WO2009140466A2

WO2009140466A2 - Linezolid co-crystals

Info

Publication number: WO2009140466A2
Application number: PCT/US2009/043903
Authority: WO
Inventors: Surya Narayana Devarakonda; Ram Thaimattam; Vamsee Krishna Muppidi; Sundara Lakshmi Kanniah; Naga Kiran Duggirala
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2008-05-14
Filing date: 2009-05-14
Publication date: 2009-11-19
Also published as: WO2009140466A3

Abstract

Co-crystals of linezolid, comprising linezolid and a co-crystal former, and processes for preparing them.

Description

LINEZOLID CO-CRYSTALS

INTRODUCTION

Aspects of the present invention relate to co-crystals, comprising linezolid and a co-crystal former, and processes for preparing them.

The drug with the adopted name "linezolid" has a chemical name (S)-N-[[3- [3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide, and is represented by the structure of Formula I.

Formula I

Linezolid is a synthetic antibacterial agent of the oxazolidinone class, useful for the treatment of bacterial infections in humans, and is available in products sold with the trademark ZYVOX, in the form of an I. V. injection, an oral suspension, and tablets.

U.S. Patent No. 5,688,792 discloses linezolid and pharmaceutically acceptable salts thereof. Various other crystalline forms, an amorphous form, hydrates and solvates of linezolid have been discribed in U.S. Patent No. 6,559,305, and International Application Publication Nos. WO 2005/035530 A1 , WO 2006/004922 A1 , WO 2006/110155 A1 , and WO2007026369 A1.

International Application Publication No. WO 2004/078163 A2 discloses pharmaceutical co-crystal compositions comprising an active pharmaceutical ingredient (API) and a co-crystal former.

Crystalline APIs are strongly preferred, due to their relative ease of isolation, the rejection of impurities inherent in the crystallization process and the physico-chemical stability that the crystalline solid state affords. But, the problems that arise with the use of crystalline material are usually related to poor solubility properties and the existence of more than one crystalline form of an API.

There remains a need for forms of linezolid providing desirable physico- chemical parameters such as solubility, rate of dissolution of the drug, chemical stability, melting point, and hygroscopicity, which can result in solids with superior properties.

SUMMARY

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and a co-crystal former.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and a co-crystal former in a molar ratio about 1 :1.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and benzoic acid.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 4-hydroxybenzoic acid.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 1 ,5-naphthalenedisulphonic acid.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and salicylic acid.

In an aspect, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, an embodiment of a process including grinding linezolid and a co-crystal former, optionally in the presence of an organic solvent.

In an aspect, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, an embodiment including milling a mixture of linezolid and a co-crystal former.

In an aspect, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, an embodiment including melting a mixture of linezolid and a co-crystal former, optionally in the presence of an organic solvent.

In an aspect, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, an embodiment including providing a solution comprising linezolid and a co-crystal former in a solvent, optionally seeding with co-crystals of linezolid, and forming co- crystals.

In an aspect, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, an embodiment including providing a solution comprising linezolid and a co-crystal former in a solvent, and combining an anti-solvent with the solution.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and benzoic acid, characterized by a powder X-ray diffraction (PXRD) pattern having peaks located substantially at about 3.8, 12.4, 16.4, 18.4, 23.9, and 25.1 , ± 0.2 degrees 2-theta.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and benzoic acid, characterized by a differential scanning calohmetry (DSC) curve having an endothermic peak at about 112°C.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and benzoic acid, characterized by any one or more of a PXRD pattern, DSC curve, and infrared (IR) absorption spectrum, substantially as illustrated by Fig. 1 , Fig. 2, and Fig. 3, respectively.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 4-hydroxybenzoic acid, characterized by a PXRD pattern having peaks located substantially at about 3.8, 15.6, 18.8, 24.6, 25.9, and 28.4, ± 0.2 degrees 2-theta.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 4-hydroxybenzoic acid, characterized by a DSC curve having endothermic peaks at about 73°C and 76°C.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 4-hydroxybenzoic acid, characterized by one or more of a PXRD pattern, DSC thermogram, and IR absorption spectrum substantially as illustrated by Fig. 4, Fig. 5, and Fig. 6, respectively.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 1 ,5-naphthalenedisulphonic acid, characterized by a PXRD pattern having peaks located substantially at about 9.1 , 15.4, 17.1 , 20.2, 22.5, and 24.1 , ± 0.2 degrees 2-theta.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 1 ,5-naphthalenedisulphonic acid, characterized by a DSC curve having an endothermic peak at about 167°C. -A-

