FIELD OF THE INVENTION

The present invention relates to a novel crystalline Piperaquine free base and a process for preparation thereof.

The present invention also relates to crystalline salts of Piperaquine herein after designated as Piperaquine monophosphate, Piperaquine diphosphate, Piperaquine triphosphate, Piperaquine tetraphosphate, Piperaquine pentaphoshpate and process for preparation thereof.

BACK GROUND OF THE INVENTION

Piperaquine is an antimalarial drug that belongs to the bisquinoline class of chemical compounds. It is chemically known as 1, 3-Bis [l-(7-chloro-4-quinolyl)-4'-piperazinyl] propane and is represented by the compound of formula I.

US Patent 3173918 discloses process for the preparation of Piperaquine and its non¬toxic acid addition salts, wherein 4,7-dichloroquinoline is reacted with 1,3-bis-l'-piperazinylpropane in phenol at 115-120°C and the resultant mixture is poured into an aqueous base solution to obtain crude Piperaquine. The crude is recrystallized in mixture of dimethylformamide and water to get pure Piperaquine as shown in scheme-I.

The US'918 patent does not disclose the process for the preparation of acid addition salt of Piperaquine.

IN patent 218633 discloses a process for the preparation of Piperaquine and Piperaquine tetraphosphate tetrahydrate, wherein combining piperaquine base with orthophosphoric acid in aqueous solvent medium to obtain crystalline piperaquine tetraphosphate tetrahydrate.
The present invention discloses crystalline form of Piperaquine free base and its crystalline phosphate salts. The present invention also provides cost effective and commercially viable in large scale preparation with free flowing nature of crystalline phosphate salts.

SUMMARY OF THE INVENTION

The main aspect of the present invention provides novel crystalline Piperaquine free
base.

Another aspect of the present invention is the novel crystalline Piperaquine free base is characterized by PXRD.

Another aspect of the present invention provides a process for the preparation of crystalline Piperaquine free base, which comprising the steps of:

a) dissolving Piperaquine in a solvent, and
b) isolating crystalline Piperaquine free base.

Yet another aspect of the present invention provides Piperaquine monophosphate.

Yet another aspect of the present invention provides a process for the preparation of Piperaquine monophosphate, which comprising the steps of:

a) dissolving Piperaquine in solvent,
b) adding one mole of o-phosphoric acid, and
c) isolating Piperaquine monophosphate.

Yet another aspect of the present invention provides Piperaquine diphosphate.

Yet another aspect of the present invention provides a process for the preparation of Piperaquine diphosphate, which comprising the steps of:

a) dissolving Piperaquine in solvent,
b) adding two moles of o-phosphoric acid, and
c) isolating Piperaquine diphosphate.

Yet another aspect of the present invention provides Piperaquine triphosphate.

Yet another aspect of the present invention provides a process for the preparation of Piperaquine triphosphate, which comprising the steps of:

a) dissolving Piperaquine in a solvent,
b) adding three moles of o-phosphoric acid, and
c) isolating Piperaquine triphosphate.

Yet another aspect of the present invention provides Piperaquine tetraphosphate.

Yet another aspect of the present invention provides a process for the preparation of Piperaquine tetraphosphate, which comprising the steps of: a) dissolving Piperaquine in solvent, b) adding four or five moles of o-phosphoric acid, and c) isolating Piperaquine tetraphosphate.

Yet another aspect of the present invention provides Piperaquine pentaphosphate.
Yet another aspect of the present invention provides a process for the preparation of Piperaquine pentaphosphate, which comprising the steps of: a) dissolving Piperaquine in solvent, b) adding six moles of o-phosphoric acid, and c) isolating Piperaquine pentaphosphate.

Yet another aspect of the present invention the phosphate salts of piperaquine is confirmed by phosphoric acid content.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig.l depicts an X-ray powder diffraction pattern of Piperaquine. Fig.2 depicts an X-ray powder diffraction pattern of Piperaquine monophosphate. Fig.3 depicts an X-ray powder diffraction pattern of Piperaquine diphosphate. Fig.4 depicts an X-ray powder diffraction pattern of Piperaquine triphosphate. Fig.5 depicts an X-ray powder diffraction pattern of Piperaquine tetraphosphate. Fig.6 depicts an X-ray powder diffraction pattern of Piperaquine pentaphosphate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel crystalline Piperaquine free base, wherein piperaquine free base is dissolved in a solvent and evaporated the solvent to get novel crystalline piperaquine. The present invention also provides novel crystalline salts of Piperaquine herein after designated as Piperaquine monophosphate, Piperaquine diphosphate, Piperaquine triphosphate, Piperaquine tetraphosphate, Piperaquine pentaphosphate, wherein piperaquine free base is reacted with in appropriate mole ratios of phosphoric acid.

