Claims:1. A co-crystal of Piribedil with a co-crystal former; wherein co-crystal former is selected from oxalic acid, fumaric acid, glutaric acid, succinic acid and malonic acid.
2. A process for the preparation of Piribedil co-crystal of claim 1 comprising crystallization of Piribedil and co-crystal former 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/or mixtures thereof.
4. A Piribedil: oxalic acid co-crystal characterized by at least one of:
(a) powder X-ray diffraction pattern comprising peaks at 8.88, 11.93, 14.21, 17.23, 18.89, 22.68 and 23.04 degree 2-? ± 0.2 degree 2-theta as shown in figure 4;
(b) IR spectrum comprising peaks at 1722, 2595, 2897 and 3010 cm-1 as shown in figure 5;
(c) endotherm with an onset temperature of 203.96°C and a peak maximum of 205.63°C in differential scanning calorimetry (DSC) as shown in figure 6.
5. A Piribedil: fumaric acid co-crystal characterized by at least one of:
(a) powder X-ray diffraction pattern comprising peaks at 9.81, 12.67, 14.24, 19.67, 22.21, 24.49, 26.79 and 29.68 degree 2-? ± 0.2 degree 2-theta as shown in figure 7;
(b) IR spectrum comprising peaks at 1718, 2420, 2904 and 3019 cm-1 as shown in figure 8;
(c) endotherm with an onset temperature of 174.38°C and a peak maximum of 176.20°C in differential scanning calorimetry (DSC) as shown in figure 9.
6. A Piribedil: succinic acid co-crystal characterized by at least one of:
(a) powder X-ray diffraction pattern comprising peaks at 9.80, 13.76, 14.24, 16.75, 17.86, 21.97, 24.52 and 26.80 degree 2-? ± 0.2 degree 2-theta as shown in figure 10,
(b) IR spectrum comprising peaks at 1720, 2439, 2930 and 3018 cm-1 as shown in figure 11,
(c) minor endotherm at onset temperature of 95.13°C, peak at 96.47°C and major endotherm with an onset temperature of 127.72°C and a peak maximum of 129.05°C in differential scanning calorimetry (DSC) as shown in figure 12.
7. A Piribedil: glutaric acid co-crystal characterized by at least one of:
(a) powder X-ray diffraction pattern comprising peaks at 10.54, 14.32, 15.43, 16.05, 17.63, 19.22, 20.86 and 24.67 degree 2-? ± 0.2 degree 2-theta as shown in figure 13,
(b) IR spectrum comprising peaks at 1712, 1970, 2489, 2918 and 2945 cm-1 as shown in figure 14,
(c) endotherm with an onset temperature of 114.98°C and a peak maximum of 116.38°C in differential scanning calorimetry (DSC) as shown in figure 15.
8. A Piribedil: malonic acid co-crystal characterized by at least one of:
(a) powder X-ray diffraction pattern comprising peaks at 8.88, 15.57, 17.83, 18.45, 21.68, 22.49, 24.51 and 26.73 degree 2-? ± 0.2 degree 2-theta as shown in figure 16,
(b) IR spectrum comprising peaks at 1713, 2361, 2798, 3004 and 3431 cm-1 as shown in figure 17.
9. A process for the preparation of Piribedil co-crystal of claim 4, 5, 6, 7, and 8 comprising crystallization of Piribedil and co-crystal former selected from oxalic acid, fumaric acid, succinic acid, glutaric acid and malonic acid respectively in a suitable solvent.
10. The process of claim 9 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/or mixtures thereof.
, Description:TECHNICAL FIELD OF INVENTION:
The present invention is directed towards novel co-crystals of Piribedil and the process for the preparation thereof.

BACKGROUND OF THE INVENTION:
Chemically Piribedil is known as 2-[4-(benzo[1,3]dioxol-5-ylmethyl)piperazin-1-yl] pyrimidine and is represented by formula (I),

Piribedil is useful in treating a patient suffering from Parkinson's disease or hyperactive bladder, and it can also be used as a peripheral vasodilator, analgesic agent or anti-inflammatory agent.

The U.S. patent 3,299,067 discloses process for the preparation of crystalline Piribedil by crystallizing from boiling ethanol.

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.

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.

The present invention provides various co-crystals of Piribedil to achieve the desired properties like better solubility, bioavailability and stability.