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 1 ,5-naphthalenedisulphonic acid, characterized by a TGA curve corresponding to a weight loss of less than about 5% by weight.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 1 ,5-naphthalenedisulphonic acid, characterized by one or more of a PXRD pattern, DSC curve, and TGA curve, substantially as illustrated by Fig. 7, Fig. 8, and Fig. 9, respectively.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and salicylic acid, characterized by a PXRD pattern having peaks located substantially at about 6.2, 14.1 , 16.2, 21.9, 23.9, and 26.9, ± 0.2 degrees 2-theta.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and salicylic acid, characterized by a DSC curve having an endothermic peak at about 156°C.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and salicylic acid, characterized by a TGA curve corresponding to a weight loss of less than about 3% by weight.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and salicylic acid, characterized by one or more of a PXRD pattern, DSC curve, and TGA curve, substantially as illustrated by Fig. 10, Fig. 11 , and Fig. 12, respectively.

An aspect of the present invention provides pharmaceutical compositions comprising co-crystals of linezolid, together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an illustration of a powder X-ray diffraction pattern of linezolid- benzoic acid co-crystals, prepared according to Example 1.

Fig. 2 is an illustration of a differential scanning calohmetry (DSC) curve of linezolid-benzoic acid co-crystals, prepared according to Example 1.

Fig. 3 is an illustration of an infrared absorption spectrum of linezolid- benzoic acid co-crystals, prepared according to Example 1. Fig. 4 is an illustration of a powder X-ray diffraction pattern of linezolid-4- hydroxybenzoic acid co-crystals, prepared according to Example 8.

Fig. 5 is an illustration of a DSC curve of linezolid-4-hydroxybenzoic acid co-crystals, prepared according to Example 8.

Fig. 6 is an illustration of an infrared absorption spectrum of linezolid-4- hydroxybenzoic acid co-crystals, prepared according to Example 8.

Fig. 7 is an illustration of a powder X-ray diffraction pattern of linezolid-1 ,5- naphthalenedisulphonic acid co-crystals, prepared according to Example 9.

Fig. 8 is an illustration of a DSC curve of linezolid-1 ,5- naphthalenedisulphonic acid co-crystals, prepared according to Example 9.

Fig. 9 is an illustration of a thermogravimetric analysis (TGA) curve of linezolid-1 ,5-naphthalenedisulphonic acid co-crystals, prepared according to Example 9.

Fig. 10 is an illustration of a powder X-ray diffraction pattern of linezolid- salicylic acid co-crystals, prepared according to Example 10.

Fig. 11 is an illustration of a DSC curve of linezolid-salicylic acid co- crystals, prepared according to Example 10.

Fig. 12 is an illustration of a TGA curve of linezolid-salicylic acid co- crystals, prepared according to Example 10.

Fig. 13 is an illustration showing comparative powder X-ray diffraction patterns of linezolid-benzoic acid co-crystals as prepared in Example 1 , benzoic acid, linezolid Form II, and linezolid Form IV.

Fig. 14 is an illustration showing comparative powder X-ray diffraction patterns of linezolid-4-hydroxybenzoic acid co-crystals as prepared in Example 8, 4-hydroxybenzoic acid, linezolid Form II, and linezolid Form IV.

Fig. 15 is an illustration showing comparative powder X-ray diffraction patterns of linezolid-1 ,5-naphthalenedisulphonic acid co-crystals as prepared in Example 9, 1 ,5-naphthalenedisulphonic acid, linezolid Form II, and linezolid Form IV.

Fig. 16 is an illustration showing comparative powder X-ray diffraction patterns of linezolid-salicylic acid co-crystals as prepared in Example 10, salicylic acid, linezolid Form II, and linezolid Form IV. DETAILED DESCRIPTION

Aspects of the present invention relates to co-crystals, comprising linezolid and a co-crystal former, and processes for preparation thereof.

