Field of invention:

The present invention relates to novel polymorph of metopimazine or its pharmaceutically acceptable salts and process for its preparation. Metopimazine is chemically known as l-(3-[2-(methylsulfonyl)-10i/-phenothiazin-10-yl]propyl) piperidine-4-carboxamide represented by the following structural formula-1.

Formula-1 Metopimazine (Vogalene®) is a dopamine D2 receptor antagonist that has been used in France for many years for the prevention and treatment of nausea and vomiting. It has not been approved in US and Europe.

Background of invention:

Metopimazine and process for their preparation was disclosed in DEI092476. The disclosed process is schematically represented in the below scheme-I: Scheme-I:

The disclosed process involves the reaction of methyl thioether (1) with sodium amide followed by acetic anhydride to provide an amide (2), which on oxidation with peracid followed by treatment with sodium hydroxide affords the phenothiazine (3). The said intermediate-(3) on reaction with 3-chloro-l-bromo-propane provides the compound-(4), which on condensation with piperidine-4-carboxamide provides metopimazine. The above process uses very strong base such as NaNEk which is difficult to handle in a large scale process. Also as it is having high basicity it leads to formation by-products. In the acetylation process acetic anhydride is used which is difficult to procure commercially as well as with the required purity. As it has to be used in large excess, therefore it generates large quantities of acetic acid which contaminates the effluent. In the preparation of compound (3) by oxidation, meta-chloroperbenzoic acid is used which produces meta-chlorobenzoic acid as a byproduct which is not easily removed. Hence the yield and purity of the compound obtained is not satisfactory and the process cannot be scaled up to commercially level.

Hence it is advantageous to have improved or alternate/novel processes for the preparation of pharmaceutically important compounds like metopimazine with high yield and purity.

The present invention overcomes the disadvantages of the prior art process. The main objective of the present invention is to provide an improved and novel process for the preparation of metopimazine which provides product with high yield and purity and also which is easy to scale up.

Brief description of the invention:

The first aspect of the present invention is to provide a novel polymorph of metopimazine compound of formula-1, hereinafter referred as crystalline form-M.

The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of metopimazine compound of formula-1.

The third aspect of the present invention is to a process for the purification of metopimazine compound of formula-1.

Brief Description of the Drawings:

Figure-1: Illustrates the powder X-ray diffractogram of crystalline form-M of metopimazine compound of formula-1.

Figure-2: Illustrates the differential scanning calorimetric thermogram (DSC) of crystalline form-M of metopimazine compound of formula-1.

Advantages of the present invention:

• The present invention provides anhydrous Metopimazine, which is highly stable.

• The present invention provides anhydrous Metopimazine in highly pure form.

• The anhydrous Metopimazine of the present invention is non-hygroscopic in nature which is highly advantageous for formulators.

• Anhydrous Metopimazine of the present invention is more suitable for pharmaceutical compositions.

Detailed description of the invention:

As used here in the term "alcohol solvents" refers to methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, tert-butanol and the like; the term "ester solvents" refers to methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate and the like; the term "hydrocarbon solvents" refers to pet ether, n-hexane, cyclohexane, n-heptane, benzene, toluene, xylene and the like; the term "chloro solvents" refers to methylene chloride, ethylene dichloride, chloroform, carbon tetra chloride and the like; "polar-aprotic solvents" refers to dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl tert-butyl ether (MTBE), 1,4-dioxane, tetrahydrofuran and the like; the term "nitrile solvents" refers to acetonitrile, propionitrile, isobutyronitrile and the like; "ketone solvents" refers to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; polar solvents such as water or their mixtures.

As used herein the term "inorganic base" refers to the bases selected from alkali metal carbonates like sodium carbonate, potassium carbonate, lithium carbonate; alkali metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroixde; alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; the term "organic base" refers to methylamine, ethyl amine, triethylamine, tributyl amine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine, diisopropyl amine, diisopropylethyl amine, lithium diisopropylaminde (LDA), n-butyl lithium, imidazole and the like.

