The present invention provides a novel polymorphic form of memantine hydrochloride. The novel polymorphic form has been designated as Form R of memantine hydrochloride. The invention further provides a process for preparation of this polymorphic form. In addition the invention provides pharmaceutical compositions comprising the novel polymorphic form for the treatment of moderate to severe dementia of the Alzheimer's type.
Memantine of Formula I, is an orally active NMDA (N-methyl d-asptartate) receptor antagonist, chemically known as 1-amino-3,5-dimethyladamantane hydrochloride which is indicated for the treatment of moderate to severe dementia of the Alzheimer's type.
Formula Remove
J. Med. Chem. 1963, 6, 6 pp 760-763 provides a process for the preparation of memantine hydrochloride. US Patent No. 3,391,142 (herein after referred to as the '142 patent) provides a process for the preparation of memantine hydrochloride which involves precipitating memantine hydrochloride form an ether solution and crystallizing the crude product in mixture of alcohol and ether.
PCT Application No. WO 2005/069742 describes crystalline Form II of memantine hydrochloride and process for preparation thereof. It further designates the Form obtained when memantine hydrochloride is recrystallized using alcohol and ether solvent mixtures as Form I.
PCT Application No. WO 2006/076560 describes a crystalline Form II of memantine hydrochloride and process for preparation thereof which involves

admixing acetone with a solution of memantine hydrochloride and water; removing the water and acetone to obtain memantine hydrochloride Form II.
The present inventors have now prepared memantine hydrochloride in novel polymorphic form, designated as Form R of memantine hydrochloride. The novel polymorphic Form R has characteristically different XRD and DSC pattern as compared with the known polymorphic forms of memantine hydrochloride.
A first aspect of the present invention provides novel polymorphic Form R of memantine hydrochloride having typical XRD pattern as depicted in Figure 1 of the accompanied drawing. The XRD of Form R shows characteristic 29 values at 10.79, 12.47, 14.10, 18.75, 22.91, 32.62. Form R Memantine hydrochloride may be further characterized by X-Ray Powder Diffraction pattern having peaks at 6.23, 16.52, 21.17, 21.79, 24.36, 27.39, 30.28, 31.52, 34.06, 37.63, 38.61. The novel polymorphic Form R has characteristic DSC thermogram as depicted in Figure 2 of the accompanied drawing. The DSC thermogram shows three characteristic endothermic peaks at about 202 °C, 279 °C and 342 °C.
A second aspect of the present invention provides a process for the preparation of novel polymorphic Form R of memantine hydrochloride which comprises of:
a) stirring memantine hydrochloride in an organic solvent,
b) isolating Form R of memantine hydrochloride from the reaction mixture
thereof.
Memantine hydrochloride can be prepared by methods known in the art such as for example the process reported in the '142 patent or according to the process of the present invention.
Memantine hydrochloride is suspended in a suitable organic solvent and stirred at about 20 to 35 °C for about 30 minutes. The resultant mass is cooled to about -5 to 5 °C and stirred at about -10 to 10 °C for about 30 minutes. The product so

obtained is filtered, washed and dried under vacuum to obtain Form R of memantine hydrochloride.
The organic solvent used can be selected from the group comprising of but not limited to water, Ci-4 alkanols; Ca-io ketones; polar aprotic solvents; chlorinated hydrocarbons; non-polar aprotic solvents; C2-io esters; C4.8 ethers. Preferably the organic solvent is selected from the group comprising of water, methanol, isopropyl alcohol, ethyl acetate, acetonitrile, acetone, toluene and the mixtures thereof.
A third aspect of the invention provides a process for the preparation of novel polymorphic Form R of memantine hydrochloride which comprises of:
a) treating 1-acetamido-3,5-dimethyladamantane with an acid to obtain
memantine hydrochloride,
b) stirring crude memantine hydrochloride in an organic solvent,
c) isolating Form R of memantine hydrochloride from the reaction mixture
thereof.
1-acetamido-3,5-dimethyladamantane is treated with a suitable acid and refluxed at about 90 to 120 °C under stirring for about 5 to 15 hours. The clear solution so obtained or the suspension as such is cooled to about 70-90 °C. The solvent is recovered at about 70-90 °C under vacuum. The crude memantine hydrochloride obtained is suspended with a suitable organic solvent and stirred at about 20 to 35 °C for about 30 minutes. The resultant mass is cooled to about -5 to 5 °C, and stirred at about -10 to 10 °C for about 30 minutes. The product so obtained is filtered, washed and dried under vacuum to obtain Form R of memantine hydrochloride.
The acid used can be selected from the group comprising of but not limited to concentrated or dilute inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or mixtures thereof.