As used herein, the term "co-crystal" denotes crystalline molecular complexes, encompassing hydrates and solvates. "Co-crystals" are composed of multi-component, stoichiometric and neutral molecular species, each existing as a solid under ambient conditions.

Co-crystals exhibit properties different from free drugs or salts. The solid form influences relevant physico-chemical parameters such as solubility, dissolution rate of the drug, chemical stability, melting point, and hygroscopicity, which can result in solids with superior properties.

Useful co-crystal formers of the present invention include, but are not limited to, benzoic acid, 4-hydroxybenzoic acid, 1 ,5-naphthalenedisulphonic acid, salicylic acid, and the like.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and benzoic acid, characterized by a powder X-ray diffraction (PXRD) pattern having peaks located at about 3.8, 12.4, 16.4, 18.4, 23.9, and 25.1 , ± 0.2 degrees 2-theta.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and benzoic acid, characterized by one or more of a PXRD pattern, DSC thermogram, and infrared (IR) absorption spectrum, substantially as illustrated by Fig. 1 , Fig. 2 and Fig. 3, respectively.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 4-hydroxybenzoic acid, characterized by a PXRD pattern having peaks located at about 3.8, 15.6, 18.8, 24.6, 25.9, and 28.4, ± 0.2 degrees 2-theta. In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 4-hydroxybenzoic acid, characterized by a DSC curve having endothermic peaks at about 73°C and 76°C.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 4-hydroxybenzoic acid, characterized by one or more of a PXRD pattern, DSC thermogram, and IR spectrum, substantially as illustrated by Fig. 4, Fig. 5 and Fig. 6, respectively.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 1 ,5-naphthalenedisulphonic acid, characterized by a PXRD pattern having peaks located at about 9.1 , 15.4, 17.1 , 20.2, 22.5, and 24.1 , ± 0.2 degrees 2-theta.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 1 ,5-naphthalenedisulphonic acid, characterized by a DSC curve having an endothermic peak at about 167°C.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and 1 ,5-naphthalenedisulphonic acid, characterized by one or more of a PXRD pattern, DSC curve, and TGA curve, substantially as illustrated by Fig. 7, Fig. 8 and Fig. 9, respectively.

In an embodiment, the present invention provides co-crystals of linezolid, comprising linezolid and salicylic acid, characterized by a PXRD pattern having peaks located at about 6.2, 14.1 , 16.2, 21.9, 23.9, and 26.9, ± 0.2 degrees 2- theta.

X-ray diffraction patterns reported herein were obtained using Bruker AXS D8 Advance and PANalytical Xpert-pro equipment, with an X-ray source producing copper Ka radiation.

Differential scanning calorimetry analyses reported herein were carried out using a conventional differential scanning calorimetric method with a DSC Q1000 V 9.4 Build 287 model from TA Instruments, and a ramp of 10°C/minute up to 200⁰C.

Thermogravimethc analysis was performed using a model Q500 from TA Instruments.

Illustrative examples of certain analytical data for the co-crystals of linezolid obtained in the examples are set forth in Figs. 1 -16.

In an aspect, the present invention provides processes for preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, certain processes including solvent drop grinding, ball milling, melt crystallization, crystallization from solvents by seeding, solvent evaporation, and anti-solvent addition methods.

In an embodiment, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, including grinding a mixture of linezolid and a co-crystal former, optionally adding a small quantity of an organic solvent. The quantity of the solvent that may be used is not particularly critical, ranging from about 0.1 to about 5 ml_ (e.g., about 2 to about 30 drops), per gram of linezolid.

In an embodiment, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, including milling a mixture of linezolid and a co-crystal former.

In an embodiment, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, including melting linezolid and a co-crystal former together, optionally, after melting of the components, adding a small quantity of an organic solvent.

Any physical form of linezolid, such as crystalline, amorphous, and their mixtures may be utilized as a starting material for providing co-crystals of the present invention. Among the useful polymorphic forms are linezolid crystalline Form II, described in U.S. Patent No. 6,559,305, and linezolid crystalline Form IV, described in International Application Publication No. WO 2006/004922. PXRD patterns for these crystalline forms are shown in Figs. 13-16.