SUMMARY OF THE INVENTION
The present invention provides co-crystals of Piribedil with a co-crystal former and the process for preparation thereof. Co-crystal former is selected from oxalic acid, fumaric acid, glutaric acid, succinic acid and malonic acid.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1- PXRD diffractogram of Piribedil
Figure 2- IR of Piribedil
Figure 3- DSC of Piribedil
Figure 4- PXRD diffractogram of Piribedil: oxalic acid co-crystal
Figure 5- IR of Piribedil: oxalic acid co-crystal
Figure 6- DSC of Piribedil: oxalic acid co-crystal
Figure 7- PXRD diffractogram of Piribedil: fumaric acid co-crystal
Figure 8- IR of Piribedil: fumaric acid co-crystal
Figure 9- DSC of Piribedil: fumaric acid co-crystal
Figure 10- PXRD diffractogram of Piribedil: succinic acid co-crystal
Figure 11- IR of Piribedil: succinic acid co-crystal
Figure 12- DSC of Piribedil: succinic acid co-crystal
Figure 13- PXRD diffractogram of Piribedil: glutaric acid co-crystal
Figure 14- IR of Piribedil: glutaric acid co-crystal
Figure 15- DSC of Piribedil: glutaric acid co-crystal
Figure 16- PXRD diffractogram of Piribedil: malonic acid co-crystal
Figure 17- IR of Piribedil: malonic acid co-crystal

DETAILED DESCRIPTION OF THE INVENTION
“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 conformer 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.

In one embodiment, the present invention provides co-crystal of Piribedil with a co-crystal former. The co-crystal former selected from oxalic acid, succinic acid, glutaric acid, fumaric acid and malonic acid.

In another embodiment the invention provides process for the preparation of co-crystal of Piribedil by crystallization of Piribedil and co-crystal former from a suitable solvent.
In the crystallization process, Piribedil and the co-crystal former are mixed in the ratio of 1:1.5, preferably 1:1.

The crystallization process can be carried out at a temperature of 0-100°C, preferably 5-55°C.

The suitable solvent is selected from polar aprotic, polar protic and non-polar solvents.
Polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide; esters like ethyl acetate; ketones like acetone, methyl isobutyl ketone, methyl isopropyl ketone and mixtures thereof. Polar protic solvent is selected from alcohol like methanol, ethanol, isopropanol, n-butanol and mixtures thereof. Non-polar solvent is selected from toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform; alkanes like hexane, cyclohexane.

The solvent volume utilized for the crystallization process is 5-30 times by weight/volume of Piribedil preferably 5-15 times.

The co-crystals of Piribedil are characterized by their powder X-ray crystallography (PXRD), differential scanning calorimetry (DSC), and IR spectroscopy.

In another embodiment the invention provides Piribedil: oxalic acid co-crystal and process for the preparation thereof by crystallization of Piribedil and oxalic acid from a suitable solvent.

In the crystallization process, Piribedil and oxalic acid are mixed in the ratio of 1:15, preferably 1:1.

The crystallization process can be carried out at a temperature of 0-100°C, preferably room temperature- 60oC.

The suitable solvent is selected from polar aprotic, polar protic and non-polar solvents.
Polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide; esters like ethyl acetate; ketones like acetone, methyl isobutyl ketone, methyl isopropyl ketone and mixtures thereof. Polar protic solvent is selected from alcohol like methanol, ethanol, isopropanol, n-butanol and mixtures thereof. Non-polar solvent is selected from toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform; alkanes like hexane, cyclohexane, preferably methanol.

The solvent volume utilized for the crystallization process is 5-15 times by weight/volume of Piribedil.

In another embodiment the invention provides Piribedil: oxalic acid co-crystal characterized by a powder X-ray diffraction pattern comprising peaks at 8.88, 11.07, 11.93, 14.21, 16.54, 17.23, 17.82, 18.89, 22.68, 23.04, 26.82, 28.64, 30.24, and 31.75 degree 2? ±0.2 as shown in figure 4.

The Piribedil: oxalic acid co-crystal is further characterized by an IR spectrum comprising peaks at 1585, 1608, 1722, 2460, 2595, 2787, 2897, 3010 and 3167 cm-1as shown in figure 5.

A DSC curve, obtained at a heating rate of 10oC/min, exhibiting endotherm at onset temperature of 203.96°C and peak at 205.63°C as shown in figure 6.

