powders.

"pharmaceutically acceptable" is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
The term "high drug content" as used herein represents a solid pharmaceutical composition e.g. tablet wherein, the quantity of linezolid form I is equal to or greater than about 50% weight of total weight of the solid dosage form, Preferably from about 60 to about 80 % weight of the total weight of the solid dosage form.
Preferably, the pharmaceutically acceptable excipients in accordance with the invention include at least one binder and/or at least one disintegrant and/or at least one diluent and/or at least one lubricant and/or at least one compressibility improving agent.
Preferably, the binder includes hydroxypropyl methylcellulose (hydroxypropylmethyl cellulose), polyvinylpyrrolidone k-30, hydroxypropyl cellulose (low-substituted), starch or mixtures thereof and more preferable binder is hydroxypropyl cellulose and/or starch.
Preferably, the disintegrant includes sodium starch glycolate, croscarmellose sodium, polacrilin potassium and cross-linked polyvinyl pyrrolidone or mixtures thereof and more preferable disintegrant is sodium starch glycolate.

Preferably, the diluent includes mannitol, sorbitol, xylitol, lactose monohydrate, microcrystalline cellulose, light magnesium carbonate, dicalcium phosphate, tribasic calcium phosphate, calcium sulphate or mixture thereof, and more preferable diluent is microcrystalline cellulose.
Preferably, the lubricant includes magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate and stearic acid or mixtures thereof and more preferable lubricant is magnesium stearate. Preferably, the glidant includes hydrophilic fumed silica.
Other ingredients such as compressibility improving agent and anti-adherants, conventionally used for pharmaceutical formulations may also be included in the present formulation.
The "direct compression" is the process by which tablets are compressed directly from the powder blends of active ingredient/s and suitable excipients. No pre-treatment of the powder blends by wet or dry granulation is involved. The simplicity of the direct compression process is apparent from a comparison of the steps involved in the manufacture of tablets by wet granulation, roller compaction and direct compression techniques.

Comparison of major steps involved in the granulation methods.

Step Direct compression Dry Granulation Wet granulation
1 Mixing /blending of API and Adjuvants Mixing /blending of API and Adjuvants Mixing / blending of API and Adjuvants

i + i
2 Coinpiessian. Compression m to slugs Preparation ofbinder solution 1
3 Size reduction of slugs and sieving 1 Massing ofbinder solution of step 2 with powder mixture of step 1. ▼
4 Mixing of granules with pharmaceutical aid/s. ^ Wet screening of damp mass
5 GoinniJHEttiioin Drying of wet granules

1
6 Resifting of dried granules and blending with pharmaceutical aid/s. ^
7 Co mp session
It has been estimated that less than 20 percent of pharmaceutical materials can be compressed directly into tablets. The rest of the materials lack flow, cohesion or lubricating properties necessary for the production of tablets by direct compression. The use of directly compressible adjuvants may yield satisfactory tablets for such materials.
Dilution potential can be defined as the amount of an active ingredient that can be satisfactorily compressed in to tablets with the given directly compressible excipient. A directly compressible adjuvant should have high dilution potential so that the final dosage form has a minimum possible

weight The dilution potential is influenced by the compressibility of the active pharmaceutical ingredient. A directly compressible adjuvant should be capable of being reworked without loss of flow or compressibility.
A directly compressible adjuvant should have a particle size equivalent to the active ingredients present in the formulation. The particle size distribution should be consistent from batch to batch. Reproducible particle size distribution is necessary to achieve uniform blending with the active ingredient(s) in order to avoid segregation.
The prime advantage of direct compression over wet granulation is economic since the direct compression requires fewer unit operations. This means less equipment, lower power consumption, less space, less time and less labor leading to reduced production cost of tablets. Direct compression is more suitable for moisture and heat sensitive APIs, since it eliminates wetting and drying steps and increases the stability of active ingredients by reducing detrimental effects. Changes in dissolution profiles are less likely to occur in tablets made by direct compression on storage than in those made from granulations. This is extremely important because the official compendium now requires dissolution specifications in most solid dosage forms.

Disintegration or dissolution is the rate-limiting step in absorption in the case of tablets of poorly soluble API prepared by wet granulation. The tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster dissolution. The high compaction pressure involved in the production of tablets by slugging or roller compaction can be avoided by adopting direct compression. The chances of wear and tear of punches and dies are less. Materials are "in process" for a shorter period of time, resulting in less chance for contamination or cross contamination, and making it easier to meet the requirement of current good manufacturing practices. Due to fewer unit operations, the validation and documentation requirements are reduced. Due to the absence of water in granulation, chance of microbial growth is minimal in tablets prepared by direct compression.
The directly compressible adjuvant should be free flowing. Flowability is required in case of high-speed rotary tablet machines, in order to ensure homogenous and rapid flow of powder for uniform die filling. During the short dwell-time (milliseconds), the required amount of powder blend should be transferred into the die cavities with reproducibility of + 5%. Many common manufacturing problems are attributed to incorrect powder flow, including non-uniformity in blending, under or over dosage and inaccurate filling.
The directly compressible diluent should have good compressibility, i.e. relation between compaction pressure and volume.