Organic solvents that may be used for preparation of the co-crystals of the present invention include, but are not limited to: water; alcohols such as methanol, ethanol, 1 -propanol, 1 -butanol, 2-butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, 2-ethoxyethanol, ethylene glycol, glycerol, and the like; ketones such as acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl iso-butyl ketone, and the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like; aliphatic and alicyclic hydrocarbons, unsubstituted and substituted, such as hexanes, n-heptane, n-pentane, cyclohexane, methylcyclohexane, nitromethane, and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-thchloroethane, 1 ,2-dichloroethene, and the like; aromatic hydrocarbons such as toluene, xylenes, chlorobenzene, tetraline, and the like; nithles such as acetonitrile, propionitrile, and the like; and any mixtures thereof.

In an embodiment, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, including providing a solution comprising linezolid and a co-crystal former in a solvent, optionally seeding with co-crystals of linezolid, and forming solid co- crystals.

In an embodiment, the present invention provides processes for the preparation of co-crystals of linezolid, comprising linezolid and a co-crystal former, including providing a solution comprising linezolid and a co-crystal former in a solvent, and adding a co-crystal anti-solvent to the solution.

Providing a solution comprising linezolid and a co-crystal former in a solvent may include dissolving linezolid and a co-crystal former in a suitable solvent or mixture of solvents, or such a solution may be obtained by dissolving a co-crystal former in a reaction mixture containing linezolid that is obtained in the course of its synthesis. The dissolution may be carried out at temperatures suitable for complete dissolution of the components, without affecting its quality.

Any physical form of linezolid, such as crystalline, amorphous, and their mixtures may be utilized for providing the solution.

Solvents that may be used for providing a solution of linezolid and a co- crystal former include, but are not limited to: water; alcohols such as methanol, ethanol, 1 -propanol, 1 -butanol, 2-butanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, 2-ethoxyethanol, ethylene glycol, glycerol, and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; and any mixtures thereof.

Optionally, seeding the solution with co-crystals of linezolid may be performed at temperatures about 20 to about 60⁰C. The quantity of co-crystals of Linezolid that may be used for seeding may range from less than about 15%, or less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, by weight of the solids content of the solution, or any other suitable quantity may be used.

Suitable anti-solvents that may be used include, but are not limited to: ethers such as diethyl ether, dimethyl ether, diisopropylether, tetrahydrofuran, 1 ,4- dioxane, and the like; hydrocarbons such as n-hexane, n-heptane, cyclohexane, toluene, xylene, and the like; and mixtures thereof.

The anti-solvent may be added to the solution comprising linezolid and a co-crystal former at temperatures ranging from about 20⁰C to about 60°C, or at room temperature.

Formation of co-crystals of linezolid occurs either by slow evaporation of solvent, fast evaporation of solvent, or crash cooling methods. For more complete formation to occur, the solution or mixture may be maintained at temperatures lower than the dissolution temperatures.

The method by which the solid co-crystals are recovered from the final mixture, with or without cooling below the operating temperature, can utilize any of suitable techniques such as filtration by gravity or by suction, decantation, centrifugation, and the like. Other techniques for separating solids from liquids are also within the scope of this invention. The co-crystals so isolated can carry a small portion of occluded mother liquor containing a higher percentage of impurities. If desired, the co-crystals may be washed with a solvent to wash out the mother liquor.

The isolated or recovered product may be optionally further dried to afford the co-crystals of linezolid. Drying may be suitably carried out in a tray dryer, vacuum oven, rotavapour, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures of about 35°C to about 70⁰C. The drying may be carried out for any time periods necessary for obtaining a desired quality, such as from about 15 minutes to several hours or days.

In an embodiment, the present invention provides pharmaceutical compositions comprising co-crystals of linezolid, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions comprising co-crystals of linezolid may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using procedures such as direct blending, dry granulation, wet granulation, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that find use in the present application 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, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodiums, 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, ethyl celluloses, methyl celluloses, 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, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

Certain specific aspects and embodiments of the present invention will be explained in more 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 invention in any manner.

EXAMPLE 1 : PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS Linezolid (500 mg) and benzoic acid (180.8 mg) are subjected to grinding for 30 minutes, adding 4-5 drops of methanol within the first 15 minutes, to afford

650.9 mg of co-crystals.

Analysis of the co-crystal product gives the powder X-ray diffraction pattern of Fig. 1 , the differential scanning calorimetry curve of Fig. 2, and the infrared absorption spectrum of Fig. 3.

