DESC:FIELD OF THE INVENTION
The present invention relates to co-crystals of Metaxalone including Metaxalone : Salicylamide co-crystal, Metaxalone : Nicotinamide co-crystal and Metaxalone : 4-hydroxy benzoic acid co-crystal. The present invention also relates to the process for preparation of these cocrystals.

The present complete specification is prepared by cognating the contents provisional patent specification of application numbered 393/mum/2015 dated February 05, 2015 with the contents of the specification of patent application no. 3234/mum/2015 dated August 24, 2015. The combined contents of the present specification constitute a single invention within the meaning of the Act.

BACKGROUND OF THE INVENTION
Metaxalone is a muscle relaxant. It is used to relax muscles and relieve pain caused by strains, sprains, and other musculoskeletal conditions, under the trade name Skelaxin®. It was first approved by the US FDA on Aug 30, 2002. It is chemically known as 5-[(3,5- dimethylphenoxy) methyl]-2-oxazolidinone & is shown below.

It is known that crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof.

Obtaining suitable crystalline forms of a drug is a necessary stage for many orally available drugs. Suitable crystalline forms possess the desired properties of a particular drug. Such suitable crystalline forms may be obtained by forming a co-crystal between the drug and a coformer.

“Co-crystal” means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion when compared to those of the drug and coformer individually. The co-crystals comprise a co-crystal former H-bonded to an API.
Following are the advantages of the co-crystals:
i) increase or decrease the dissolution rate of API-containing pharmaceutical compositions in water,
ii) increased stability,
iii) improved processability, or preparation of pharmaceutical formulations
iv) increase or decrease the bioavailability of orally-administered compositions, and provide a more rapid or more delayed onset to therapeutic effect.

Metaxalone is a white to almost white, odorless crystalline powder freely soluble in chloroform, soluble in methanol and in 96% ethanol, but practically insoluble in water which makes Metaxalone less bioavailable & creates huge problems for the pharmaceutical industry.

Metaxalone & its preparation is described in U.S. Pat. No. 3,062,827.

Metaxalone exhibits polymorphism. It shows different physical forms such as amorphous and various crystalline forms.

The U.S. Pat. No. 7,750,165 discloses crystalline Metaxalone Form A & Form B.

The U.S. Pat. Appl. No. 20090163561 discloses Amorphous Metaxalone.

The U.S. Pat. No. 8,871,793 discloses cocrystals of Metaxalone with adipic acid, fumaric acid, salicylic acid, succinic acid, maleic acid respectively.

SUMMARY OF THE INVENTION
The present invention relates to Metaxalone : Salicylamide co-crystal, Metaxalone : Nicotinamide co-crystal and Metaxalone : 4-hydroxy benzoic acid co-crystal.

The present invention further provides process for the preparation of Metaxalone : Salicylamide co-crystal, Metaxalone : Nicotinamide co-crystal and Metaxalone : 4-hydroxy benzoic acid co-crystal.
The process for the preparation of Metaxalone : Salicylamide co-crystal comprises crystallization of Metaxalone and Salicylamide in a suitable solvent.
The process preparation of Metaxalone : Nicotinamide co-crystal comprises crystallization of Metaxalone and Nicotinamide in a suitable solvent.
The process preparation of Metaxalone : 4-hydroxy benzoic acid co-crystal comprises crystallization of Metaxalone and 4-hydroxy benzoic acid in a suitable solvent.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1 - XRPD diffractogram for Metaxalone : Salicylamide co-crystal
Figure 2 - DSC thermogram for Metaxalone : Salicylamide co-crystal
Figure 3 - IR spectrum for Metaxalone : Salicylamide co-crystal
Figure 4 - ORTEP drawing of the Metaxalone : Salicylamide co-crystal
Figure 5 - packing diagram of the Metaxalone : Salicylamide co-crystal
Figure 6 - XRPD diffractogram for Metaxalone : Nicotinamide co-crystal
Figure 7 - DSC thermogram for Metaxalone : Nicotinamide co-crystal
Figure 8 - IR spectrum for Metaxalone : Nicotinamide co-crystal
Figure 9 - XRPD diffractogram for Metaxalone : 4-hydroxy benzoic acid co-crystal
Figure 10 - IR spectrum for Metaxalone : 4-hydroxy benzoic acid co-crystal