Summary of various methods used to prepare directly compressible adjuvant

Method Advantages and Limitations Examples
Chemical Modification Relatively expensive. Requires. toxicoLogical data. Tunc consuming Ethyl cellulose, MctttylccGhilosc, Hydroxypropyl mcthylccilulose, and Sodium corboxymcthyl cclluloic from cellulose (i!) , Cyclodextrin from starch < 11)T Lactitol
Physical Modification Relatively simple and economical Dextrates or Compressible sugar. Sorbitol
Grinding
and'or
Sieving Compressibility may also Alter because of changes in particle properties such as surface area and amface activation (IS). tt-tactose monohydrjte (100 #), Dibasic dicalcium phosphate
Crystallization Impart flow-ability to cscipicntbut nnt necessarily self-binding properties, Require stringent controG on possible polymorphie conversion* and processing conditions i18>. fHactosc. Dipac
Spray Di'yirti; Spherical shape and uniform size give* spray-dried materials good flowxbility, poor re workability < 1S>. Spray dried lactose. limdcJL Fast Flo lactase* Aviuet PH. K jriun Instant t'Rl-CAFOS ST Advantose 100
Granulation/ Agglomeration Transformation of small, cohesive, poorly ilowable powders into a flowabte and directly compressible. Granulated Lactitol, Tabletto&e
Dehydration Increased binding properties by thermal and chemical dehydration, Anhydrous cx-lactose

Preferably, the solid pharmaceutical compositions prepared according to direct compress process of the invention are tablet, capsule, granules, powder, pill or a sachet.
The solid pharmaceutical dosage form of present invention contains from about 200 mg to about 700 mg of linezolid form I and optionally one or more pharmaceutically acceptable excipients.
In one embodiment, linezolid crystalline form I, for use in the high drug load solid dosage forms of the present invention can have a D90 particle size of less than or equal to about 100 microns. The particle sizes can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to converting the solid state linezolid into desired particle size range.
In another aspect, the invention relates to a method of formulating high drug content linezolid composition employs directly compressing the mixture of linezolid form 1 and 10 to 80% of direct compression base (w/w).
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Example 1

SI No. Name of Ingredients Mg/ Tablet
1 Linezolid (Polymorphism Form-I) 600
2 Com Starch 50
3 Microcrystalline cellulose 100
4 Sodium Starch Glycolate 34
5 Copovidone(Kollidone V A64) 25
6 Colloidal silicon dioxide 10
7 Hydroxypropyl cellulose(HPC-L) 15
8 Magnesium Stearate 6
9 Total weight of tablet(Uncoated) 840
10 Opadry white (build up about 3%) 25
11 Coated Tablet weight 865
Manufacturing process: Direct compression
Linezolid form-1 API was sifted through #40. Corn starch, microcrystalline cellulose, sodium starch glycolate, copovidone (Kollidone VA64), colloidal silicon dioxide, hydroxypropyl cellulose (HPC-L) were sifted through #40 and collected separately. After initial sieving procedure, Linezolid and other excipients were co-sifted through #40 and collected separately. The sifted materials were blended for 15 minutes and collected in polyethylene bag. The blend was lubricated with magnesium stearate for 3 minutes. The blend was compressed by using suitable punches.

We claim:
1. A high drug load solid pharmaceutical dosage form comprising about 200 mg to about 700 mg Linezolid Form-1 and optionally one or more pharmaceutically acceptable excipients.
2. The high drug load solid dosage form of claim 1, wherein the amount of Linezolid Form-I is greater than about 50% weight of the total weight of the high drug load solid dosage form.
3. The high drug load solid dosage form of claim 1, wherein Linezolid Form-I has a particle size distribution in which d90 is less than or equal to about 100 microns.
4. The high drug load solid dosage form of claim 1, wherein the pharmaceutically acceptable excipients include a diluent, a binder, a lubricant, a disintegrant and a compressibility improving agent or mixture thereof.
5. The high drug load solid dosage form of claim 1, wherein the binder is selected from corn starch, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, povidone, polyvinylpyrrolidone k-30, hydroxypropyl cellulose (low-substituted) or mixture thereof.
6. The high drug load solid dosage form of claim 1, wherein the diluent is selected from microcrystalline cellulose, mannitol, sorbitol, xylitol, lactose monohydrate, microcrystalline cellulose, magnesium carbonate, dicalcium phosphate, tribasic calcium phosphate or mixture thereof.

7. The high drug load solid dosage form of claim 1, wherein the compressibility improving agent is copovidone.
8. The high drug load solid dosage form of claim 1, wherein the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate and stearic acid or mixture thereof.
9. A method of producing a high drug load solid dosage form comprising the step of directly compressing the mixture of about 200 mg to about 700 mg Linezolid Form-I and direct compression base.
10. The method of producing a high drug load solid dosage form of claim 9, in which the direct compression base is microcrystalline cellulose (MCC).