In another embodiment the invention provides Piribedil: fumaric acid co-crystal and process for the preparation thereof by crystallization of Piribedil and fumaric acid from a suitable solvent.

In the crystallization process, Piribedil and fumaric acid are mixed in the ratio of 1:15, preferably 1:1.
The crystallization process can be carried out at a temperature of 0-100°C, preferably 5-55oC.

The suitable solvent is selected from polar aprotic, polar protic and non-polar solvents.
Polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide; esters like ethyl acetate; ketones like acetone, methyl isobutyl ketone, methyl isopropyl ketone and mixtures thereof. Polar protic solvent is selected from alcohol like methanol, ethanol, isopropanol, n-butanol and mixtures thereof. Non-polar solvent is selected from toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform; alkanes like hexane, cyclohexane, preferably acetone, methanol and mixtures thereof.

The solvent volume utilized for the crystallization process is 5-15 times by weight/volume of Piribedil.

In another embodiment the invention provides Piribedil: fumaric co-crystal characterized by a powder X-ray diffraction pattern comprising peaks at 4.91, 9.81, 12.67, 14.24, 14.24, 14.73, 17.05, 19.67, 22.21, 24.49, 26.79, 29.68 and 34.77degree 2? ±0.2 as shown in figure 7.

The Piribedil: fumaric acid co-crystal is further characterized by an IR spectrum comprising peaks at 1580, 1658, 1718, 1846, 2420, 2904, 2933 and 3019 cm-1as shown in figure 8.

A DSC curve, obtained at a heating rate of 10oC/min, exhibiting endotherm at onset temperature of 174.38°C and peak at 176.20°C as shown in figure 9.

In another embodiment the invention provides Piribedil: succinic acid co-crystal and process for the preparation thereof by crystallization of Piribedil and succinic acid from a suitable solvent.

In the crystallization process, Piribedil and succinic acid are mixed in the ratio of 1:15, preferably 1:1.
The crystallization process can be carried out at a temperature of 0-100°C, preferably 5-55oC.

The suitable solvent is selected from polar aprotic, polar protic and non-polar solvents.
Polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide; esters like ethyl acetate; ketones like acetone, methyl isobutyl ketone, methyl isopropyl ketone and mixtures thereof. Polar protic solvent is selected from alcohol like methanol, ethanol, isopropanol, n-butanol and mixtures thereof. Non-polar solvent is selected from toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform; alkanes like hexane, cyclohexane, preferably methanol.

The solvent volume utilized for the crystallization process is 5-10 times by weight/volume of Piribedil.

In another embodiment the invention provides Piribedil: succinic co-crystal characterized by a powder X-ray diffraction pattern comprising peaks at 4.89, 9.80, 10.59, 12.66, 13.76, 14.24, 14.73, 16.05, 16.75, 17.86, 19.69, 21.74, 21.97, 24.17, 24.52, 25.51,26.80, 29.74 and 32.96 degree 2? ±0.2 as shown in figure 10.

The Piribedil: succinic acid co-crystal is further characterized by an IR spectrum comprising peaks at 1581, 1628, 1720, 1838, 2439, 2930 and 3018 cm-1as shown in figure 11.

A DSC curve, obtained at a heating rate of 10oC/min, exhibiting minor endotherm at onset temperature of 95.13°C, peak at 96.47°C and major endotherm at onset temperature of 127.72°C and peak at 129.05°C as shown in figure 12.

In another embodiment the invention provides Piribedil: glutaric acid co-crystal and process for the preparation thereof by crystallization of Piribedil and glutaric acid from a suitable solvent.
In the crystallization process, Piribedil and glutaric acid are mixed in the ratio of 1:15, preferably 1:1.

The crystallization process can be carried out at a temperature of 0-100°C, preferably room temperature- 55oC.

The suitable solvent is selected from polar aprotic, polar protic and non-polar solvents.
Polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide; esters like ethyl acetate; ketones like acetone, methyl isobutyl ketone, methyl isopropyl ketone and mixtures thereof. Polar protic solvent is selected from alcohol like methanol, ethanol, isopropanol, n-butanol and mixtures thereof. Non-polar solvent is selected from toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform; alkanes like hexane, cyclohexane, preferably acetone.

The solvent volume utilized for the crystallization process is 5-10 times by weight/volume of Piribedil.