Powder X-ray diffraction patterns of the co-crystal product, benzoic acid, linezolid crystalline Form II, and linezolid crystalline Form IV are shown in Fig. 13.

EXAMPLE 2: PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS Linezolid (2 g) and benzoic acid (723.2 mg) are milled in a Retsch PM100 ball mill (bowl) for 5 hours to afford 2.257 g of co-crystals.

Operating parameters of Retsch PM100 ball mill (bowl): RPM: 400 EXAMPLE 3: PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS Linezolid (200 mg) and benzoic acid (72.32 mg) are mixed and heated to 100-160⁰C. The mass is maintained for 15 minutes at 120-160⁰C and then is cooled to room temperature, to afford 140 mg of co-crystals.

EXAMPLE 4: PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS Linezolid (200 mg) and benzoic acid (72.32 mg) are mixed and heated to 110-160°C. The mass is maintained at 110-160⁰C for a period of 5 minutes. Methanol (4 drops) is added to the above mass and the mass is cooled to room temperature, to afford 160 mg of co-crystals.

EXAMPLE 5: PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS Linezolid (500 mg), benzoic acid (180.8 mg) and methanol (7-10 mL) are mixed and heated to 60°C to form a solution. The solution is cooled to room temperature, a small amount of linezolid-benzoic acid co-crystals (34 mg) is added, and the mixture is allowed to evaporate slowly at room temperature for complete evaporation of the solvent.

EXAMPLE 6: PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS

Linezolid (500 mg), benzoic acid (180.8 mg) and tetrahydrofuran (7-10 mL) are mixed and heated to 60°C to form a solution. The solution is cooled to room temperature, a small amount of linezolid-benzoic acid co-crystals (34 mg) is added, and the mixture was allowed to evaporate slowly at room temperature for complete evaporation of the solvent.

EXAMPLE 7: PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS

Linezolid (500 mg), benzoic acid (180.8 mg) and dichloromethane (2-3 mL) are mixed and heated to 60⁰C to form a solution. The solution is cooled to room temperature, a small amount of linezolid-benzoic acid co-crystals (34 mg) is added, and the mixture is allowed to evaporate slowly at room temperature for complete evaporation of the solvent. EXAMPLE 8: PREPARATION OF LINEZOLID^-HYDROXYBENZOIC ACID CO- CRYSTALS

Linezolid (400 mg) and 4-hydroxybenzoic acid (165.3 mg) are charged in to a mortar and pestle and subjected to grinding for 20 minutes, adding 4-5 drops of methanol in the first 15 minutes, to afford 550 mg of co-crystals.

Analysis of the co-crystal product gives the powder X-ray diffraction pattern of Fig. 4, the differential scanning calorimetry curve of Fig. 5, and the infrared absorption spectrum of Fig. 6.

Powder X-ray diffraction patterns of the co-crystal product, 4- hydroxybenzoic acid, linezolid crystalline Form II, and linezolid crystalline Form IV are shown in Fig. 14.

EXAMPLE 9: PREPARATION OF LINEZOLID-1 ,5-NAPHTHALENE- DISULPHONIC ACID CO-CRYSTALS

Linezolid (300 mg) and 1 ,5-naphthalenedisulphonic acid (227.8 mg) are and subjected to grinding with a mortar and pestle for 30 minutes, adding 7 drops of methanol within the first 15 minutes, to afford 520.7 mg of co-crystals.

Analysis of the co-crystal product gives the powder X-ray diffraction pattern of Fig. 7, the differential scanning calorimetry curve of Fig. 8, and the thermogravimetric analysis curve of Fig. 9.

Powder X-ray diffraction patterns of the co-crystal product, 1 ,5- naphthalenedisolphonic acid, linezolid crystalline Form II, and linezolid crystalline Form IV are shown in Fig. 15.

EXAMPLE 10: PREPARATION OF LINEZOLID-SALICYLIC ACID CO- CRYSTALS

Linezolid (400 mg) and salicylic acid (162 mg) are subjected to grinding in a mortar and pestle for 30 minutes, adding methanol (1 mL) within the first 15 minutes, to afford 510 mg of co-crystals.