The organic solvent used can be selected from the group comprising of but not limited to water, Ci_4 alkanols; C3.10 ketones; polar aprotic solvents; chlorinated hydrocarbons; non-polar aprotic solvents; 62-10 esters; C4-8 ethers. Preferably the organic solvent is selected from the group comprising of water, methanol, isopropyl alcohol, ethyl acetate, acetonitrile, acetone, toluene and the mixtures thereof.
A fourth aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form R of memantine hydrochloride optionally containing an excipient / diluent.
A fifth aspect of the present invention provides a method of treating moderate to severe dementia of the Alzheimer's type which comprises of administering to a mammal in need thereof a therapeutically effective amount of polymorphic Form R of memantine hydrochloride.
Figure 1 depicts XRD of Form R of memantine hydrochloride. Figure 2 depicts DSC of Form R of memantine hydrochloride.
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
DSC thermograms were recorded using DSC821 e, Mettler Toledo, Sample weight: 3-5 mg, Temperature range: 50-350° C, Heating rate: 20° C/min, Nitrogen 80.0 mL/min, Number of holes in the crucible: 1
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those

skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1 PREPARATION OF FORM R OF MEMANTINE HYDROCHLORIDB
1-Acetamido-3,5-dimethyl adamantine (100 g) was charged to a solution of concentrated hydrochloric acid (400 ml) at ambient temperature. The reaction mass was heated to reflux at 100-105 °C under stirring for 6-12 hours and then cooled to 80-85°C. The solvent was recovered completely at 80-85 °C under vacuum. Acetone (300 ml) was charged to the solid precipitate at 25-30 °C and stirred at 25-30 °C for 30 minutes. The mixture was cooled to 0 °C in 30 minutes and stirred at 0-5°C for 30 minutes. The solid was filtered, washed with chilled acetone (100 ml) and dried under vacuum at 50-55°C to get the title compound.
Yield: 12 g

WE CLAIM:
1. Polymorphic Form R of memantine hydrochloride having X-Ray Powder
Diffraction (XRPD) pattern as depicted in Figure 1.
2. Polymorphic Form R of memantine hydrochloride having a XRPD pattern
wherein characteristic 26 values are obtained at 10.79, 12.47, 14.10, 18.75,
22.91,32.62.
3. Polymorphic Form R of memantine hydrochloride according to claim 2, further
characterized by having 26 values at 6.23, 16.52, 21.17, 21.79, 24.36, 27.39,
30.28, 31.52, 34.06, 37.63, 38.61.
4. Polymorphic Form R of memantine hydrochloride having a DSC thermogram
as depicted in Figure 2.
5. Polymorphic Form R of memantine hydrochloride having a DSC thermogram
wherein three characteristic endothermic peaks are obtained at about 202 °C,
279°Cand342°C.
6. A process for the preparation of polymorphic Form R of memantine
hydrochloride which comprises of:

a) stirring memantine hydrochloride in an organic solvent,
b) isolating Form R of memantine hydrochloride from the reaction mixture
thereof.
7. A process for the preparation of novel polymorphic Form R of memantine
hydrochloride which comprises of:
a) treating 1-acetamido-3,5-dimethyladamantane with an acid to obtain
memantine hydrochloride,
b) stirring crude memantine hydrochloride in an organic solvent,

c) isolating Form R of memantine hydrochloride from the reaction mixture thereof.
8. A process according to claim 6 and claim 7, wherein the organic solvent is
selected from the group comprising of water, Ci-4 alkanols; C^o ketones;
polar aprotic solvents; chlorinated hydrocarbons; non-polar aprotic solvents;
62-10 esters; C4-s ethers.
9. A pharmaceutical composition comprising polymorphic Form R of memantine
hydrochloride optionally containing a pharmaceutically acceptable diluents or
excipients.
10. A method of treating moderate to severe dementia of the Alzheimer's type
which comprises of administering to a mammal in need thereof a
therapeutically effective amount of polymorphic Form R of memantine
hydrochloride.