Improved Process for Carbinoxamine Maleate and Its Novel polymorph

Filed of the invention:
The present invention relates to an improved process for the preparation of carbinoxamine maleate and its novel polymorph. Carbinoxamine maleate chemically known as 2-[(4-Chlorophenyl)-2-pyridinylmethoxy]-N,N-dimethylethanamine maleate represented by the compound of formula-1

The diallyl aminoalkyl mono-(α-aryl)"Substituted pyridyl methyl ethers comprise a group of compounds possessing antihistaminic properties. One of the most valuable of these antihistamine compounds is 2-[(4-chlorophenyl)-2-pyridinyl methoxy]-N, N-dimethyl ethanamine known as carbinoxamine. It is an HI class antihistamine, first launched in the United States by the McNeil Corporation under the brand name Glisten. It is now available under the brand name Palgic®. It is useful for combating, reducing or minimizing the physiological effects of histamine and other allergens especially for the relief of hay fever, asthma, urticaria, and like. It has mild anti-cholinergic and sedative effects and is used for symptomatic relief of seasonal and perennial allergic rhinitis.
Background of the Invention:
Carbinoxamine is highly active and can be administered in the form of its maleate salt, therefore would be a promising antihistaminic pharmaceutical agent. But an economically viable and safe method for its synthesis on a large scale has not been developed till date.
Carbinoxamine and its pharmaceutically acceptable salts, process for their preparation were first disclosed way back in US patent 2606195. The process illustrated in the US patent 2606195 involves the condensation of (4-chlorophenyl) (pyridin-2-yl) methanol with 2-dimethyl amino ethyl chloride in presence of sodium metal as a condensing agent to give carbinoxamine base. The use of sodium metal at a large scale is

detrimental as it is highly explosive and difficult to handle. Hence this method is not useful on commercial scale.
There has been no substantial progress in the development of process for the preparation of antihistamine drug like carbinoxamine. But to meet the demand for an antihistamine drug in the market, we felt there is a need to develop an ideal commercial process, which is a safe, ecologically sound, economically viable and meets the quality specifications for the synthesis of carbinoxamine.
In order to overcome the problems in the prior art, we tried alternative methods using strong bases like aqueous NaOH for the condensation step. But these methods provided very poor yields of the final product, as the (4-chloro phenyl) (pyridine-2-yl) methanol got converted into a corresponding ketone compound of formula-8.

The formation of extended conjugated system may be the driving force for this conversion. The presence of moisture may also be one of the reasons for it. Therefore we tried to overcome this problem by using anhydrous sodium hydroxide, which is prepared by adding sodium hydroxide to toluene and removing water by azeotropic distillation. We were rewarded with promising results and the yields of the final compounds increased substantially.
The US patent 2800485 disclosed process for the preparation of dialkylamino alkyl mono(a-aryl)-substituted pyridylmethyl ethers especially carbinoxamine maleate. The disclosed process comprises of reacting pyridinealdehyde with aryl magnesium halide to form corresponding mono(a-aryl) substituted pyridine methanol followed by condensation with dialkyl aminoalkyl halide in presence of sodium or sodium amide. Thus obtained carbinoxamine reacted with maleic acid in ether solvent gives carbinoxamine maleate, which was further recrystallised from ethyl acetate. This patent disclosed melting range of carbinoxamine maleate as 117-119°C. Other than melting point, any further details on polymorphic characterization was not disclosed in the prior art for carbinoxamine maleate.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like carbinoxamine maleate, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behaviors different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC")? which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities. The discovery of new polymorphic forms of a pharmaceutical useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.
The present invention provides an improved process for the preparation of carbinoxamine maleate which avoids all the prior art problems.
The present invention also provides novel crystalline polymorphic form of carbinoxamine maleate, can be obtained in a well defined, perfectly reproducible crystalline form having high purity, free flow solid that especially exhibits valuable characteristics for formulation.

