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

BACKGROUND OF THE INVENTION
Metolazone is used for treating high blood pressure. Metolazone is a quinazoline diuretic with actions similar to thiazide type diuretics (eg, hydrochlorothiazide). It works by causing the kidneys to eliminate certain chemicals, which in turn allow large amounts of water to be eliminated. It is under the trade name Ztanix® or Zaroxolyn®. It is chemically known as 7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide & 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.

Metolazone & its preparation is described in U.S. Pat. No. 3,360,518.

SUMMARY OF THE INVENTION
The present invention relates to Metolazone : isonicotinamide co-crystal, Metolazone : salicylic acid co-crystal and Metolazone : 4-hydroxy benzoic acid co-crystal.

The present invention further provides process for the preparation of Metolazone : isonicotinamide co-crystal, Metolazone : salicylic acid co-crystal and Metolazone : 4-hydroxy benzoic acid co-crystal.
The process for the preparation of Metolazone : isonicotinamide co-crystal comprises crystallization of metolazone and isonicotinamide in a suitable solvent.
The process preparation of Metolazone : salicylic acid co-crystal comprises crystallization of metolazone and salicylic acid in a suitable solvent.
The process preparation of Metolazone : 4-hydroxy benzoic co-crystal comprises crystallization of metolazone and 4-hydroxy benzoic acid in a suitable solvent.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1 - XRPD diffractogram for Metolazone : isonicotinamide co-crystal
Figure 2 - IR spectrum for Metolazone : isonicotinamide co-crystal
Figure 3 - XRPD diffractogram for Metolazone : salicylic acid co-crystal
Figure 4 - IR spectrum for Metolazone : salicylic acid co-crystal
Figure 5 - XRPD diffractogram for Metolazone : 4-hydroxy benzoic acid co-crystal
Figure 6 - IR spectrum for Metolazone : 4-hydroxy benzoic acid co-crystal

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment there is provided Metolazone : isonicotinamide co-crystal.
Metolazone : isonicotinamide co-crystal of the present invention can be characterized by X-ray crystallography, and IR spectroscopy.
In another embodiment there is provided Metolazone : salicylic acid co-crystal.
Metolazone : salicylic acid co-crystal of the present invention can be characterized by X-ray crystallography, and IR spectroscopy.
In another embodiment there is provided Metolazone : 4-hydroxy benzoic acid co-crystal.
Metolazone : 4-hydroxy benzoic acid co-crystal of the present invention can be characterized by X-ray crystallography, and IR spectroscopy.
In another embodiment there is provided Metolazone : isonicotinamide co-crystal wherein said Metolazone : isonicotinamide co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks at 6.6, 7.7, 14.4, 15.2, 16.7, 21.3, 26.3 and 27.8 degree 2-theta + 0.2 degree 2-theta.
The XRPD of crystalline Metolazone : isonicotinamide co-crystal is as shown in figure 1.
In another embodiment there is provided Metolazone : isonicotinamide co-crystal wherein said Metolazone : isonicotinamide is characterized by an IR spectrum comprising peaks at 1633, 1684, 1856, 3201 and 3384 cm-1.
The IR spectrum of Metolazone : isonicotinamide co-crystal is as shown in figure 2.
In yet another embodiment there is provided Metolazone : salicylic acid co-crystal wherein said Metolazone : salicylic acid co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks 5.10, 12.20, 13.69, 21.71, 25.01, 25.15 degree 2-theta + 0.2 degree 2-theta.
The XRPD of crystalline Metolazone : salicylic acid co-crystal is as shown in figure 3.
In another embodiment there is provided Metolazone : salicylic acid co-crystal wherein said Metolazone : salicylic acid is characterized by an IR spectrum comprising peaks at 1627, 1664, 2923, 3087 and 3371 cm-1.
The IR spectrum of Metolazone : salicylic acid co-crystal is as shown in figure 4.
In another embodiment there is provided Metolazone : 4-hydroxy benzoic acid co-crystal wherein said Metolazone : 4-hydroxy benzoic acid co-crystal is characterized by a powder X-ray diffraction pattern comprising peaks at 8.3, 13.3, 14.6, 17.3, 23.6 and 27.7 degree 2-theta + 0.2 degree 2-theta.
The XRPD of crystalline Metolazone : 4-hydroxy benzoic acid co-crystal is as shown in figure 5.
In another embodiment there is provided Metolazone : 4-hydroxy benzoic acid co-crystal wherein said Metolazone : 4-hydroxy benzoic acid co-crystal is characterized by an IR spectrum comprising peaks at 1166, 1340, 1454, 1502, 1606, 1692, 3373 and 3638 cm-1.
The IR spectrum of Metolazone : 4-hydroxy benzoic acid co-crystal is as shown in figure 6.
In another embodiment there is provided process for the preparation of Metolazone : isonicotinamide co-crystal comprising crystallization of Metolazone and isonicotinamide in a suitable solvent.
Suitable solvent for the preparation of Metolazone : isonicotinamide co-crystal is selected from the group consisting of polar aprotic solvent, protic solvent, and halogenated solvent 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 Metolazone : isonicotinamide co-crystal is acetonitrile and methanol.
In another embodiment there is provided process for the preparation of Metolazone : salicylic acid co-crystal comprising crystallization of Metolazone : salicylic acid in a suitable solvent.
Suitable solvent for the preparation of Metolazone : salicylic 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 and mixtures thereof. The C1-C4 alcohol is selected from methanol, ethanol, isopropanol, n-butanol and mixtures thereof.
The preferred solvent for Metolazone : salicylic acid co-crystal is methanol.
In another embodiment there is provided process for the preparation of Metolazone : 4-hydroxy benzoic acid co-crystal comprising crystallization of Metolazone : 4-hydroxy benzoic acid in a suitable solvent.
Suitable solvent for the preparation of Metolazone : 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 and mixtures thereof. The C1-C4 alcohol is selected from methanol, ethanol, isopropanol, n-butanol and mixtures thereof.
The preferred solvent Metolazone : 4-hydroxy benzoic acid co-crystal is methanol.
Metolazone used in the present invention may be amorphous or crystalline form such as anhydrous, hydrated, solvated or desolvated etc.
The molar ratio of Metolazone used to prepare its co-crystal with isonicotinamide, salicylic acid 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 50 times of Metolazone.
The crystallization was carried out by mixing Metolazone with isonicotinamide or salicylic acid 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.
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 Metolazone : isonicotinamide co-crystal
Ground the mixture of Metolazone (0.5 g, 0.0013 mol) and isonicotinamide (0.167 g, 0.0013 mol) into a mortar and pestle using methanol at 25-30°C.
Example 2: Preparation of Metolazone : isonicotinamide co-crystal
Metolazone (4 g, 0.011 mol) was dissolved in acetonitrile (80 ml) at 25°C and heat the mixture upto 75-77°C. Charge isonicotinamide (1.34 g, 0.011 mol). The reaction mixture was stirred till clear solution and cooled to 40°C. The mixture was seeded with metolazone : isonicotinamide co-crystal at 40°C under stirring. The solid obtained was filtered, and dried under vacuum at 45 °C.

