FIELD OF INVENTION
The present invention relates to a novel crystalline polymorph of armodafinil. In
another aspect the invention relates to an improved process for preparation of
the novel polymorph of armodafinil.
BACKGROUND OF THE INVENTION
Modafinil is currently marketed by Cephalon Inc under the trade name Provigil ®
as a racemic mixture of its R and S enantiomers. Provigil ® is indicated for the
treatment of excessive sleepiness associated with narcolepsy, shift work sleep
disorder, and obstructive sleep apnea/hyponea syndrome.
Studies have shown that while both enantiomers of modafinil are
pharmacologically active, the S enantiomer is eliminated from the body three
times faster than the R enantiomer. Prisinzano et al, Tetrahedron Asymmetry,
vol. 15, 1053-1058 (2004). It is therefore, preferable to develop pharmaceutical
compositions of the R enantiomer of modafinil, as opposed to its racemic
mixture.
The R enantiomer of modafinil is known as armodafinil and has the chemical
name 2-[(R) -(diphenylmethyl) sulfinyl] acetamide, and has the following chemical
structure:

Armodafinil and a method of its preparation were first disclosed in the US Patent
4,927,855 (assigned to: Laboratoire L Lofan; Filed on Jan 28, 1987; set to expire
in August 2008). The US '855 patent describes a method for synthesis of
armodafinil by following the general scheme:
2


There are various polymorphs, crystalline as well as amorphous, reported for
armodafinil. For e.g. WO 2005/077894, WO 2004/060858, WO 2005/023198 and
WO 2007/098273.
SUMMARY OF THE INVENTION
In one aspect the present invention relates to novel crystalline polymorph of
armodafinil characterized by Powder XRD pattern having peaks at about 6.6,
10.4, 13.3, 14.0, 16.5, 17.4, 17.7, 19.0, 19.4, 20.0, 20.8, 21.1, 21.4,22.3, 22.8,
23.4, 25.6, 26.0, 26.0, 26.8, 27.6, 28.3, 28.6, 29.1, 29.8, 31.9, 34.3, 35.2, 39.3 +
0.2 degrees 2-theta.
In another aspect the present invention relates to an improved process for
preparing the novel crystalline polymorph of armodafinil, which is cost effective
and industrially applicable.
3

BRIEF DESCRIPTION OF THE FIGURES
Figure 1: Powder X Ray Diffractogram for crystalline anhydrous armodafinil.
Figure 2: TGA thermogram for crystalline anhydrous armodafinil.
DETAILED DESCRIPTION OF THE INVENTION
Polymorphism is a property of some molecules wherein the solids arising out of
this property have distinct physical properties such as melting point, X-ray
diffraction pattern, infrared absorption spectra and NMR spectra. The differences
in the physical properties of polymorphs result from the orientation and
intermolecular interactions of adjacent molecules in the bulk solid.
Accordingly, polymorphs are distinct solids sharing the same molecular formula
yet have distinct physical properties compared to other forms of the same
molecule. One of the most important physical properties of pharmaceutical
polymorph is their solubility in aqueous solution, particularly 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 the patient's
stomach or intestine to dissolve slowly so that it does not accumulate in a
deleterious environment.
On the other hand, where the effectiveness of a drug correlates with peak
bloodstream levels of the drug, and provided the drug is rapidly absorbed by the
Gl system, then a more rapidly dissolving form is likely to exhibit increased
effectiveness over a comparable amount of a more slowly dissolving form.
The discovery of new crystalline polymorphic forms of a drug enlarges the
repertoire of materials with which a formulation scientist can design a
pharmaceutical dosage form of a drug with a targeted release profile or other
desired characteristics.
4

The present invention relates to novel crystalline polymorph for armodafinil and a
novel process for preparing the same.
In one embodiment, the invention encompasses a novel crystalline form of
armodafinil characterized by a powder XRD pattern having peaks at about 6.6,
10.4, 13.3, 14.0, 16.5, 17.4, 17.7, 19.0, 19.4, 20.0, 20.8, 21.1, 21.4,22.3, 22.8,
23.4, 25.6, 26.0, 26.0, 26.8, 27.6, 28.3, 28.6, 29.1, 29.8, 31.9, 34.3, 35.2, 39.3 +
0.2 degrees 2-theta; depicted in Figure 1. In one embodiment the invention
provides a novel process for preparing crystalline armodafinil.
The process of the invention is depicted in the following scheme I:
5