Brief Description of the Invention:
Accordingly the first aspect of the present invention is to provide an improved process for the preparation of carbinoxamine maleate compoimd of formula-1, which comprises of the following steps,
a) Reacting l-bromo-4-chloro benzene compound of formula-2 with magnesium metal in a suitable ether solvent or aromatic hydrocarbon solvent or mixtures thereof gives magnesiimi bromide compound of formula-3, which in-situ reacting with aldehyde compound of formula-4 in a suitable organic solvent gives hydroxy compoimd of formula-5,
b) Reacting the hydroxy compound of formula-5 with chloro dimethyl amino compound of formula-6 in presence of a suitable alkali or alkaline earth metal base in a suitable organic solvent gives the carbinoxamine base compound of formula-7, which on in-situ reacting with maleic acid in suitable ester solvents or alcohol solvents or mixtures thereof gives carbinoxamine maleate compound of formula-1,
c) Purifying the carbinoxamine compound of formula-1 in suitable ester solvents or alcohol solvents or mixtures thereof gives pure carbinoxamine maleate compoimd of formula-1.
The second aspect of the present invention is to provide a novel polymorph form of carbinoxamine maleate, herein defined as form-M, characterized by X-ray powder diffraction peaks at about 9.9,15.4,19.1,19.4,20.2, 20.8,21.9,22.8, 23.3,25.5,27.9 and 31.7 ± 0.2 degrees two-theta.
Crystalline form-M of carbinoxamine maleate of the present is characterized by XRD pattern as illustrated in figure-1, IR spectrum as illustrated in figure-2 and DSC thermo gram as illustrated in figure-3.
The third aspect of the present invention is to provide a process for the preparation of crystalline form-M of carbinoxamine maleate compound of formula-1, which comprises of the following steps,
a) Dissolving the carbinoxamine maleate in a suitable solvents at reflux temperature,

b) Cooling the reaction mixture to 25-3 0°C,
c) Stirring the reaction mixture,
d) Isolating the solid by filtration,
e) Drying the solid gives form-M of carbinoxamine maleate.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-M of carbinoxamine maleate compoimd of formula-1, which comprises of the following steps,
a) Dissolving the carbinoxamine maleate in a suitable solvents at reflux temperature,
b) Cooling the reaction mixture to 25-3 0°C,
c) Adding a suitable anti-solvent,
d) Stirring the reaction mixture,
e) Isolating the solid by filtration,
f) Drying the solid gives form-M of carbinoxamine maleate.
Brief Description of the Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of novel crystalline form-M of
carbinoxamine maleate compound of formula-1.
Figure-2: Illustrates the IR spectrum of novel crystalline form-M of carbinoxamine
maleate compound of formula-1.
Figure-3: Illustrates the DSC Thermo gram of novel crystalline form-M of
carbinoxamine maleate compound of formula-1.
Advantageous of the present Invention:
• Usage of cheap and easy to handle base like sodium hydroxide or potassium hydroxide in condensation reaction, which avoids the usage of highly explosive metal like sodium in condensation reaction.
• Provides an improved process for the preparation of carbinoxamine maleate with high purity.
• Provides novel crystalline form-M of carbinoxamine maleate.
• Easy to scale-up and eco-friendly process.

Detailed Description of the Invention:
The present invention provides an improved process for the preparation of carbinoxamine maleate compound of formula-1 and its novel polymorphic form. Carbinoxamine maleate is chemically known as 2-[(4-Chlorophenyl)-2-pyridinyl methoxyl-N,N-dimethylethanamine maleate.

Accordingly the first aspect of the present invention is to provide an improved process for the preparation of carbinoxamine maleate compound of formula-1, which comprises of the following steps, a) Reacting l-bromo-4-chloro benzene compound of formula-2

with magnesium metal in a suitable ether solvents like tertrahydrofuran or a mixture of ether solvents like tetrahydrofuran and aromatic hydrocarbon solvents like toluene and tetrahydrofiiran preferably mixture of solvents toluene and tetrahydrofuran in presence of catalytic amount of iodine gives magnesium bromide compoimd of formula-3,


Which on in-situ reacting with aldehyde compound of formula-4

in a suitable hydrocarbon solvents like toluene, cyclohexane and hexanes preferably toluene gives hydroxy compound of formula-5,

b) Reacting the hydroxy compound of formula-5 with chloro dimethyl amino compound of formula-6

in presence of a suitable base selected from alkali base like sodium hydroxide, potassium hydroxide, sodium tertiary butoxide and potassium tertiary butoxide preferably sodium hydroxide in a suitable hydrocarbon solvent like toluene gives carbinoxamine base compound of formula-7,