As used herein the term "phase transfer catalyst" refers to tetraethylammonium p-toluenesulfonate, tetrapropyl ammonium trifluoromethanesulfonate, tetraphenyl phosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenyl phosponium chloride, benzyltriethyl ammonium chloride, benzyltrimethylammomum chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyl triethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyl triphenylphosphonium iodide, phenyl trimethylammomum chloride, tetrabutylammonium hydroxide, tetrabutyl ammonium perchlorate, tetrabutylammonium bromide, tetrabutyl ammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium terra fluoroborate, tetrabutyl ammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammomum iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctyl ammonium bromide, tetraphenyl phosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride.

The first aspect of the present invention provides crystalline form-M of metopimazine compound of formula-1.

The crystalline form-M of the present invention is characterized by its X-Ray powder diffraction pattern having peaks at about 4.3, 8.3, 12.1, 13.5, 16.4, 17.4, 18.4, 19.6, 20.3, 21.8, 23.9, 25.2 and 28.3 ± 0.2 degrees of 20 values. The crystalline form-M of the present invention is further characterized by its X-Ray powder diffraction pattern having peaks at about 8.6, 13.0, 16.7, 18.9 and 24.5 ± 0.2 degrees of 26 values. The crystalline form-M is further characterized by its PXRD pattern as illustrated in figure-1 and its differential scanning calorimetric (DSC) thermogram as illustrated in figure-2.

The crystalline form-M of metopimazine is further characterized by its IR absorption spectrum having absorption bands at wavelength of 3430, 3324, 2949, 2918, 2769, 1657,1621, 1455, 1409,1306, 1144, 968, 764 and 748 cm"1.

It is known in the art that X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of the peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used. The skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a powder diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure.

Generally, a measurement error of a diffraction angle in an X-ray powder diffraction pattern is typically ± 0.2° of 2-theta.

A person skilled in the art will also appreciate that slight variations in the melting point measured by DSC may occur as a result of variations in sample purity, sample preparation and the measurement conditions (e.g. heating rate). It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described hereinafter. Hence the melting point and endotherm figures quoted herein are not to be taken as absolute values and such measurement errors are to be taken into account when interpreting the DSC data. As a skilled person will realize, melting point can vary with sample purity and degree of crystallinity of the sample. Even low levels of impurities can affect the measured melting point. Therefore, the melting points disclosed herein may vary by ± 5°C from the values quoted herein.

The second aspect of the present invention provides a process for the preparation of crystalline form-M of metopimazine compound of formula-1, which comprises of;

a) Reacting the compound of 2-(methylsulfonyl)-10//-phenothiazine compound of formula-2. Formula-2 with l-bromo-3-chloropropane compound of formula formula-3, Formula-3 in presence of suitable base, optionally in presence of a phase transfer catalyst in a suitable solvent to provide the compound of general formula-4 Formula-4 Wherein X is halogen, selected from CI, Br or I;

b) Reacting the compound of general formula-4 with piperidine-4-carboxamide in presence of a suitable base to provide the metopimazine compound of formula-1,

c) Optionally purifying the compound of formula-1 from a suitable solvent to provide the pure crystalline form-M of compound of formula-1.

Wherein in step a) & step b) the suitable base is selected from inorganic or organic base or its aqueous solution; the suitable solvent selected from alcohol solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents or mixtures thereof, preferably hydrocarbon solvents;

In step-a) the phase transfer catalyst is selected from tetraethylammomum p-toluenesulfonate, tetrapropyl ammonium trifluoromethanesulfonate, tetraphenyl phosphonium hexafiuoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenyl phosponium chloride, benzyltriethyl ammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyl triethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyl triphenylphosphonium iodide, phenyl trimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutyl ammonium perchlorate, tetrabutylammomum bromide, tetrabutyl ammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetra fluoroborate, tetrabutyl ammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctyl arnmonium bromide, tetraphenyl phosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride;

In step-c) the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents or mixtures thereof.

The preferred embodiment of the present invention provides an improved process for the preparation of the metopimazine compound of formula-1, comprising of; a) Reacting the 2-( methylsulfonyl)-10i/-phenothiazine compound of formula-2 with l-bromo-3-chloropropane compound of formula formula-3 in presence of aqueous sodium hydroxide and tetrabutylammomum bromide in toluene provides mixture of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine compound of formula-4a and 10-(3-bromopropyl)-2-(methylsulfonyl)-10H-phenothiazine compound of formula-4b,Formula-4a Formula-4b

b) reacting the mixture of compounds of formula-4a and formula-4b with piperidine-4-carboxamide in presence of triethylamine in toluene to provide the metopimazine compound of formula-1,

c) purifying the compound of formula-1 by recrystallizing it from a mixture of dimethyl sulfoxide and ethyl acetate and slurring the obtained compound from isopropyl alcohol to provide the pure crystalline form-M of Metopimazine compound of formula-1.