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment there is provided Metaxalone : Salicylamide co-crystal.
Metaxalone : Salicylamide co-crystal of the present invention can be characterized by X-ray crystallography, differential scanning calorimetry (DSC), and IR spectroscopy.
In another embodiment there is provided Metaxalone : Nicotinamide co-crystal.
Metaxalone : Nicotinamide co-crystal of the present invention can be characterized by X-ray crystallography, differential scanning calorimetry (DSC), and IR spectroscopy.
In another embodiment there is provided Metaxalone : 4-hydroxy benzoic acid co-crystal.
Metaxalone : 4-hydroxy benzoic acid co-crystal of the present invention can be characterized by X-ray crystallography, differential scanning calorimetry (DSC), and IR spectroscopy.
In another embodiment there is provided Metaxalone : Salicylamide co-crystal wherein said Metaxalone : Salicylamide co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks at 5.6, 16.4, and 24.1 degree 2-theta + 0.2 degree 2-theta.
The XRPD of crystalline Metaxalone : Salicylamide co-crystal is as shown in figure 1.
Table 1 lists the angles, degree 2-theta + 0.2 degree 2-theta, d-spacing, and intensity of the peaks identified in the XRPD pattern of figure 1.
Table 1
Position
degree
2? (±0.2) d-spacing I/I0
(%) Position
degree
2? (±0.2) d-spacing I/I0
(%)
5.6 15.518 100 18.9 4.667 6
8.1 10.903 3 20.3 4.352 6
10.5 8.373 4 23.3 3.803 7
11.3 7.774 1 24.1 3.688 39
12.9 6.805 5 25.0 3.557 17
14.9 5.931 10 25.3 3.506 11
16.4 5.393 45 28.5 3.121 5
17.1 5.175 16 29.4 3.033 8
17.8 4.975 11 32.4 2.757 3

In another embodiment there is provided Metaxalone : Salicylamide co-crystal wherein said Metaxalone : Salicylamide co-crystal is characterized by endotherm with an onset temperature of 117.26°C and a peak maximum of 119°C in differential scanning calorimetry (DSC).
The DSC of Metaxalone : Salicylamide co-crystal is shown in figure 2.
In another embodiment there is provided Metaxalone : Salicylamide co-crystal wherein said Metaxalone : Salicylamide is characterized by an IR spectrum comprising peaks at 1677, 1751, 3196 and 3391 cm-1.
The IR spectrum of Metaxalone : Salicylamide co-crystal is as shown in figure 3.
The single crystal data and structure refinement parameters for Metaxalone : Salicylamide co-crystal are reported in Table 2. Figure 4 is an ORTEP drawing of Metaxalone : Salicylamide co-crystal. Figure 5 shows the crystal packing of the Metaxalone : Salicylamide co-crystal.
Table 2
Molecular formula C19H22N2O5
Molecular weight 358.39
Crystallization solvent Methanol
Crystal color Colorless
Crystal Structure triclinic
Space Group P-1
Unit cell dimensions a (Å) = 5.2373 (5)
b (Å) = 10.9485 (11)
c (Å) = 15.5370 (16)
a (°) = 83.000(6)
ß (°) = 88.982(6)
? (°) = 81.834(6)
Cell volume 875.29 (15) Å3
Z 2
Theta (max) 27.480
Density (calculated) 1.360 gm/cm3
Absorption coefficient 0.099 mm-1
Temperature 298 K
R indices R1 = 0.0472, wR2 = 0.1216
Goodness-of-fit on F2 1.53
Diffractometer Rigaku-CCD

In another embodiment there is provided Metaxalone : Nicotinamide co-crystal wherein said Metaxalone : Nicotinamide co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks 5.7, 17.4, 23.6 and 24.1 degree 2-theta + 0.2 degree 2-theta.
The XRPD of crystalline Metaxalone : Nicotinamide co-crystal is as shown in figure 6.
Table 3 lists the angles, degree 2-theta + 0.2 degree 2-theta, d-spacing, and intensity of the peaks identified in the XRPD pattern of figure 6.
Table 3
Position degree
2? (±0.2) d-spacing I/I0
(%)
4.4 19.888 15.28
5.7 15.377 100.00
14.4 5.076 78.71
18.4 4.812 15.55
23.6 3.764 33.90
24.1 3.683 36.11
25.2 3.522 24.11
25.4 3.496 27.47