Which on in-situ reacting with maleic acid in suitable ester solvents selected from Cj-Cs alkyl esters and/or alcoholic solvents like methanol, isopropyl alcohol or mixtures thereof gives carbinoxamine maleate compound of formula-1,

c) Purifying the carbinoxamine compound of formula-1 in suitable ester solvents selected from C1-C5 alkyl esters or alcoholic solvents like methanol and isopropyl alcohol or mixtures thereof gives pure carbinoxamine maleate compound of formula-1.
The second aspect of the present invention is to provide a novel polymorph form-M of carbinoxamine maleate compound of formula-1 characterized by the PXRD as illustrated in Figure-1.
Crystalline form-M of carbinoxamine maleate of the present is also characterized by IR spectrum as illustrated in Figure-2 and DSC thermo gram as illustrated in Figure-3.
Crystalline form-M of carbinoxamine maleate of the present invention is characterized by the X-ray powder diffraction peaks at about 9.9, 15.4, 19.1, 19.4, 20.2, 20.8, 21.9, 22.8, 23.3, 25.5, 27.9 and 31.7 ± 0.2 degrees two-theta.

The third aspect of the present invention is to provide a process for the preparation of crystalline form-M of carbinoxamine maleate compound of formula-1, which comprise of the following steps,
a) Dissolving the carbinoxamine maleate in a suitable solvents selected from alcohol solvents like methanol, isopropyl alcohol, ketone solvent like acetone, ester solvents selected from C1-C5 alkyl esters, polar solvent like water and chloro solvent like methylene chloride or mixtures thereof at reflux temperature,
b) Cooling the reaction mixture to 25-3 0°C,
c) Stirring the reaction mixture for 45 minutes at 25-30°C,
d) Isolating the solid by filtration,
e) Drying the solid gives crystalline form-M of carbinoxamine maleate.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-M of the carbinoxamine maleate compound of formula-1, which comprises of the following steps,
a) Dissolving the carbinoxamine maleate in a suitable solvents selected from alcohol solvents like methanol, isopropyl alcohol, ketone solvent like acetone, ester solvents selected form C1-C5 alkyl esters, polar solvent like water and chloro solvent like methylene chloride or mixtures thereof at reflux temperature,
b) Cooling the reaction mixture to 25-3 0°C,
c) Adding suitable anti-solvent selected from organic solvents like hexane, heptane, cyclohexane and toluene,
d) Stirring the reaction mixture for 45 minutes at 25-30°C,
e) Isolating the solid by filtration,
f) Drying the solid gives crystalline form-M of carbinoxamine maleate.
XRD analysis of carbinoxamine maleate is carried out using SIEMENS/D-5000 X-Ray Diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min.

Related substances by HPLC of carbinoxamine maleate is carried out using a liquid chromatograph is equipped with variable wavelength UV-Detector, Eclipse XDB-C18, 150 X 4.6 mm, 5μm or equivalent column, 1.0 ml/min flow rate at 260 nm, ambient temperature, load 50μ,l, and the buffer used is 2.0 ml of triethyl amine added to 1000 ml of water. Mobile phase used is 400 ml of buffer and 600 ml of methanol.
The present invention is schematically represented by the following scheme-1.