Analysis of the co-crystal product gives the powder X-ray diffraction pattern of Fig. 10, the differential scanning calorimetry curve of Fig. 11 , and the thermogravimetric analysis curve of Fig. 12.

Powder X-ray diffraction patterns of the co-crystal product, salicylic acid, linezolid crystalline Form II, and linezolid crystalline Form IV are shown in Fig. 16. EXAMPLE 11 : PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS Linezolid (500 mg), benzoic acid (181.2 mg) and dichloromethane (2-5 mL) are mixed and stirred at room temperature to form a solution. The solvent is allowed to evaporate slowly at room temperature to afford 648.2 mg of co-crystals.

EXAMPLE 12: PREPARATION OF LINEZOLID BENZOIC ACID CO-CRYSTALS

Linezolid (1 g), benzoic acid (361 mg) and dichloromethane (10 mL) are mixed and heated to 40⁰C to form a solution. The solution is evaporated at 45°C under vacuum and the residue is dried at 45°C, to afford 1.317 g of co-crystals.

EXAMPLE 13: PREPARATION OF LINEZOLID BENZOIC ACID CO-CRYSTALS

Linezolid (1 g), benzoic acid (361 mg) and dichloromethane (5 mL) are mixed and heated to 40⁰C. The mixture is stirred at 40⁰C for 5-10 minutes to form a solution, then is cooled to 0-5°C and hexane (10 mL) is added at 0-5⁰C and the mixture is stirred for 15-20 minutes. The formed solid is filtered to obtain 1.24 g of co-crystals.

EXAMPLE 14: PREPARATION OF LINEZOLID BENZOIC ACID CO-CRYSTALS

Linezolid (10 g), benzoic acid (3.6 g) and dichloromethane (50 mL) are mixed and stirred at room temperature for 15-20 minutes to form a solution. Heptane (100 mL) is added at room temperature and the mixture is stirred for 15- 20 minutes. The formed solid is filtered, washed with hexane (10 mL), and dried at 50°C to afford 12.7 g of co-crystals.

EXAMPLE 15: PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS Linezolid (500 mg), benzoic acid (181.2 mg) and dichloromethane (2-5 mL) are mixed and heated to 38°C. The mixture is stirred at 38°C to form a solution.

The solution is subjected to sudden cooling to 10⁰C at a rapid rate of 2.8°C per minute, to afford 510.0 mg of co-crystals.

A comparison of solubilities of the co-crystals of linezolid and linezolid Form

Il at room temperature and at 60⁰C is given in the following tables. Solubility enhancement (% SE) is calculated by the following equation: % SE = 100 x (Co-crystal solubility - Linezolid solubility) ÷ Linezolid solubility.

Solubility of linezolid-benzoic acid co-crystals.

Solubility of linezolid-4-hydroxybenzoic acid co-crystals.

Solubility of linezolid-1 ,5-naphthalenedisulphonic acid co-crystals.

Acetone 10.0 Insoluble 41 .2 Insoluble

Acetonithle 25.0 Insoluble 100.0 Insoluble

Linezolid-benzoic acid co-crystals are stable for at least 23 days under ambient conditions, when packaged in a polyethylene bag.

Linezolid-4-hydroxybenzoic acid co-crystals are stable for at least 22 days under ambient conditions, when packaged in a polyethylene bag.

Claims

CLAIMS:

1. Co-crystals of linezolid, comprising linezolid and a co-crystal former.

2. The co-crystals of linezolid according to claim 1 , wherein linezolid and the co-crystal former are present in a molar ratio of about 1 :1.

3. The co-crystals of linezolid according to claim 1 , wherein the co- crystal former comprises benzoic acid, 4-hydroxybenzoic acid, 1 ,5- naphthalenedisulphonic acid, or salicylic acid.

4. The co-crystals of linezolid according to claim 1 or 2, comprising linezolid and benzoic acid.

5. The co-crystals of linezolid according to claim 4, characterized by powder X-ray diffraction pattern having peaks located substantially at about 3.8, 12.4, 16.4, 18.4, 23.9, and 25.07, ± 0.2 degrees 2-theta.

6. The co-crystals of linezolid according to claim 4, characterized by powder X-ray diffraction pattern substantially as illustrated in Fig. 1.

