PROCESSES FOR PREPARING APREPITANT FORM I AND FORM II
INTRODUCTION TO THE INVENTION The present invention relates to processes for the preparation of aprepitant
polymorphs. More specifically, the present invention provides processes for the
preparation of aprepitant crystalline Form I and Form II.
Aprepitant is a tachykinin receptor antagonist, chemically described by the
formula 5-[[(2R, 3S)-2-[(1R)-1-[3,5-bis (trifluoromethyl) phenyl] ethoxy]-3-(4-
fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1, 2,4-triazoI-3-one and
represented structurally by Formula I.

Aprepitant is useful in the treatment of emesis concomitant with cancer chemotherapy and is manufactured and commercially sold under the brand name EMEND™ as 80 or 125 mg capsules by Merck and Co.
U.S. Patent No. 5,719,147 discloses the preparation of aprepitant and its pharmaceutically acceptable salts, their pharmaceutical compositions, and methods of treatment using these compounds and their compositions.
U.S. Patent Nos. 6,096,742 and 6,583,142 disclose crystalline Form I and Form II of aprepitant, process for making these forms, pharmaceutical compositions comprising these forms and method of treating or preventing depression, anxiety, psychosis, schizophrenia and emesis using these forms. These patents specifically claim aprepitant Form I substantially free from Form II, and Form II substantially free from Form I of aprepitant.

The process for the preparation of crystalline Form I of aprepitant involves crystallizing Form II of aprepitant in ethanol, 2-propanol, acetonitrile and isopropyl acetate. Alternatively Form I is prepared by heating a sample of aprepitant Form II to a temperature range of 215 to 230 °C and cooling to ambient conditions. Further Form I of aprepitant is prepared on a larger scale by suspending aprepitant in solution of methanol/water in the ratio of 2:1 (v/v), adding seed crystals of Form I and stirring the resultant mixture at about 0-50 °C. for a period sufficient to result in the formation of Form I.
A process for the preparation of crystalline Form II of aprepitant is disclosed in Example 75 of U.S. Patent No. 5,719,147.
Crystalline Form I of aprepitant has superior properties over other forms of aprepitant, i.e., Form II, in that this form demonstrates superior thermodynamic stability and is non-hygroscopic when compared with other crystalline forms of aprepitant. Further, crystalline Form I of aprepitant has been shown to have a marginally lower solubility (0.9 ± 0.1 mg/ml) when compared with Form II (1.3 ± 0.2 mg/ml) in a 2/1 v/v
methanol/water mixture at 0 °C. The ratio of these solubilities (1.4) was said to indicate a higher stability of Form I over Form II. The X-ray powder diffraction (XRPD) patterns of the two forms have been disclosed in the aforementioned patents and the thermal properties characterized by differential scanning calorimetry (DSC). There is no significant difference in the proton and carbon nuclear magnetic resonance spectra of the two crystalline forms as described in the aforementioned patents.
Nevertheless, a process for the preparation of aprepitant Form I and II is desirable.
SUMMARY OF THE INVENTION
The present invention relates to processes for the preparation of aprepitant polymorphs.
In one aspect, the present invention provides a process for the preparation of aprepitant crystalline Form I, which process comprises of:
a) providing a solution of aprepitant in suitable solvent(s);
b) adding an anti solvent to the reaction solution of step (a) for precipitation of solid; and

c) recovering the aprepitant crystalline Form I.
In another aspect, the present invention provides a process for the preparation of aprepitant crystalline Form II, which process comprises of:
a) providing a solution of aprepitant in a first organic solvent(s);
b) adding a second organic solvent to the reaction solution of step (a) for precipitation of solid; and
c) recovering the aprepitant crystalline Form II.
In yet another aspect, the present invention provides an alternative process for the preparation of aprepitant crystalline Form II, which process comprises of:
a) providing a solution of aprepitant in an organic solvent(s); and
b) removing the solvent from solution of step a) for isolation of solid.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an X-ray power diffraction ("XRPD") pattern of aprepitant crystalline
Form I prepared according to Example 1.
Fig. 2 is an X-ray power diffraction ("XRPD") pattern of aprepitant crystalline
Form II prepared according to Example 2.
Fig. 3 is an X-ray power diffraction ("XRPD") pattern of aprepitant crystalline
Form II prepared according to Example 3.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to processes for the preparation of aprepitant
polymorphs.
In one aspect, the present invention provides a process for the preparation of
aprepitant crystalline Form I, which process comprises of:
a) providing a solution of aprepitant in suitable solvent(s);
b) adding an anti solvent to the reaction solution of step (a) for precipitation of solid; and
c) recovering the aprepitant crystalline Form I.