In another embodiment there is provided Metaxalone : Nicotinamide co-crystal wherein said Metaxalone : Nicotinamide co-crystal is characterized by endotherm with an onset temperature of 104.77°C and a peak maximum of 106.58°C in differential scanning calorimetry (DSC).
The DSC of Metaxalone : Nicotinamide co-crystal is shown in figure 7.
In another embodiment there is provided Metaxalone : Nicotinamide co-crystal wherein said Metaxalone : Nicotinamide is characterized by an IR spectrum comprising peaks at 1686, 1751, 3154 and 3370 cm-1.
The IR spectrum of Metaxalone : Nicotinamide co-crystal is as shown in figure 8.
In another embodiment there is provided Metaxalone : 4-hydroxy benzoic acid co-crystal wherein said Metaxalone : 4-hydroxy benzoic acid co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks at 5.9, 13.5, 19.0, 22.5 and 26.3 degree 2-theta + 0.2 degree 2-theta.
The XRPD of crystalline Metaxalone : 4-hydroxy benzoic acid co-crystal is as shown in figure 9.
Table 4 lists the angles, degree 2-theta + 0.2 degree 2-theta, d-spacing, and intensity of the peaks identified in the XRPD pattern of figure 9.
Table 4
Position degree
2? (±0.2) d-spacing I/I0
(%)
5.9 14.765 38.69
6.4 13.752 26.53
13.5 6.552 100.00
13.7 6.416 24.82
14.4 5.069 36.02
19.0 4.659 54.33
22.5 3.938 44.09
26.3 3.382 48.72

In another embodiment there is provided Metaxalone : 4-hydroxy benzoic acid co-crystal wherein said Metaxalone : 4-hydroxy benzoic acid is characterized by an IR spectrum comprising peaks at 1686, 1726, 3271 and 3423cm-1.
The IR spectrum of Metaxalone : 4-hydroxy benzoic acid co-crystal is as shown in figure 10.
In another embodiment there is provided process for the preparation of Metaxalone : Salicylamide co-crystal comprising crystallization of Metaxalone and Salicylamide in a suitable solvent.
Suitable solvent for the preparation of Metaxalone : Salicylamide co-crystal is selected from the group consisting of polar aprotic solvents, protic solvents, and halogenated solvents and mixtures thereof. Polar aprotic solvent is selected from the group consisting of acetonitrile, dimethylformamide, tetrahydrofuran, acetone, and dimethylsulphoxide. Polar protic solvent is selected from the group consisting of acetic acid, water, C1-C4 alcohol. The C1-C4 alcohol is selected from methanol, ethanol, isopropanol, n-butanol. Halogenated solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform.
The preferred solvent for Metaxalone : Salicylamide co-crystal is THF and methanol.
In another embodiment there is provided process for the preparation of Metaxalone : Nicotinamide co-crystal comprising crystallization of Metaxalone and Nicotinamide in a suitable solvent.
Suitable solvent for the preparation of Metaxalone : Nicotinamide co-crystal is selected from the group consisting of polar aprotic solvents. Polar aprotic solvent is selected from the group consisting of acetonitrile, dimethylformamide, tetrahydrofuran, acetone, and dimethylsulphoxide and mixtures thereof.
The preferred solvent for Metaxalone : Nicotinamide co-crystal is acetone.
In another embodiment there is provided process for the preparation of Metaxalone : 4-hydroxy benzoic acid co-crystal comprising crystallization of Metaxalone and 4-hydroxy benzoic acid in a suitable solvent.
Suitable solvent for the preparation of Metaxalone : : 4-hydroxy benzoic acid co-crystal is selected from the group consisting of polar protic solvent. Polar protic solvent is selected from the group consisting of acetic acid, water, C1-C4 alcohol. The C1-C4 alcohol is selected from methanol, ethanol, isopropanol, n-butanol. and mixtures thereof.
The preferred solvent Metaxalone : 4-hydroxy benzoic acid co-crystal is methanol.
Metaxalone used in the present invention may be amorphous or crystalline form such as anhydrous, hydrated, solvated or desolvated etc.
The molar ratio of Metaxalone used to prepare its co-crystal with Salicylamide, Nicotinamide and 4-hydroxy benzoic acid is 1:0.5 to 1:1.5, more preferably 1:1.
The quantity of solvent used for preparation of these co-crystals is 1 to 15 times of Metaxalone.
The crystallization was carried out by warming the mixture of Metaxalone with Salicylamide or Nicotinamide or 4-hydroxy benzoic acid at a temperature in the range 20-70°C, preferably the temperature is between 25-60 °C. The solution allowed to cool to 20-25 ° C.
These co-crystals can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.
To understand the present invention following examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