Example 3: Preparation of Metolazone : salicylic acid co-crystal
Ground the mixture of Metolazone (2.5 g, 0.0055 mol) and salicylic acid (0.76 g, 0.0055 mol) into a mortar and pestle using methanol at 25-30°C. Yield: 2.25g.
Example 4: Preparation of Metolazone : salicylic acid co-crystal
3 gm of Metolazone and 1.13 gm of salicylic acid were dissolved in 110 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, Metolazone : salicylic acid co-crystal. Yield: 3.3 gm.
Example 5: Preparation of Metolazone : 4-hydroxy benzoic acid co-crystal
0.5 gm of Metolazone and 0.19 gm of 4-hydroxy benzoic acid dissolved in 15 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, Metolazone : 4-hydroxy benzoic acid co-crystal obtained. Yield: 0.68 gm.
,CLAIMS:1. A metolazone : isonicotinamide co-crystal characterized by at least one of:
powder X-ray diffraction pattern comprising peaks at 6.6, 7.7, 14.4, 15.2, 16.7, 21.3, 26.3 and 27.8 degree 2-theta + 0.2 degree 2-theta as shown in figure 1,
IR spectrum comprising peaks at 1633, 1684, 1856, 3201 and 3384 cm-1 as shown in figure 2.
2. A process for preparation of metolazone : isonicotinamide co-crystal of claim 1 comprises crystallizing metolazone and isonicotinamide in a suitable solvent.
3. The process of claim 2, wherein the suitable solvent is selected from the group consisting of polar aprotic solvent selected from acetonitrile, dimethylformamide, tetrahydrofuran, acetone, and dimethylsulphoxide; polar protic solvent selected from acetic acid, water and C1-C4 alcohol; halogenated solvent selected from the group consisting of dichloromethane, dichloroethane and chloroform; and mixtures thereof.
4. A metolazone : salicylic acid co-crystal characterized by at least one of:
powder X-ray diffraction pattern comprising peaks at 5.10, 12.20, 13.69, 21.71, 25.01, and 25.15 degree 2-theta + 0.2 degree 2-theta as shown in figure 3,
IR spectrum comprising peaks at 1627, 1664, 2923, 3087 and 3371 cm-1 as shown in figure 4.
5. A process for preparation of metolazone : salicylic acid co-crystal of claim 4 comprises crystallizing metolazone and salicylic acid in a suitable solvent.
6. The process of claim 5, 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.
7. A metolazone : 4-hydroxy benzoic acid co-crystal characterized by at least one of:
powder X-ray diffraction pattern comprising peaks at 8.3, 13.3, 14.6, 17.3, 23.6 and 27.7 degree 2-theta + 0.2 degree 2-theta as shown in figure 5,
IR spectrum comprising peaks at 1166, 1340, 1454, 1502, 1606, 1692, 3373 and 3638 cm-1 as shown in figure 6.
8. A process for preparation of metolazone : 4-hydroxy benzoic acid co-crystal of claim 7 comprises crystallizing metolazone and 4-hydroxy benzoic acid in a suitable solvent.
9. The process of claim 8, 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.