The step of providing solution of aprepitant includes dissolving aprepitant in a suitable solvent or such a solution may be obtained directly from a reaction in which aprepitant is formed.
When the solution is prepared by dissolving aprepitant in a suitable solvent, any form of aprepitant such as any crystalline or amorphous form, including any salts, solvates and hydrates may be utilized for preparing the solution.
Suitable solvents that can be used for providing a solution of aprepitant include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, isobutyl alcohol, tertiary butyl alcohol and the like; ketones such as acetone, methylisobutylketone and the like; nitriles such as acetonitrile, propionitrile and the like; or mixtures thereof.
It may be required to raise the temperature of the solvent to ensure complete dissolution of aprepitant. The preferred temperatures for the dissolution of aprepitant in a solvent or a mixture of solvent are about 0 °C to about 120° C or about 50 °C to about 70 °C. Any temperature is acceptable as long as the stability of the aprepitant is not compromised and the required components are completely dissolved.
The concentration of the solution can be about 0.1 g/ml to 5 g/ml or more. Any other concentration may be used as long as a clear solution is obtained
Step b) involves adding an anti solvent to the reaction solution of step (a) for precipitation of solid.
Suitable anti solvents include but are not limited to water and the like, in which aprepitant is insoluble.
Suitable temperatures for addition of the anti solvent to the solution may range from about 10 °C to about 50 °C or about 25 °C to about 35 °C. Useful ratios of solvent to the anti solvent range from 1:0.25 to about 1:5 by volume, or about 1:1 to about 1:2 by volume.
To enhance crystallization, the reaction mixture may be further maintained at temperatures lower than the temperatures at which the anti solvent is added to solution, such as for example about 1 °C to about 10°C, or about 10° C to about 25° C, for a period of time as required for a more complete isolation of the product. The exact cooling temperature and time required for complete crystallization can be readily

determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
In all of the above-mentioned processes, the crystallization step can be performed with or without stirring. The crystallization step can require various times, as can easily be determined through simple experiments.
Step c) involves recovering the aprepitant crystalline Form I by techniques well known in the art, such as filtration, centifugation, decanting and the like.
The recovered solid may be further dried by using fluid bed drying (FBD), aerial drying, oven drying or other techniques know in the art with or without application of vacuum and/or under inert conditions at a temperature of about 25 °C to about 80 °C.
Aprepitant crystalline Form I of the present invention is characterized by the XRPD pattern as measured on a Bruker Axe D8 Advance Powder X-ray Diffractometerwith a Cu K alpha-1 radiation source, substantially in accordance with Fig. 1.
In another aspect, the present invention provides a process for the preparation of aprepitant crystalline Form II, which process comprises:
a) providing a solution of aprepitant in a first organic solvent(s);
b) adding a second organic solvent to the solution of step (a) for precipitation of solid; and
c) recovering the aprepitant crystalline Form II.
The step of providing a solution of aprepitant includes dissolving aprepitant in a suitable solvent, or such a solution may be obtained directly from a reaction in which aprepitant is formed.
When the solution is prepared by dissolving aprepitant in a suitable solvent, any form of aprepitant such as any crystalline or amorphous form, including any salts, solvates and hydrates may be utilized for preparing the solution.
Suitable first organic solvents that can be used for providing a solution of aprepitant include but are not limited to tetrahydrofuran, 1,4-dioxane and the like or mixtures thereof.
It may be required to raise the temperature of the solvent to ensure complete dissolution of aprepitant. The preferred temperatures for the dissolution of aprepitant

in a solvent or a mixture of solvent are about 0 °C to about 120° C or about 50 °C to about 70 °C. Any temperature is acceptable as long as the stability of the aprepitant is not compromised and the required components are completely dissolved.
The concentration of the solution can be about 0.1 g/ml to 5 g/ml or more. Any other concentration may be used as long as a clear solution is obtained
Step b) involves adding a second solvent to the solution of step (a) for precipitation of solid.
Suitable second solvents that can be used include, but are not limited to: C5 to C12 saturated hydrocarbons such as hexane and heptane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; and mixtures thereof.
Suitable temperatures for addition of the second solvent to the solution may range from about 10 °C to about 50 °C, or about 25 °C to about 35 °C. Useful ratios of first solvent to the second solvent range from 1:0.5 to about 1:5 by volume, or about 1:1 to about 1:2 by volume.
To enhance crystallization, the mixture may be further maintained at temperatures lower than the temperatures at which the second solvent is added to the solution, such as for example about 1 °C to about 10°C, or about 10° C to about 25° C, for a period of time as required for a more complete isolation of the product. The exact cooling temperature and time required for complete crystallization can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
In all of the above-mentioned processes, the crystallization step can be performed with or without stirring. The crystallization step can require various times, as can easily be determined through simple experiments.
Step c) involves recovering the aprepitant crystalline Form II by techniques known in the art, such as filtration, centifugation, decanting and the like.
The recovered solid may be further dried by using fluid bed drying (FBD), aerial drying, oven drying or other techniques known in the art with or without application of vacuum, and/or under inert conditions, at a temperature of about 25 °C to about 80 °C.