Experimental:
The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.
Differential scanning calorimetry (DSC) was done using Diamond DSC Perkin Elmer instrument. The scans were recorded between 50 and 300 °C at a constant heating rate of 10°C/min.
FTIR spectrum was obtained using a Perkin Elmer Precisely Spectrum 400 instrument using KBr pellet method.
The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.
Example 1: Preparation of Metaxalone: Salicylamide co-crystal
Metaxalone (50 g, 0.226 mol) was dissolved in methanol (100 mL) at 25°C and Salicylamide (31.0 g, 0.226 mol) was added. Methanol (100 mL) was added and stirred for 10 min. The temperature was raised to 60-65°C, the clear solution obtained. The mixture was cooled to 25-30°C and stirred for 60 min. The solid obtained was filtered, washed with methanol (25 ml) and dried under vacuum at 45 °C for 24 hours. Yield: 62 g, melting point: 118.9-119.7°C.
Example 2: Preparation of Metaxalone : Salicylamide co-crystal
Ground the mixture of Metaxalone (5 g, 0.0226 mol) and Salicylamide (3.099 g, 0.0226 mol) into a mortar and pestle using 10 mL of THF for 1 hour at 25-30°C. Yield: 7.5 g, melting point: 117.1-118.3°C.
Example 3: Preparation of Metaxalone: Nicotinamide co-crystal
5 gm of Metaxalone and 2.74 gm of Nicotinamide dissolved in 60 ml of acetone and kept on hot water bath at 40-60°C to obtain clear solution. The clear solution is then transferred to mortar and pestle, and grinded for 60 mins, Metaxalone : Nicotinamide co-crystal obtained. Yield: 7.1 gm.
Example 4: Preparation of Metaxalone : 4-hydroxy benzoic acid co-crystal
2 gm of Metaxalone and 1.24 gm of 4-hydroxy benzoic acid dissolved in 20 ml of methanol and kept on hot water bath at 40-60°C to obtain clear solution. The clear solution is then transferred to mortar and pestle, and grinded for 60 mins, Metaxalone : 4-hydroxy benzoic acid co-crystal obtained. Yield: 3.16 gm.
,CLAIMS:1. A Metaxalone : Salicylamide co-crystal characterized by at least one of:
powder X-ray diffraction pattern comprising peaks at 5.6, 16.4, and 24.1 degree 2-theta + 0.2 degree 2-theta as shown in figure 1,
endotherm with an onset temperature of 117.26°C and a peak maximum of 119°C in differential scanning calorimetry (DSC) as shown in figure 2,
IR spectrum comprising peaks at 1677, 1751, 3196 and 3391 cm-1 as shown in figure 3.
2. A process for preparation of Metaxalone : Salicylamide co-crystal of claim 1 comprises crystallizing Metaxalone and Salicylamide in a suitable solvent.
3. The process of claim 2, wherein the suitable solvent is selected from the group consisting of polar aprotic solvents selected from the group consisting of acetonitrile, dimethylformamide, tetrahydrofuran, acetone, and dimethylsulphoxide; polar protic solvent selected from the group consisting of acetic acid, water, C1-C4 alcohol; halogenated solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform; and mixtures thereof.
4. The process of claim 3, wherein the suitable solvent is THF and methanol.
5. A Metaxalone : Nicotinamide co-crystal characterized by at least one of:
powder X-ray diffraction pattern comprising peaks at 5.7, 17.4, 23.6 and 24.1 degree 2-theta + 0.2 degree 2-theta as shown in figure 6,
endotherm with an onset temperature of 104.77°C and a peak maximum of 106.58°C in differential scanning calorimetry (DSC) as shown in figure 7,
IR spectrum comprising peaks at 1686, 1751, 3154 and 3370 cm-1 as shown in figure 8.
6. A process for preparation of Metaxalone : Nicotinamide co-crystal of claim 5 comprises crystallizing Metaxalone and Nicotinamide in a suitable solvent.
7. The process of claim 6, wherein the suitable solvent is selected from the group consisting of polar aprotic solvents selected from acetonitrile, dimethylformamide, tetrahydrofuran, acetone, and dimethylsulphoxide and mixtures thereof.
8. The process of claim 7, wherein the suitable solvent is acetone.
9. A Metaxalone : 4-hydroxy benzoic acid co-crystal characterized by at least one of:
powder X-ray diffraction pattern comprising peaks at 5.9, 13.5, 19.0, 22.5 and 26.3 degree 2-theta + 0.2 degree 2-theta as shown in figure 9,
IR spectrum comprising peaks at 1686, 1726, 3271 and 3423cm-1 as shown in figure 10.
10. A process for preparation of Metaxalone : 4-hydroxy benzoic acid co-crystal of claim 9 comprises crystallizing Metaxalone and 4-hydroxy benzoic acid in a suitable solvent.
11. The process of claim 10, wherein the suitable solvent is selected from the group consisting of polar protic solvent selected from acetic acid, water, C1-C4 alcohol and mixtures thereof.
12. The process of claim 11, wherein the suitable solvent is methanol.