One embodiment of the present invention provides novel crystalline Piperaquine free base.
Another embodiment of the present invention provides crystalline Piperaquine free base is characterized by X-ray powder diffraction pattern as shown in Figure 1 with peaks at 14.83, 16.53, 19.38, 20.94 and 26.83 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides crystalline form of Piperaquine free base is further characterized by X-ray powder diffraction pattern as shown in Figure 1 with peaks at 14.83, 15.06, 16.53, 19.01, 19.38, 20.94, 21.83, 22.08, 22.80, 25.51, 26.83, 27.20 and 46.14 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation of crystalline form of Piperaquine free base which comprising the steps of:

a) dissolving Piperaquine in a solvent, and
b) isolating crystalline Piperaquine free base.

According to the present invention Piperaquine base is dissolved in a solvent at room temperature, stirred for about 2-3 hrs. The mixture is cooled to 10-15°C, the obtained solid is filtered and dried under vacuum at 40-60°C to get crystalline Piperaquine free base.
According to the present invention Piperaquine base is dissolved in a solvent selected from methanol, ethanol, isopropanol, methylene dichloride, chloroform, dirnethylformamide or mixtures thereof.

Yet another embodiment of the present invention provides Piperaquine monophosphate.
Yet another embodiment of the present invention provides Piperaquine monophosphate having the phosphoric acid content in the range of 14-17%, preferably 16.97%.

Yet another embodiment of the present invention provides Piperaquine monophosphate characterized by X-ray powder diffraction pattern as shown in Figure 2 with peaks at 19.45,20.98 and 24.59 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides Piperaquine monophosphate further characterized by X-ray powder diffraction pattern as shown in Figure 2 with peaks at 16.60, 18.16, 19.45, 20.98, 21.88, 24.59 and 26.84 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation of Piperaquine monophosphate which comprising the steps of:

a) dissolving Piperaquine in solvent,
b) adding one equivalent of o-phosphoric acid, and
c) isolating Piperaquine monophosphate.

According to the present invention Piperaquine base is dissolved in solvent at room temperature and cooled the solution to about 0-10°C. One mole of o-phosphoric acid solution in water is added drop-wise to the pre-cooled solution for about 1 -2 hrs. The reaction mass is stirred for about 2-5 hrs at 5-10°C. The obtained solid is filtered, washed with water and dried at about 30-50°C under high vacuum to get Piperaquine monophosphate.

According to the present invention the solvent used for dissolution of piperaquine base is selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol; chlorinated solvents such as dichloromethane, chloroform or mixtures thereof.

Yet another embodiment of the present invention provides Piperaquine diphosphate.

Yet another embodiment of the present invention provides Piperaquine diphosphate having the phosphoric acid content in the range of 26-29%, preferably 28%.

Yet another embodiment of the present invention provides Piperaquine diphosphate characterized by X-ray powder diffraction pattern as shown in Figure 3 with peaks at 17.89, 21.44, 21.67, 21.92 and 25.95± 0.2 two-theta values.

Yet another embodiment of the present invention provides Piperaquine diphosphate further characterized by X-ray powder diffraction pattern as shown in Figure 3 with peaks at 5.95, 10.68, 11.09, 11.91, 17.89, 21.08, 21.44, 21.67, 21.92, 22.14, 24.63, 25.95, 26.68 and 27.28 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation of Piperaquine diphosphate which comprising the steps of:

a) dissolving Piperaquine in solvent,
b) adding two equivalents of o-phosphoric acid, and
c) isolating Piperaquine diphosphate.

According to the present invention Piperaquine is dissolved in solvent at room temperature and cooled the solution to about 0-10°C. Two moles of o-phosphoric acid solution in water is added drop-wise to the pre cooled solution for about 1-2 hrs. The reaction mass is stirred for about 2-5 hrs at 5-10°C. The obtained solid is filtered, washed with water and dried at about 30-50°C under high vacuum to get Piperaquine diphosphate.

According to the present invention the solvent used for dissolution is selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol; chlorinated solvents such as dichloromethane, chloroform or mixtures thereof.

Yet another embodiment of the present invention provides Piperaquine triphosphate.
Yet another embodiment of the present invention provides Piperaquine triphosphate having the phosphoric acid content in the range of 31-35%, preferably 32.56%.