7. The co-crystals of linezolid according to claim 4, characterized by differential scanning calorimetry curve having an endothermic peak at about 112°C.

8. The co-crystals of linezolid according to claim 4, characterized by differential scanning calorimetry curve substantially as illustrated in Fig. 2.

9. The co-crystals of linezolid according to claim 4, characterized by infrared absorption spectrum substantially as illustrated in Fig. 3.

10. The co-crystals of linezolid according to claim 1 or 2, comprising linezolid and 4-hydroxybenzoic acid.

11. The co-crystals of linezolid according to claim 10, characterized by powder X-ray diffraction pattern having peaks located substantially at about 3.8, 15.6, 18.8, 24.6, 25.9, and 28.4, ± 0.2 degrees 2-theta.

12. The co-crystals of linezolid of claim 10, characterized by powder X- ray diffraction pattern substantially as illustrated in Fig. 4.

13. The co-crystals of linezolid according to claim 10, characterized by differential scanning calorimetry curve having endothermic peaks at about 73°C and 76°C.

14. The co-crystals of linezolid according to claim 10, characterized by differential scanning calorimetry curve substantially as illustrated in Fig. 5.

15. The co-crystals of linezolid according to claim 10, characterized by an infrared absorption spectrum substantially as illustrated in Fig. 6.

16. The co-crystals of linezolid according to either of claims 1 or 2, comprising linezolid and 1 ,5-naphthalenedisulphonic acid.

17. The co-crystals of linezolid according to claim 16, characterized by powder X-ray diffraction pattern from copper Ka radiation having peaks located substantially at about 91 , 15.4, 17.1 , 20.2, 22.5, and 24.1 , ± 0.2 degrees 2-theta.

18. The co-crystals of linezolid according to claim 16, characterized by powder X-ray diffraction pattern from copper Ka radiation substantially as illustrated in Fig. 7.

19. The co-crystals of linezolid according to claim 16, characterized by differential scanning calorimetry curve having an endothermic peak at about 167°C.

20. The co-crystals of linezolid according to claim 16, characterized by differential scanning calorimetry curve substantially as illustrated in Fig. 8.

21. The co-crystals of linezolid according to claim 16, characterized by thermogravimetric analysis curve corresponding to a weight loss less than about 5 percent by weight.

22. The co-crystals of linezolid according to claim 16, characterized by thermogravimetric analysis curve substantially as illustrated in Fig. 9.

23. The co-crystals of linezolid according to claim 1 or 2, comprising linezolid and salicylic acid.

24. The co-crystals of linezolid according to claim 23, characterized by powder X-ray diffraction pattern having peaks located substantially at about 6.2, 14.1 , 16.2, 21.9, 23.9, and 26.9, ± 0.2 degrees 2-theta.

25. The co-crystals of linezolid according to claim 23, characterized by powder X-ray diffraction pattern substantially as illustrated in Fig. 10.

26. The co-crystals of linezolid according to claim 23, characterized by differential scanning calorimetry curve having an endothermic peak at about 156°C.

27. The co-crystals of linezolid according to claim 23, characterized by differential scanning calorimetry curve substantially as illustrated in Fig. 11.

28. The co-crystals of linezolid according to claim 23, characterized by thermogravimetric analysis curve corresponding to a weight loss less than about 3 percent by weight.

29. The co-crystals of linezolid according to claim 23, characterized by thermogravimetric analysis curve substantially as illustrated in Fig. 12.

30. A process for preparing co-crystals of linezolid according to any of claims 1-3, comprising grinding linezolid and a co-crystal former, optionally with a small quantity of an organic solvent.

31. A process for preparing co-crystals of linezolid according to any of claims 1 -3, comprising milling linezolid and a co-crystal former.

32. A process for preparing co-crystals of linezolid according to any of claims 1-3, comprising melting linezolid and a co-crystal former, optionally adding a small quantity of an organic solvent.

33. A process for preparing co-crystals of linezolid according to any of claims 1-3, comprising providing a solution comprising linezolid and a co-crystal former in a solvent, optionally seeding with co-crystal of linezolid, and forming solid co-crystal.

34. A process for preparing co-crystals of linezolid according to any of claims 1-3, comprising providing a solution comprising linezolid and a co-crystal former in a solvent, and adding an anti-solvent to the solution.