The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as an illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1:
Preparation of a-(p-chlorophenyl)-2-pyridme methanol compound of formula-5:
A mixture of 34 grams of magnesium metal, 1 gram of iodine, 200 ml of toluene and 200 ml of tetrahydrofuran was heated to reflux. A solution of p-bromochlorobenzene (268.4 grams in 400 ml of toluene) was added lot wise to the above reaction mixture at reflux temperature for 30 minutes. The reaction mixture was stirred for 60 minutes at reflux. The reaction mixture was cooled to 35-45°C, Pyridine-2-carboxaldehyde (100 grams) was added to the reaction mixture at 35-45°C. The reaction mixture was cooled to 25-35°C. The reaction mixture was stirred for 90 minutes at 25-35°C. Distilled off the reaction mixture completely under reduced pressure at below 50°C. 100 ml of toluene followed by 500 ml of water was added to the above residue. The pH of the reaction mixture was adjusted to below 1 using aqueous hydrochloric acid solution. Organic and aqueous phases were separated. Aqueous phase was washed with toluene. The pH of the aqueous phase was adjusted to 8.8 with ammonia solution. The reaction mixture was extracted with toluene. The total organic phase was washed with water. Distilled off the organic layer completely under reduced pressure at below 50°C. Co-distilled off the reaction mixture with acetonitrile under reduced pressure. Acetonitrile (100 ml) was added to the above reaction mixture. The reaction mixture was heated to 45-50°C. The reaction mixture was cooled to 25-35°C. The reaction mixture was further cooled to 0-5°C. The reaction mixture was stirred for 2 hours at 0-5°C. Filtered off the solid and washed with chilled acetonitrile. Dried the compound at 40-45°C to get the title compound. Yield: 138 grams

Exainple-2:
Preparation of carbinoxamine maleate compound of formula-1:
Toluene (500 ml) was added to the 1 liter R.B flask equipped with azeotropic reflux apparatus. Sodium hydroxide (27.3 grams) powder was added at 25-35°C. The above mixture was heated to reflux. The reaction mixture was stirred at reflux for 120 minutes and water traces removed by azeotropic distillation. The reaction mixture was cooled to 25-35°C. α=-(p-chlorophenyl)-2-pyridine methanol (100 grams) was added to the above mixture at 25-35°C under nitrogen atmosphere. This is labeled as reaction mixture-1. Sodium carbonate (85 grams) was added to the solution of 147.54 grams of 2-dimethyl amino ethyl chloride hydrochloride in 100 ml of water at 25-35°C. The aqueous phase was extracted with toluene. The organic phase was separated and dried over sodium sulphate. This organic phase was added to the reaction mixture-1 at 25-35°C imder nitrogen atmosphere. The reaction mixture was heated to reflux. The reaction mixture was stirred at reflux for 8 hours and collected the water traces azeotropically. The reaction mixture was cooled to 25-35°C. The reaction mixture was quenched with water. The organic and aqueous phase was separated. The obtained aqueous layer was extracted with toluene and the organic layer was extracted with acetic acid solution. The pH of the aqueous layer was adjusted to 10.5 using aqueous sodiumk hydroxide solution at 25"35°C. The aqueous layer was extracted with toluene. Distilled off the organic layer completely under reduced pressure at below 60°C. The crude was dissolved in 600 ml of ethyl acetate at 25-35°C. Maleic acid (52,80 grams) was added to the reaction mixture at 25-35°C. The reaction mixture was heated to 50-60°C. Then the reaction mixture was cooled to 25-35°C. The reaction mixture was stirred for 90 minutes at 25-35oC. Filtered off the compound and washed with ethyl acetate. Yield: 108 grams
Particle size: 5 μm to 300μm, [D(4,3) is about 5 to 200μm and D(v,0.9) is about 150 to 300 μm]