According to the invention, a novel industrially applicable process is disclosed
which consists of:
1) Reaction of benzhydrol with Thioglycolic acid to obtain the benzhydryl thio
acetic acid
2) Oxidation of the benzhydryl thio acetic acid with hydrogen per oxide/acetic
acid in acetonitrile to obtain benzhydryl sulfinyl acetic acid
3) Reacting racemic benzhydrylsulfinyl acetic acid with (-)-α-
methylbenzylamine in water to obtain the levorotatory or (-) isomer of
benzhydrylsulfinyl acetic acid
4) Esterification of the (-) benzhydrylsulfinyl acetic acid CH3I/K2CO3
5) Amidification of the methyl (-) benzhydrylsulfinyl acetate with ammonical
methanol
6) Crystallization of the (-) benzhydrylsulfinyl acetamide in neat ethanol
(ethanol with 5% acetone) to obtain crystalline anhydrous armodafinil.
In order to improve the synthetic method, the inventors of the present invention
have reacted the benzhydrol with Thioglycolic acid in dichloromethane and
catalytic amount of p-toluene sulfonic acid. The earlier processes used trifluoro
acetic acid, which is not only hazardous on industrial scale but also not
commercially viable, as it requires distillation of TFA. Further the product
obtained has lot of impurities and needs purification.
Further the inventiveness of the process resides in oxidation of the benzhydryl
thioacetic acid using acetonitrile as the solvent with hydrogen peroxide. The
formation of the sulfone impurity by the process of the invention is very low and
hence results into high yield and high quality product. The prior art processes
used hydrogen peroxide in methanol as a solvent, which resulted in over oxidized
product and ester formation.
7

The crude armodafinil is crystallized in ethanol, denatured with 5% acetone. The
product thus obtained is anhydrous crystalline armodafinil. The product is
characterized by XRD peaks at about 6.6, 10.4, 13.3, 14.0, 16.5, 17.4, 17.7,
19.0, 19.4, 20.0, 20.8, 21.1, 21.4,22.3, 22.8, 23.5, 25.6, 26.0, 26.0, 26.8, 27.6,
28.3, 28.6, 29.1, 29.8, 31.9, 34.3, 35.2, 39.3 + 0.2 degrees 2-theta; depicted in
Figure 1; and a TGA thermogram; as depicted in figure 2; which shows that the
product is essentially anhydrous.
The present invention is illustrated by means of following examples:
Preparation of novel crystalline anhydrous polymorph of armodafinil
Step I: Preparation of the benzhydrvl thio acetic acid from benzhydrol:
Benzhydrol (10 g), Thioglycolic acid (7.8 g) and pTSA (0.2g) were charged in 100
mL of dichloromethane at room temperature. The reaction mixture was refluxed
azeotropically till benzhydrol is not more than 1%. 50 mL of DM water was added
and the organic layers separated. The solvent was distilled out under vacuum till
slurry is formed. 100 mL of cyclohexane was added to the slurry to get a solid,
which was filtered and dried, under vacuum at 40-45 °C.
Yield: 8.5 g
Purity: 98-99%
Step II: Oxidation of the benzhydryl thio acetic acid with hydrogen per oxide and
acetic acid in acetonitrile to obtain benzhvdryl sulfinyl acetic acid:
10 g of benzhydryl thio acetic acid was charged to 100 mL of methanol. To it 10
mL of acetic acid and 17g (50%) of hydrogen peroxide was added drop wise and
the reaction mixture stirred for 6-8hours. The reaction was monitored till
benzhydryl thio acetic acid was not more than 1%. 300 mL of DM water was
added and the reaction mixture stirred. The solid was filtered, washed with water
and dried under vacuum at 45-50 °C.
Yield: 8.0 g
Purity: 98-99%
8

Step III: Resolution of the benzhydrylsulfinyl acetic acid with (-)-α-
methylbenzylamine to obtain the (-) isomer of benzhydrylsulfinyl acetic acid:
10 g of benzhydryl sulfmyl acetic acid is charged in 200 mL of DM water. 4.8g
of (-)-a-methylbenzylamine were added to the reaction mixture and heated up
to 75-80 °C to get a clear solution. Filtered the hot solution and heated again
to 70-75 °C followed by cooling at 64-65 °C and seeded the solution with pure
salt of R-isomer. Stirred the solution for 1-2 hours at 64-65 °C and then
cooled it to 0-5 °C over the period of 2-3 hours. Stir at 0-5 °C for 1 hour and
filtered. Washed with DM water and suck dried. The process is repeated
twice.
Yield: 5.0 g
10 g of the (-)-a-methylbenzylamine salt of the benzhydryl sulfinyl acetic acid
obtained herein before is dissolved in 200 mL of DM water and to this 2.5 mL
of cone. HCI was added at room temperature and the reaction mixture was
stirred for 3-4 hours. The solid was filtered and washed with DM water and
dried under vacuum at 45-50 °C.
Yield: 3.0 g
Chiral purity: 98-99%
Step IV: Esterification of the (-) benzhydrylsulfinyl acetic acid CH3l/KgCO3
10 g of the (-) benzhydrylsulfinyl acetic acid was added to 600 mL of acetone,
5.4 g of K2CO3 and 7.7 g of methyl iodide in four lots over four hours under
reflux and the reaction was monitored to obtain reaction mixture wherein
benzhydryl sulfinyl acetic acid was not more than 1%. The solvent was
distilled out under vacuum. Reaction mixture was extracted with
dichloromethane. The organic layer was washed with DM water. The organic
layer was distilled off to obtain a residual mass. The product was isolated by
100 mL of diiso propyl ether (DIPE).
Yield: 9.0 g
Purity: 98-99%
9