Yet another embodiment of the present invention provides Piperaquine triphosphate characterized by X-ray powder diffraction pattern as shown in Figure 4 with peaks at 16.57, 19.38, 19.71,22.87,24.52,25.31 and 27.12 ± 0.2 two-theta values. Yet another embodiment of the present invention provides Piperaquine triphosphate further characterized by X-ray powder diffraction pattern as shown in Figure 4 with peaks at 9.83, 12.20, 13.47, 16.57, 18.08, 19.38, 19.71, 20.47, 21.46, 21.92, 22.87, 24.52, 25.31, 26.47, 27.12 and 29.72 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation of Piperaquine triphosphate which comprising the steps of:

a) dissolving Piperaquine in solvent,
b) adding three equivalents of o-phosphoric acid, and
c) isolating Piperaquine triphosphate.

According to the present invention Piperaquine is dissolved in solvent at room temperature and cooled the solution to about 0-10°C. Three moles of o-phosphoric acid solution in water is added drop-wise to the pre cooled solution for about 1-2 hrs. The reaction mass is stirred for about 2-5 hrs at 5-10°C. The obtained solid is filtered, washed with water and dried at about 30-50°C under high vacuum to get Piperaquine triphosphate.

According to the present invention the solvent used for dissolution is selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol; chlorinated solvents such as dichloromethane, chloroform or mixtures thereof.

Yet another embodiment of the present invention provides Piperaquine tetraphosphate.
Yet another embodiment of the present invention provides Piperaquine tetraphosphate having the phosphoric acid content in the range of 37-42%, preferably 38.20%.

Yet another embodiment of the present invention provides Piperaquine tetraphosphate characterized by X-ray powder diffraction pattern as shown in Figure 5 with peaks at 16.56, 17.37, 19.27,19.73, 20.49, 22.90, 24.53, 25.21 and 27.11± 0.2 two-theta values.
Yet another embodiment of the present invention provides Piperaquine tetraphosphate further characterized by X-ray powder diffraction pattern as shown in Figure 5 with peaks at 9.83, 13.47, 16.56, 17.37, 17.96, 19.27, 19.73, 20.49, 21.46, 21.95, 22.90, 23.40, 24.02, 24.53, 25.21, 25.96, 27.11, 27.63 and 29.76 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation of Piperaquine tetraphosphate which comprising the steps of:

a) dissolving Piperaquine in solvent,
b) adding four equivalents of o-phosphoric acid, and
c) isolating Piperaquine tetraphosphate.

According to the present invention Piperaquine is dissolved in solvent at room temperature and cooled the solution to about 0-10°C. Four or five moles of o-phosphoric acid solution in water is added drop-wise to the cooled solution for about 1-2 hrs. The reaction mass is stirred for about 2-5 hrs at 5-10°C. The obtained solid is filtered, washed with water and dried at about 30-50°C under high vacuum to get Piperaquine tetraphosphate.

According to the present invention the solvent used for dissolution is selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol; chlorinated solvents such as dichloromethane, chloroform or mixtures thereof.

Yet another embodiment of the present invention provides Piperaquine pentaphosphate.
Yet another embodiment of the present invention provides Piperaquine pentaphosphate having the phosphoric acid content in the range of 42-47%, preferably 43.70%.

Yet another embodiment of the present invention provides Piperaquine pentaphosphate characterized by X-ray powder diffraction pattern as shown in Figure 6 with peaks at 16.52, 19.26, 19.67, 20.48, 22.75, 24.44, 25.19 and 27.02 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides Piperaquine pentaphosphate further characterized by X-ray powder diffraction pattern as shown in Figure 6 with peaks at 9.12, 9.79, 13.43, 16.52, 17.32, 19.26, 19.67, 20.48, 22.75, 24.44, 25.19, 27.02, 27.52 and 29.74 ± 0.2 two-theta values.

Yet another embodiment of the present invention provides a process for the preparation of Piperaquine pentaphosphate which comprising the steps of:

a) dissolving Piperaquine in solvent,
b) adding six equivalents of o-phosphoric acid, and
c) isolating Piperaquine pentaphosphate.

According to the present invention Piperaquine is dissolved in solvent at room temperature and cooled the solution to about 0-10°C. Six moles of o-phosphoric acid solution in water is added drop-wise to the pre cooled solution for about 1-2 hrs. The reaction mass is stirred for about 2-5 hrs at 5-10°C. The obtained solid is filtered,

washed with water and dried at about 30-50°C under high vacuum to get Piperaquine pentaphosphate.