The 2-(methylsulfonyl)-10//-phenothiazine compound of formula-2 utilized in step-a) of the second aspect of the present invention can be prepared by any of the processes known in the art.

The third aspect of the present invention provides a process for the purification of Metopimazine compound of formula-1, which comprises of the following steps;

a) Dissolving the metopimazine in a suitable solvent at a suitable temperature,

b) Subjecting the solution to charcoal treatment,

c) Filtering the solution through hyflow bed and washing with corresponding solvent,

d) Cooling the reaction mixture and filtering the precipitated solid,

e) Suspending the solid obtained in step-d) in a suitable solvent,

f) Heating the reaction mixture,

g) Cooling the reaction mixture,

h) Filtering the solid and washing with a suitable solvent,

i) Drying the solid to get the pure crystalline form-M of metopimazine compound of formua-1.
Wherein in step-a), step-c), step-e) & step-h) the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or their mixtures;

In step-a) the suitable temperature ranges from 25°C to reflux temperature of the solvent used.

The preferred embodiment of the present invention provides a process for the purification of Metopimazine compound of formula-1, comprises of the following steps;

a) Dissolving the metopimazine in a mixture of dimethylsulfoxide and ethyl acetate,

b) Subjecting the solution to charcoal treatment,

c) Filtering the solution through hyflow bed and washing with a mixture of dimethylsulfoxide and ethyl acetate,

d) Cooling the reaction mixture and filtering the precipitated solid,

e) Optionally repeating the process of step-a) to step-d),

f) Suspending the solid obtained in step-d) or in step-e) in isopropyl alcohol,

g) Heating the reaction mixture,

h) Cooling the reaction mixture,

i) Filtering the solid and washing with isopropyl alcohol,

j) Drying the solid to get the pure crystalline form-M of Metopimazine.

The novel crystalline form-M of metopimazine compound of formula-1 of the present invention is advantageous to the formulators as it is obtained as a free flow solid with high purity and stability and can be directly used for formulation as an active pharmaceutical ingredient.

The anhydrous crystalline form-M of metopimazine obtained in the present invention is stable and non-hygroscopic in nature. The non-hygroscopic nature of the compound is determined by the method described in European pharmacopeia.

The non-hygroscopic nature of crystalline form-M on Metopimazine obtained by the process of the present invention is confirmed by the fact that there is no substantial change in the water content even after the compound is placed in a desiccators containing aqueous ammonium chloride solution for a period of 24 hours at 80±2% relative humidity (RH). The water content of crystalline form-M produced according to the present invention is increased by 0.02% in 24 hours, which confirms the non-hygroscopic nature of the compound. The said characteristic nature is always an advantageous property for formulations.

The PXRD analysis of the crystalline Metopimazine of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.54 A° and at a continuous scan speed of 0.03 7min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C/min.

Metopimazine compound of formula-1 of the present invention was analyzed by HPLC under the following conditions;

Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector and integrator; Column: Symmetry shield RP18, 250 X 4.6, 5 urn or equivalent; Flow rate: 1.0 mL/min; Wavelength: 270 nm; Column temperature: 30°C; Injection volume: 10 uL; Run time: 55 min; Elution: Gradient; Buffer: 1.0 mL of H3P04 (85%) and 1.0 mL of triethylamine in 1000 mL of milli-Q water and adjust its pH to 6.0 with dil.KOH and filtered the solution through 0.22um Nylon membrane paper; Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile: water (90:10, v/v); Diluent: Acetonitrile : Water (60:40 v/v).