Example-3:
Preparation of carbinoxamine maleate compound of formula-1:
Toluene (500 ml) was added to the 1 liter R.B flask equipped with azeotropic reflux apparatus. Sodium hydroxide (27.3 grams) powder was added at 25-35°C. The above mixture was heated to reflux. The reaction mixture was stirred at reflux for 120 minutes and water traces removed by azeotropic distillation. The reaction mixture was cooled to 25-35°C. a-(p-chlorophenyl)-2-pyridine methanol (100 grams) was added to the above mixture at 25-35°C under nitrogen atmosphere. This is labeled as reaction mixture-1. Sodium carbonate (85 grams) was added to the solution of 147.54 grams of 2-dimethyl amino ethyl chloride hydrochloride in 100 ml of water at 25-35°C. The aqueous phase was extracted with toluene. The organic phase was separated and dried over sodium sulphate. This organic phase was added to the reaction mixture-1 at 25-35°C under nitrogen atmosphere. The reaction mixture was heated to reflux. The reaction mixture was stirred at reflux for 8 hours and collected the water traces azeotropically. The reaction mixture was cooled to 25-35°C. The reaction mixture was quenched with water. The organic and aqueous phase was separated. The obtained aqueous layer was extracted with toluene and the organic layer was extracted with acetic acid solution. The pH of the aqueous layer was adjusted to 10.5 using aqueous sodium hydroxide solution at 25-35°C. The aqueous layer was extracted with toluene. Distilled off the organic layer completely under reduced pressure at below 60°C. The crude was dissolved in 600 ml of isopropyl alcohol at 25-35°C. Maleic acid (52.80 grams) was added to the reaction mixture at 25-35°C. The reaction mixture was heated to 50-60°C. Then the reaction mixture was cooled to 25-35°C. The reaction mixture was stirred for 90 minutes at 25-35°C. Filtered off the compoimd and washed with isopropyl alcohol. Yield: 104 grams
Particle size: 5 μm to 200 μm, [0(4,3) is about 5 to 200 μm and D(v50.9) is about 150 to 300μm]

Example-4:
Purification of carbinoxamine maleate compound of formula-1:
A mixture of 100 grams of carbinoxamine maleate and 500 ml of isopropyl alcohol was heated to reflux temperature. The reaction mixture was filtered at reflux temperature. The reaction mixture was cooled to 25-3 5°C and stirred for 45 minutes at 25-35°C. Filtered off the compound and washed with isopropyl alcohol. Dried the compound at 50-55°C to get the pure title compound. Yield: 78 grams
Particle size: 5 μm to 200 μm, [D(4,3) is about 5 to 200μm and D(v50.9) is about 150 to 300 μm]
HPLC purity: 99.90%; Other impurities: < 0.1%
Example-5:
Puriflcation of carbinoxamine maleate compound of formula-1:
A mixture of 100 grams of carbinoxamine maleate, 50 ml of methanol and 500 ml of ethyl acetate was heated to reflux temperature. The reaction mixture was filtered at reflux temperature. The reaction mixture was cooled to 25-35°C and the reaction mixture was stirred for 45 minutes at 25-35°C. Filtered off the compound and washed with a mixture of ethyl acetate and methanol. Dried the compound at 50-55°C to get the pure title compound. Yield: 16 grams
Example-6:
Preparation of crystalline form-M of carbinoxamine maleate compound of
formula-1:
A mixture of 25 grams of carbinoxamine maleate and 125 ml of isopropyl alcohol was heated to reflux temperature. The reaction mixture was filtered at reflux temperature. The reaction mixture was cooled to 25-35°C and the reaction mixture was stirred for 45 minutes at 25-35°C. Filtered off the compoimd and washed with isopropyl alcohol. Dried the compound at 50-55°C to get the pure title compound. Yield: 19.5 grams

Example-7:
Preparation of crystalline form-M of carbinoxamine maleate compound of
formula-1:
A mixture of 25 grams of carbinoxamine maleate, 62.5 ml of isopropyl alcohol and 62.5 ml of ethyl acetate was heated to reflux temperature. The reaction mixture was filtered at reflux temperature. The reaction mixture was cooled to 25-35°C and the reaction mixture was stirred for 45 minutes at 25-35°C. Filtered off the compound and washed with a mixture isopropyl alcohol and ethyl acetate. Dried the compound at 50-55°C to get the pure title compound. Yield: 18 grams
Example-8:
Preparation of crystalline form-M of carbinoxamine maleate compound of
formula-1:
A mixture of 25 grams of carbinoxamine maleate, 125 ml of isopropyl alcohol was heated to reflux temperature. The reaction mixture was filtered at reflux temperature. The reaction mixture was cooled to 25-35°C. Cyclohexane (250 ml) was slowly added to the above reaction mixture at 25-30°C. The reaction mixture was stirred for 45 minutes at 25-35°C. Filtered off the compound and washed with isopropyl alcohol. Dried the compound at 50-55°C to get the pure title compound. Yield: 16.8 grams

We claim:
1. An improved process for the preparation of carbinoxamine maleate compound of formula-1