According to the present invention the solvent used for dissolution is selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol; chlorinated solvents such as dichloromethane, chloroform or mixtures thereof.

According to the present invention piperaquine free base or phosphate salt having individual impurities (4,5 isomer impurities and also including the impurities reported in Indian Journal of Heterocyclic chemistry (2010), 19(3), 215-220) less than 0.10%.

Piperaquine used as starting material in the following examples may be prepared according to the process disclosed in our PCT application WO2011095885A1.

POWDER X-RAY DIFFRACTION fPXRD)

The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 6/9 configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 29 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
Example-1: Preparation of Piperaquine free base.

Mixture of 7-chloro-4-piperazine-l-yl quinoline (100g), 1, 3-dibromopropane (85g) and triethylamine (10ml) in methanol (500ml) was refluxed at 60-65°C for about 48hrs. The reaction mass was cooled to room temperature, filtered the obtained solid, washed with methanol and water. The wet compound was dissolved in the mixture of dichloromethane and methanol, dichloromethane was distilled out at 35-55X. The solution was cooled to room temperature, filtered and dried at 40-60°C under vacuum for about 15 hrs to get crystalline form of Piperaquine free base (80g) having individual impurities less than 0.10%. Yield: 0.8 w/w; Purity (by HPLC): 99.9 %.

Example-2: Preparation of Piperaquine free base.

Piperaquine (lOOg) was crystallized using dimethyl formamide (600ml). The obtained solid was filtered and dried at 50-55°C under vacuum for about 15 hrs to give title compound of Piperaquine free base (90g). Yield: 0.9 w/w; Purity (by HPLC): 99.8%.

Example-3: Preparation of Piperaquine monophosphate.

Piperaquine (5g) was dissolved in a mixture of methanol (25ml) and methylene dichloride (25ml) and cooled to about 5-10°C. A solution of o-phosphoric acid (-85%) (0.91 g, 1.0 equivalents) in water (65ml) was added drop-wise to the cooled solution for about 1 hr and stirred for about 3-4 hours at 5-20°C. The obtained solid was filtered and washed with water (15ml). The compound is dried at 40-45°C under high vacuum for about 18 hrs to get the title compound (3.5g). Yield: 0.7 w/w; Purity (by HPLC): 99.14%; Melting range 253.4-254.5°C; Phosphoric acid content 16.97%.

Example-4: Preparation of Piperaquine diphosphate.

Piperaquine (5g) was dissolved in a mixture of methanol (25ml) and methylene dichloride (25ml) and cooled to about 5-10°C. A solution of o-phosphoric acid (-85%) (1.82 g, 2.0 equivalents) in water (65ml) was added drop-wise to the cooled solution for about 1 hr and stirred for about 3-4 hours at 5-20°C. The obtained solid was filtered and washed with water (15ml). The compound is dried at 40-45°C under high vacuum for about 18 hrs to get the title compound (7.5g). Yield: 1.5 w/w; Purity (by HPLC): 99.73%; Melting range 252.4-253.5°C; Phosphoric acid content 28%.

Example-5: Preparation of Piperaquine triphosphate.

Piperaquine (5g) was dissolved in a mixture of methanol (25ml) and methylene dichloride (25ml) and cooled to about 5-10°C. A solution of o-phosphoric acid (-85%) (2.74g, 3.0 equivalents) in water (65ml) was added drop-wise to the cooled solution for about 1 hr and stirred for about 3-4 hours at 5-20°C. The obtained solid was filtered and washed with water (15ml). The compound is dried at 40-45°C under high vacuum for about 16 hrs to get the title compound (6.57g). Yield: 1.31 w/w; Purity (by HPLC): 99.67%; Melting range 252.5-253.6°C; Phosphoric acid content 32.56%.

Example-6: Preparation of Piperaquine tetraphosphate.

Piperaquine (5g) was dissolved in a mixture of methanol (15ml) and methylene dichloride (25ml) and cooled to about 5-10°C. A solution of o-phosphoric acid (-85%) (3.65g, 4.0 equivalents) in water (65ml) was added drop-wise to the cooled solution for about 1 hr and stirred for about 3-4 hours at 5-20°C. The obtained solid was filtered and washed with water (15ml). The compound is dried at 40-45°C under high vacuum for about 16 hrs to get the title compound (8.46g). Yield: 1.69 w/w; Purity (by HPLC): 99.59%; Melting range 248.5-249.8°C; Phosphoric acid content 38.20%.

