WO2009090663A1

WO2009090663A1 - Novel crystalline polymorph of armodafinil and an improved process for preparation thereof

Info

Publication number: WO2009090663A1
Application number: PCT/IN2008/000373
Authority: WO
Inventors: Rajesh Kumar Thaper; Manoj Devilalji Prabhavat; Devendra Kumar Paramsukh Varma; Runjhun Gupta; Dinesh Jyantibhai Paghdar; Navanath Janardhan Kawade
Original assignee: Lupin Limited
Priority date: 2008-01-15
Filing date: 2008-06-13
Publication date: 2009-07-23

Abstract

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.

Description

NOVEL CRYSTALLINE POLYMORPH OF ARMODAFINIL AND AN IMPROVED PROCESS FOR PREPARATION THEREOF

FIELD OF INVENTION

BACKGROUND OF THE INVENTION

Modafinil is currently marketed by Cephalon lnc 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:

R-Modafinic acid

Modafinic acid

Dimethyl sulfate NaHCO₃

from

Armodafinil Methyl ester of modafinil acid

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 anhydrous form 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, 23.5, 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 as depicted in Figure 1.

Further aspect of the invention relates to the novel crystalline anhydrous form of armodafinil characterized by TGA as depicted in Figure 2. Another aspect of the invention relates to novel crystalline anhydrous form of armodafinil characterized by a DSC thermogram having onset peak at 163.39 ⁰C as depicted in Figure 3.

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.

BRIEF DESCRIPTION OF THE FIGURES Figure 1: Powder X Ray Diffractogram for crystalline anhydrous armodafinil of the present invention.

Figure 2: TGA thermogram for crystalline anhydrous armodafinil of the present invention.

Figure 3: DSC thermogram for crystalline anhydrous armodafinil of the present invention.

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.

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, 23.5, 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.

In another embodiment, the novel crystalline form of armodafinil of the present invention is characterized by TGA as depicted in Figure 2.

In another embodiment, the novel crystalline form of armodafinil of the present invention is characterized by DSC thermogram having onset peak at 163.39 ⁰C as depicted in Figure 3. 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:

crystallisation from ethanol (5% acetone)

Pure crystalline anhydrous armodafinil

Scheme I: Process for preparation of armodafinil According to the invention, the process for preparation of crystalline form of armodafinil comprises:

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 benzhydryi 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 and avoided use of trifluoro acetic acid. The prior art 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 had impurities and required purification.

Additionally the distinctiveness of the process of the present invention 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 in 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. 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 ; a TGA thermogram; as depicted in figure 2; and a DSC thermogram as depicted in Figure 3; 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 benzhvdryl thio acetic acid from benzhvdrol: 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 ⁰C. Yield: 8.5 g Purity: 98-99%

Step II: Oxidation of the benzhvdryl 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 ⁰C. Yield: 8.0 g Purity: 98-99%

Step III: Resolution of the benzhvdrylsulfinyl acetic acid with (-)-α- methylbenzylamine to obtain the (-) isomer of benzhydrylsulfinyl acetic acid: 10 g of benzhydryl sulfinyl acetic acid is charged in 200 mL of DM water. 4.8g of (-)- α-methylbenzylamine were added to the reaction mixture and heated up to 75-80 ⁰C to get a clear solution. Filtered the hot solution and heated again to 70-75 ⁰C followed by cooling at 64-65 ⁰C and seeded the solution with pure salt of R-isomer. Stirred the solution for 1-2 hours at 64-65 ⁰C and then cooled it to 0-5 ⁰C over the period of 2-3 hours. Stir at 0-5 ⁰C for 1 hour and filtered. Washed with DM water and suck dried. The process is repeated twice. Yield: 5.O g

10 g of the (-)-α-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 ⁰C. Yield: 3.0 g Chiral purity: 98-99%

Step IV: Esterification of the (-) benzhvdrylsulfinyl acetic acid CH3I/K2CO3 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%

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 ⁰C 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 Vl: Preparation of armodafinil:

(-) Benzhydrylsulfinyl acetamide (10 g) was dissolved in 80 m of ethanol and the reaction mixture was heated up to 65-70 ⁰C 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 ⁰C 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 ⁰C 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, 29.1 , 29.8, 31.9, 34.3, 35.2, 39.3 + 0.2

Claims

1) A 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.

2) A crystalline anhydrous polymorph of armodafinil as claimed in claim 1 having an onset peak at 163.39 ⁰C in the DSC thermogram and having a TGA as depicted in Figure 2.

3) A process for preparation of crystalline anhydrous form of armodafinil, said process comprising 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 (-)-α- 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.