Which comprises of the following steps
a) Reacting l-bromo-4-chloro benzene compound of formuIa-2

with magnesiimi metal in a suitable ether solvents like tertrahydrofuran or a mixture of ether solvent like tetrahydrofuran and aromatic hydrocarbon solvents like toluene and tetrahydrofuran preferably mixture of solvents like toluene and tetrahydrofuran in presence of catalytic amount of iodine gives magnesium bromide compound of formula-3,

Which on in-situ reacting with aldehyde compound of formula-4


in a suitable hydrocarbon solvents like toluene, cyclohexane and hexanes preferably toluene gives hydroxy compound of formula-5,

b) Reacting the hydroxy compound of formula-5 with chloro dimethyl amino compound of formula-6

in presence of a suitable base selected from alkali base like sodium hydroxide, potassium hydroxide, sodium tertiary butoxide and potassium tertiary butoxide preferably sodium hydroxide in a suitable hydrocarbon solvent like toluene gives carbinoxamine base compound of formula-7,

Which on in-situ reacting with maleic acid in suitable ester solvents selected from C1-C5 alkyl esters and/or alcoholic solvents like methanol, isopropyl alcohol or mixtures thereof gives carbinoxamine maleate compound of formula-1,

c) Purifying the carbinoxamine compound of formula-1 in suitable ester solvents selected from C1-C5 alkyl esters or alcoholic solvents like methanol and isopropyl alcohol or mixtures thereof gives pure carbinoxamine maleate compound of formula-1.
2. The process according to claim 1 b), wherein the base used for the condensation reaction is selected from bases like sodium hydroxide, potassium hydroxide, sodium tertiary butoxide and potassium tertiary butoxide.
3. The process according to claim 2, wherein the base used is sodium hydroxide.
4. The process according to claim 2, wherein the base used is potassium hydroxide.
5. The process according to claim 1 c) wherein the solvent used for the purification is alcoholic solvents like methanol and isopropyl alcohol and/or ester solvent selected from C1-C5 alkyl esters or mixtures thereof
6. Crystalline polymorphic form-M of carbinoxamine maleate compound of formula-1.
7. The crystalline form according to claim 6, wherein the novel crystalline form-M of the carbinoxamine maleate is characterized by XRD pattern substantially as shown in figure-1, IR spectrum substantially as shown in figure-2 and DSC thermo gram substantially as shown in figure-3.
8. The crystalline form according to claim 6, wherein the novel crystalline form-M of the carbinoxamine maleate is characterized by X-ray powder diffraction peaks at about 9.9, 15.4, 19.1, 19.4, 20.2, 20.8, 21.9, 22.8, 23.3, 25.5, 27.9 and 31.7 ± 0.2 degrees two-theta.
9. Process for the preparation of crystalline form-M of carbinoxamine maleate compound of formula-1 comprises of the following steps,

a) Dissolving the carbinoxamine maleate in a suitable solvents selected from alcohol solvents like methanol, isopropyl alcohol, ketone solvent like acetone, ester solvents selected from C1-C5 alkyl esters, polar solvent like water and chloro solvent like methylene chloride or mixtures thereof at reflux temperature,
b) Cooling the reaction mixture to 25-30°C,
c) Stirred the reaction mixture for 45 minutes at 25-30°C,
d) Isolating the solid by filtration,
e) Drying the solid gives form-M of carbinoxamine maleate.
10. Process for the preparation of crystalline form-M of carbinoxamine maleate compound of formula-1 comprises of the following steps,
a) Dissolving the carbinoxamine maleate in a suitable solvents selected from alcohol solvents like methanol, isopropyl alcohol, ketone solvent like acetone, ester solvents selected from C1-C5 alkyl esters, polar solvent like water and chloro solvent like methylene chloride or mixtures thereof by heating to reflux temperature,
b) Cooling the reaction mixture to 25-30°C,

c) Adding suitable anti-solvent selected from organic solvents like hexane, heptane, cyclohexane and toluene,
d) Stirred the reaction mixture for 45 minutes at 25-30°C,
e) Isolating the solid by filtration,
f) Drying the solid gives form-M of carbinoxamine maleate.