Metopimazine produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of mixture of 10-(3-chloropropyI)-2-(methylsulfonyl)-10H-phenothiazine (Formula-4a) and 10-(3-boromopropyl)-2-(methyIsulfonyl)-10H-phenothiazine (Formula-4b)

Toluene (2000 ml) was added to 2-(methylsulfonyl)-10H-phenothiazine (100 gm) at 25-30° C and stirred the reaction mixture for 15 min at the same temperature. Sodium hydroxide solution (57.68 gm of sodium hydroxide in 100 ml of water) was added to the reaction mixture at 25-30° C. The reaction mixture was heated to 95-100° C and stirred for 1 hr at the same temperature. Tetrabutylammomum bromide (8.13 gm), followed by l-bromo-3-chloro-propane (225.7 gm) was slowly added to the reaction mixture at 95-100° C and the reaction mixture was stirred for 12 hrs at the same temperature. Cooled the reaction mixture to 25-30° C and stirred for 1 hr at the same temperature. Filtered the reaction mixture and washed with toluene. Washed the filtrate with water and distilled off the organic layer under reduced pressure. Isopropanol was added to the obtained residue at 25-30° C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 102.0 gm.

Example-2: Preparation of l-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl) propyl) piperidine-4-carboxamide (Formula-l)
Toluene (500 ml) was added to 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (+) 10-(3-boromopropyl)-2-(methylsulfonyl)-10H-phenothiazine (50 gm) at 25-30° C and stirred the reaction mixture for 10 min at the same temperature. Triethylamine (57.16 gm) was added to the above reaction mixture at 25-30° C and stirred the reaction mixture for 10 min. Piperidine-4-carboxamide (54.3 gm) was added to the reaction mixture at 25-30° C and the reaction mixture was slowly heated to reflux temperature. Stirr the reaction mixture for 24 hrs at reflux temperature. After completion of the reaction the mixture was cooled to 25-30° C. Water was added to the above reaction mixture at 25-30° C and the reaction mixture was stirred for 2 hrs at the same temperature. Filtered the obtained solid, washed with water and dried to get the title compound. Yield: 50 gm.

Example-3: Purification of l-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl) propyl) piperidine-4-carboxamide (Formula-l)

A mixture of l-(3-(2-(methylsulfonyl)-10H-phenothiazin-10-yl)propyl) piperidine-4-carboxamide (50 g), 20% DMSO in ethyl acetate (1000 ml) was heated to 70-75° C and stirred for 15 min at the same temperature. The reaction mixture was cooled to 25-30° C and stirred for 1 hr at the same temperature. Filtered and washed the wet compound with 20% DMSO in ethyl acetate. Dissolve the above precipitated solid in 30% DMSO in ethyl acetate (1000 ml). Heated the reaction mixture to 70-75° C and stirred for 15 min at the same temperature. The reaction mixture was subjected to charcoal treatment. Filtered the reaction mixture through hyflow bed and washed with 30% DMSO in ethyl acetate. The filtrate was cooled to 25-30° C and stirred for 1 hr at the same temperature. Filtered the precipitated solid and washed with 30% DMSO in ethyl acetate. Isopropanol (250 ml) was added to the above wet solid. Heated the reaction mixture to 45-50° C and stirred for 30 min at the same temperature. The reaction mixture was cooled to 25-30° C and stirred for 1 hr at the same temperature. Filtered the precipitated solid with isopropanol and dried to get the title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 30.0 gm; Water content: 0.2%. Purity by HPLC: 99.97%; Sulfone impurity: Not detected; Allyl impurity: Not detected.

We Claim:

1. Crystalline form-M of metopimazine, characterized by;

a) Its powder X-Ray diffraction pattern having characteristic peaks at 4.3, 8.3, 12.1, 13.5, 16.4, 17.4, 18.4, 19.6, 20.3, 21.8, 23.9, 25.2 and 28.3 ± 0.2 degrees of 2-theta values,

b) Its powder X-Ray diffraction pattern substantially in accordance with figure-1, and

c) Its differential scanning calorimetric (DSC) thermogram having an endotherm at 188.51°C substantially in accordance with figure-2.

2. Crystalline form-M of metopimazine according to claim 1, which is further characterized by its X-Ray powder diffraction pattern having peaks at 8.6, 13.0, 16.7, 18.9 and 24.5 ± 0.2 degrees of 29 values.