Example-7: Preparation of Piperaquine tetraphosphate.

Piperaquine (7g) was dissolved in a mixture of methanol (35ml) and methylene dichloride (35ml) and cooled to about 5-10°C. A solution of o-phosphoric acid (-85%) (6.4 g, 5.0 equivalents) in water (100ml) was added drop-wise to the cooled solution for about 1 hr and stirred for about 3-4 hours at 5-20°C. The obtained solid was filtered and washed with water (15ml). The compound is dried at 40-45°C under high vacuum for about 16 hrs to get the title compound (12.5g). Yield: 1.78 w/w; Purity (by HPLC): 99.59%; Melting range 242.5-243.6°C; Phosphoric acid content 40.67%.

Example-8: Preparation of Piperaquine pentaphosphate.

Piperaquine (5g) was dissolved in a mixture of methanol (15ml) and methylene dichloride (25ml) and cooled to about 5-10°C. A solution of o-phosphoric acid (-85%) (5.48 g, 6.0 equivalents) in water (65ml) was added drop-wise to the cooled solution for about 1 hr and stirred for about 3-4 hours at 5-20°C. The obtained solid was filtered and washed with water (15ml). The compound is dried at 40-45°C under high vacuum for about 16 hrs to get the title compound (9.46 g). Yield: 1.89 w/w; Purity (by HPLC): 99.59%; Melting range 244.6-245.7°C; Phosphoric acid content 43.70%.

We Claim:

1. A crystalline Piperaquine base of formula I

and has powder X-ray diffraction peaks at two-theta values of 14.83, 16.53,
19.38, 20.94, 26.83 ±0.2;

wherein the crystalline Piperaquine monophosphate of formula II

and has powder X-ray diffraction peaks at two-theta values of 19.45, 20.98,
24.59 ± 0.2;

wherein the crystalline Piperaquine diphosphate of formula III

and has powder X-ray diffraction peaks at two- theta values ofl7.89, 21.44,
21.67, 21.92, 25.95±0.2;

wherein the crystalline Piperaquine triphosphate of formula IV


and has powder X-ray diffraction peaks at two-theta values of 16.57, 19.38, 19.71, 22.87, 24.52, 25.31, 27.12 ± 0.2; wherein the crystalline Piperaquine tetraphosphate of formula V

and has powder X-ray diffraction peaks at two-theta values of 16.56, 17.37, 19.27, 19.73, 20.49, 22.90, 24.53, 25.21 and 27.11± 0.2; wherein the crystalline Piperaquine pentaphosphate of formula VI

and has powder X-ray diffraction peaks at two-theta values of 16.52, 19.26, 19.67, 20.48, 22.75, 24.44, 25.19, 27.02 ± 0.2.

2. Process for the preparation of crystalline piperaquine base of claim 1, comprising the steps of:

a) dissolving Piperaquine in a solvent, and
b) isolating crystalline Piperaquine free base.

3. Process for the preparation of crystalline Piperaquine monophosphate of
claim 1, comprising the steps of:
a) dissolving Piperaquine in a solvent,
b) adding one equivalent of o-phosphoric acid, and
c) isolating Piperaquine monophosphate.

4. Process for the preparation of crystalline Piperaquine diphosphate of claim 1
comprising the steps of:

a) dissolving Piperaquine in a solvent,
b) adding two equivalents of o-phosphoric acid, and
c) isolating Piperaquine diphosphate.

5. Process for the preparation of crystalline Piperaquine triphosphate of claim 1
comprising the steps of:
a) dissolving Piperaquine in a solvent,
b) adding three equivalents of o-phosphoric acid, and
c) isolating Piperaquine triphosphate.

6. Process for the preparation of crystalline Piperaquine tetraphosphate of claim
1, comprising the steps of:

a) dissolving Piperaquine in a solvent,
b) adding four equivalents of o-phosphoric acid, and
c) isolating Piperaquine tetraphosphate.

7. Process for the preparation of crystalline Piperaquine pentaphosphate of
claim 1 comprising the steps of:

a) dissolving Piperaquine in solvent,
b) adding six equivalents of o-phosphoric acid, and
c) isolating Piperaquine pentaphosphate.

8. The process according to claim 2-7, wherein Piperaquine base is dissolved in a solvent methanol, ethanol, propanol, isopropanol, butanol, dichloromethane, chloroform, dichloroethane, dimethylformamide, dimehtylsulfoxide or mixtures thereof.