Step V: Amidification of the methyl (-) benzhydrylsulfinyl acetate with
ammonical methanol
100 mL (15-20%) of methanolic ammonia was charged to round bottom flask.
To it was added methyl (-) benzhydryl sulfinyl acetate and the reaction was
stirred at 25-30 °C for 8-10 hours. Reaction was monitored till the methyl (-)
benzhydryl sulfinyl acetate was not more than 1%. The solvent was distilled
out under vacuum. O the residual mass dichloromethane was added followed
by water. Dichloromethane was distilled out under vacuum and the product
was isolated from the residual solid by adding diiso propyl ether.
Yield: 9.0 g
Purity: 98.5%
Step VI: Preparation of armodafinil:
(-) Benzhydrylsulfinyl acetamide (10 g) was dissolved in 80 m of ethanol and
the reaction mixture was heated upto 65-70 °C to get a clear solution followed
by addition of activated carbon (1g) and stir the reaction mixture for 1 hour.
The reaction mixture was filtered on hyflow bed followed by the bed washing
(ethanol 2 volumes). The reaction mixture was slowly cooled to room
temperature over 1-2 hours. Further the reaction mixture was cooled to 0-5 °C
over 1 hour time. The reaction mixture was stirred for1 hour at the same
temperature and the solid was filtered and dried under vacuum till a constant
weight is obtained.
Yield: 7.0 g
Purity: 99.6%
m.p.: 153-154 °C
XRPD (2-theta values): 6.6, 10.4, 13.3, 14.0, 16.5, 17.4, 17.7, 19.0, 19.4,
20.0, 20.8, 21.1, 21.4,22.3, 22.8, 23.5, 25.6, 26.0, 26.0, 26.8, 27.6, 28.3, 28.6,
29.0, 29.8, 31.9, 34.3, 35.2, 39.3 + 0.2
10

We claim:
1) A novel crystalline anhydrous polymorph of armodafinilhaving XRD peaks
at 6.6, 10.4, 13.3, 14.0, 16.5, 17.4, 17.7, 19.0, 19.4, 20.0, 20.8, 21.1,
21.4,22.3, 22.8, 23.5, 25.6, 26.0, 26.0, 26.8, 27.6, 28.3, 28.6, 29.1, 29.8,
31.9, 34.3, 35.2, 39.3 + 0.2 degrees 2-theta.
2) A process for preparation of novel anhydrous polymorph of armodafinil.
3) A process for preparation of anhydrous form of armodafinil according to
claim 2, which comprises of

a) Reaction of benzhydrol with Thioglycolic acid to obtain the
benzhydryl thio acetic acid
b) Oxidation of the benzhydryl thio acetic acid with hydrogen per
oxide/acetic acid in acetonitrile to obtain benzhydryl sulfinyl acetic
acid

c) Reacting racemic benzhydrylsulfinyl acetic acid with (-)-a-
methylbenzylamine in water to obtain the levorotatory or (-) isomer of
benzhydrylsulfinyl acetic acid
d) Esterification of the (-) benzhydrylsulfinyl acetic acid CH3I/K2CO3
e) Amidification of the methyl (-) benzhydrylsulfinyl acetate with
ammonical methanol
f) Crystallization of the (-) benzhydrylsulfinyl acetamide in neat ethanol
(ethanol with 5% acetone) to obtain crystalline anhydrous armodafinil.

A novel crystalline anhydrous polymorph of armodafinil having XRD peaks at 6.6, 10.4,
13.3, 14.0, 16.5, 17.4, 17.7, 19.0, 19.4, 20.0, 20.8, 21.1, 21.4,22.3, 22.8, 23.5, 25.6, 26.0,
26.0, 26.8, 27.6, 28.3, 28.6, 29.1, 29.8, 31.9, 34.3, 35.2, 39.3 ± 0.2 degrees 2-theta and a
process for preparation of novel anhydrous polymorph of armodafinil.