3. Crystalline metopimazine according to claim 1 or claim 2, which is non-hygroscopic in nature.

4. A process for the preparation of crystalline form-M of metopimazine compound of formula-1, Formula-1 which comprises of;

a) Reacting the 2-(methylsulfonyl)-10/f-phenothiazine compound of formula-2, Formula-2 with l-bromo-3-chloropropane compound of formula formula-3, Formula-3 in presence of suitable base in a suitable solvent optionally in presence of a phase transfer catalyst to provide the compound of general formula-4, Formula-4 wherein, 'X' represents halogens selected from CI, Br;

b) Reacting the compound of general formula-4 with piperidine-4-carboxamide in presence of a suitable base in a suitable solvent to provide the metopimazine compound of formula-1,

c) Optionally purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure crystalline form-M of compound of formula-1.

5. The process according to claim 4, wherein in step-a) & step-b) the suitable base is selected from inorganic or organic bases; the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or their mixtures, preferably hydrocarbon solvents; in step-a) the suitable phase transfer catalyst is selected from tetraethylammonium p-toluenesulfonate, tetrapropyl ammonium trifluoromethanesulfonate, tetraphenyl phosphonium hexafiuoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenyl phosponium chloride, benzyltriethyl ammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyl triethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyl triphenylphosphonium iodide, phenyl trimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutyl ammonium perchlorate, tetrabutylammonium bromide, tetrabutyl ammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium terra fluoroborate, tetrabutyl ammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride,tetramethylammonium iodide, tetramethylammonium chloride, tetraoctyl ammonium bromide, tetraphenyl phosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride; in step c) the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or their mixtures.

6. An improved process for the preparation of the metopimazine compound of formula-1, comprising of the following steps;

a) Reacting the 2-( methylsulfonyl)- 10/f-phenothiazine compound of formula-2 with l-bromo-3-chloropropane compound of formula formula-3 in presence of aqueous sodium hydroxide and tetrabutylammomumbromide in toluene to provide mixture of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine compound of formula-4a and 10-(3 -bromopropyl)-2-(methylsulfonyl)-1 OH-phenothiazine compound of formula-4b, Formula-4a Formula-4b

b) Reacting the mixture of compound of formula-4a and compound of formula-4b with piperidine-4-carboxamide in presence of triethylamine in toluene to provide metopimazine compound of formula 1,

c) Purifying the compound of formula-1 by recrystallizing it from a mixture of dimethyl sulfoxide and ethyl acetate followed by slurrying the obtained compound from isopropyl alcohol to provide the pure crystalline form-M of compound of formula-1.

7. Use of crystalline forai-M of metopimazine in the preparation of pharmaceutical composition.

8. A process for the purification of metopimazine compound of formula-1, comprising of;

a) Dissolving metopimazine in a suitable solvent selected from alcohol solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or their mixture at a suitable temperature,

b) Subjecting the solution to charcoal treatment,

c) Filtering the solution through hyflow bed and washing with corresponding solvent,

d) Cooling the reaction mixture and filtering the precipitated solid,

e) suspending the solid obtained in step-d) in a suitable solvent selected from alcohol solvents, ester solvents, hydrocarbon solvents, chloro solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or their mixtures,

f) Heating the reaction mixture,

g) Cooling the reaction mixture,

h) Filtering the solid and washing with a suitable solvent,

i) Drying the solid to get the pure crystalline forrn-M of metopimazine compound of formua-1.

9. A process for the purification of metopimazine compound of formula-1, comprising of the following steps,

a) Dissolving the metopimazine in a mixture of dimethylsulfoxide and ethyl acetate,

b) Subjecting the solution to charcoal treatment,

c) Filtering the solution through hyflow bed and washing with a mixture of dimethylsulfoxide and ethyl acetate,

d) Cooling the reaction mixture and filtering the precipitated solid,

e) Optionally repeating the process of step-a) to step-d),

f) Suspending the solid obtained in step-d) or in step-e) in isopropyl alcohol,

g) Heating the reaction mixture,

h) Cooling the reaction mixture,

i) Filtering the solid and washing with isopropyl alcohol,

j) Drying the solid to get pure crystalline form-M of metopimazine.

10. A pharmaceutical composition comprising non-hygroscopic anhydrous crystalline metopimazine according to claim 1 or claim 2 and at least one pharmaceutical^ acceptable excipient.