Aprepitant crystalline Form II of the present invention is characterized by the XRPD pattern measured on a Bruker Axe D8 Advance Powder X-ray Diffractometer with aCuK alpha-1 radiation source, substantially in accordance with Fig. 2.
In yet another aspect, the present invention provides an alternative process for the preparation of aprepitant crystalline Form II, which process comprises:
a) providing a solution of aprepitant in an organic solvent(s); and
b) removing the solvent from solution of step a) for isolation of solid.
The step of providing solution of aprepitant includes dissolving aprepitant in a suitable solvent, or such a solution may be obtained directly from a reaction in which aprepitant is formed.
When the solution is prepared by dissolving aprepitant in a suitable solvent, any form of aprepitant such as any crystalline or amorphous form, including any salts, solvates and hydrates may be utilized for preparing the solution.
Suitable organic solvents that can be used for providing a solution of aprepitant include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, isobutyl alcohol, tertiary butyl alcohol and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; ketones such as acetone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tertiary-butyl ether and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; aprotic polar solvents such as dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and the like; and mixtures thereof.
It may be required to raise the temperature of the solvent to ensure complete dissolution of aprepitant. The preferred temperatures for the dissolution of aprepitant in a solvent or a mixture of solvent are about 0 °C to about 120° C, or about 50 °C to about 70 °C. Any temperature is acceptable as long as the stability of the aprepitant is not compromised and the required components are completely dissolved.
The concentration of the solution can be about 0.1 g/ml to 5 g/ml or more. Any other concentration may be used as long as a clear solution is obtained

Step b) involves removing the solvent from solution of step a) for isolation of solid.
Suitable techniques useful for removing the solvent include distillation under vacuum, spray drying, rotational evaporation (such as using a Buchi Rotavapor), agitated thin film drying-vertical (ATFD-V), spin-flash drying, fluid-bed drying, and the like, for isolation of the solid.
The solid thus obtained may be further dried by using aerial drying, oven drying or other techniques known in the art, with or without application of vacuum and/or under inert conditions, at a temperature of about 25 °C to about 80 °C.
Aprepitant crystalline Form I or Form II obtained by the process of present invention is substantially free of the other crystalline forms. The process of the present invention is simple, inexpensive, eco-friendly, commercially suitable and reproducible on an industrial scale.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting to the scope of the invention in any manner.
EXAMPLE 1 PREPARATION OF APREPITANT CRYSTALLINE FORM I
20 ml of methanol and 0.5 g of 5-[[(2R, 3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (aprepitant) were charged in a clean and dry round bottom flask and stirred for about 15 minutes to obtain a suspension. The suspension was and heated to about 65 °C and stirred for about 2 hours to obtain a homogeneous solution. The solution was cooled to about 25-35 °C and 5 ml of water was added. The separated solid was filtered and was washed with 24 ml of water. The solid obtained was dried at about 60-70 °C under vacuum to afford 0.4 g of the aprepitant crystalline Form I.

EXAMPLE 2 PREPARATION OF APREPITANT CRYSTALLINE FORM II
0.5 g of 5-[[(2R, 3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (aprepitant) and 10 ml of tetrahydrofuran were charged in a clean and dry round bottom flask and stirred for about 15 minutes to form a suspension. The suspension was heated to about 65 °C for about 2 hours to form a homogeneous solution. The solution was cooled to about 35 °C followed by charging 12 ml of methyl tertiary-butyl ether. The suspension was cooled to about 5 °C and stirred for about 45 minutes. The separated solid was filtered and was washed with 6 ml of methyl tertiary-butyl ether followed by drying at about 45-55 °C under vacuum to afford 0.35 g of the aprepitant crystalline Form II.
EXAMPLE 3 PREPARATION OF APREPITANT CRYSTALLINE FORM II
0.5 g of 5-[[(2R, 3S)-2-[(1 R)-1-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (aprepitant) and 12 ml of isopropyl acetate were charged in a clean and dry Buchi Rotavapor flask and stirred for about 15 minutes to form a clear homogeneous solution. The solution was filtered through perlite to obtain a clear solution. The solvent was distilled completely from the filtrate at about 55-65 °C under vacuum to afford 0.5 g of the aprepitant crystalline Form II.

We Claim:
1. A process for preparing aprepitant crystalline Form I, comprising adding water to
a solution of aprepitant in an alcohol, a ketone, a nitrile, or a mixture of any two or more.
2. The process of claim 1, wherein aprepitant is in an alcohol solution.
3. The process of claim 1, wherein aprepitant is in a methanol solution.
4. A process for preparing aprepitant crystalline Form II, comprising adding a
second organic solvent to a solution of aprepitant in a first organic solvent.
5. The process of claim 4, wherein a first organic solvent is tetrahydrofuran, 1,4-
dioxane or a mixture thereof.
6. The process of claim 4, wherein a second organic solvent is a C5 to C12 saturated
hydrocarbon, an ether, or a mixture thereof.
7. The process of claim 4, wherein a first organic solvent comprises tetrahydrofuran
and a second organic solvent comprises methyl tertiary-butyl ether.
8. A process for preparing aprepitant crystalline Form II, comprising removing
solvent from a solution of aprepitant in an organic solvent.
9. The process of claim 8, wherein an organic solvent is an alcohol, a halogenated
solvent, a ketone, a nitrile, an ether, an ester, an aprotic polar solvent, or a mixture of
any two or more.
10. The process of claim 8, wherein an organic solvent comprises isopropyl acetate.