In another embodiment the invention provides Piribedil: glutaric co-crystal characterized by a powder X-ray diffraction pattern comprising peaks at 9.55, 10.54, 12.69, 14.32, 15.43, 16.05, 17.63, 19.22, 20.03, 20.86, 21.86, 23.41, 24.67, 25.37, 27.02, 27.70 and 30.39 degree 2? ±0.2 as shown in figure 13.

The Piribedil: glutaric acid co-crystal is further characterized by an IR spectrum comprising peaks at 1587, 1619, 1712, 1970, 2489, 2772, 2918, 2945 and 2995 cm-1as shown in figure 14.

A DSC curve, obtained at a heating rate of 10oC/min, exhibiting endotherm at onset temperature of 114.98°C and peak at 116.38°C as shown in figure 15.
In another embodiment the invention provides Piribedil: malonic acid co-crystal and process for the preparation thereof by crystallization of Piribedil and malonic acid from a suitable solvent.

In the crystallization process, Piribedil and malonic acid are mixed in the ratio of 1:15, preferably 1:1.

The crystallization process can be carried out at a temperature of 0-100°C, preferably room temperature to 5-50oC.

The suitable solvent is selected from polar aprotic, polar protic and non-polar solvents.
Polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, dimethylformamide; esters like ethyl acetate; ketones like acetone, methyl isobutyl ketone, methyl isopropyl ketone and mixtures thereof. Polar protic solvent is selected from alcohol like methanol, ethanol, isopropanol, n-butanol and mixtures thereof. Non-polar solvent is selected from toluene, benzene, diethyl ether, dichloromethane, dichloroethane, chloroform; alkanes like hexane, cyclohexane, preferably acetone, cyclohexane and mixtures thereof.

The solvent volume utilized for the crystallization process is 5-10 times by weight/volume of Piribedil.

In another embodiment the invention provides Piribedil: malonic co-crystal characterized by a powder X-ray diffraction pattern comprising peaks at 8.88, 1097, 13.56, 15.57, 15.90, 17.83, 18.29, 18.45, 18.89, 20.56, 21.10, 21.68, 21.99, 22.49, 22.98, 24.51, 25.26, 26.73, 28.34, 31.04 and 33.25 degree 2? ±0.2 as shown in figure 16.

The Piribedil: malonic acid co-crystal is further characterized by an IR spectrum comprising peaks at 1552, 1618, 1713, 2361, 2798, 2889, 2991, 3004 and 3431 cm-1as shown in figure 17.

Piribedil can be synthesized by methods known in the literature.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.

Example 1: Preparation of Piribedil: oxalic acid dihydrate co-crystal:
A mixture of Piribedil (25 g) and oxalic acid dihydrate (10.58 g) in methanol (250 ml) was stirred for 1 hour at 60°C and then for 2 hours at room temperature. The solid was filtered, washed with methanol (50 ml) and dried under vacuum at 45oC. Yield: 29.45 gm

Example 2: Preparation of Piribedil: Fumaric acid co-crystal:
A mixture of Piribedil (10 g) and fumaric acid (3.89 g) in acetone (40 ml) and methanol (130 ml) was stirred for 36 hours at room temperature and then at 5-10oC for 1 hour. The solid was filtered and dried under vacuum at 45oC. Yield: 11 gm

Example 3: Preparation of Piribedil: glutaric acid co-crystal:
A mixture of Piribedil (10 g) and glutaric acid (4.42 g) in acetone (50 ml) was stirred for 2 hours at room temperature. The solid was filtered and dried under vacuum at 45oC. Yield: 13 gm.

Example 4: Preparation of Piribedil: succinic acid co-crystal:
A mixture of Piribedil (10 g) and succinic acid (3.96 g) in methanol (50 ml) was stirred for 36 hours at room temperature and then at 5-10oC for 1 hour. The solid was filtered, washed with chilled methanol (5 ml) and dried under vacuum at 45oC. Yield: 11.6 gm
Example 5: Preparation of Piribedil: malonic acid co-crystal:
A mixture of Piribedil (10 g) and malonic acid (3.485 g) in acetone (50 ml) was stirred for 15 hours at room temperature and then at 5-10oC for 1 hour. The solid was filtered, washed with cyclohexane (10 ml) and dried under vacuum. Yield: 13.7 gm