DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
SONOCRYSTALLIZATION OF APREPITANT
INTRODUCTION
The present application relates to a sonocrystallization process for the preparation of crystalline aprepitant having a particle size, D90 of about 1 µm to about 5 µm.

Aprepitant is known to be a potent antagonist of Substance P. It is an anti-emetic and mediates its effect by blocking Neurokinin-1 receptor. Aprepitant is first reported in US5719147A.

Aprepitant is classified by the Biopharmaceutical Classification System (BCS) as a Class IV drug, indicating that it is a low solubility and low permeability API. Hence, particle size plays an important role for the bioavailability of aprepitant. It has been observed that a particle size, D90 of about 1 µm to about 5 µm is desirable for development of oral dosage form of aprepitant.

US8258132B2 discloses a nanoparticulate composition comprising Aprepitant, having an average particle size of less than 400 nm.

The traditional method of particle size reduction like milling may not be suitable for the production of particles having D90 of about 1 µm to about 5 µm in plant scale since it requires repeating the milling cycle at least 3-4 times which is time consuming, causes loss in yield and not suitable environmentally.

Sonocrystallization is a relatively new technique for producing smaller particles of a substance directly from a solution. Hatkar et al., Chemical Engineering and Processing 57– 58, 2012, 16–24 discloses sonocrystallization of salicylic acid. Min-Woo Park et al., Separation Science and Technology, 45, 2010, 1402-1410 discloses reduction of particle size of roxithromycin using sonocrystallization technique. Dennehy, Organic Process Research & Development 2003, 7, 1002-1006 discloses sonocrystallization technique for particle size reduction of three drugs, although the names of those drugs have not been disclosed.

SUMMARY
One aspect of the present application relates to aprepitant having a particle size, D90 of about 1 µm to about 5 µm.

Another aspect of the present application relates to a process for the preparation of aprepitant having a particle size, D90 of about 1 µm to about 5 µm.

Yet another aspect of the present application relates to a process for the preparation of aprepitant having a particle size D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant.

Still another aspect of the present invention relates to an oral pharmaceutical composition comprising aprepitant having a particle size, D90 of about 1 µm to about 5 µm and one or more pharmaceutically acceptable excipient.

Another aspect of the present invention relates to an oral pharmaceutical composition comprising aprepitant having a particle size, D90 of about 1 µm to about 5 µm, prepared by sonocrystallization technique, and one or more pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 shows the XRD pattern of aprepitant obtained through Experiment No. 1.
Fig. 2 shows the histogram of aprepitant obtained through Experiment No. 1.

DETAILED DESCRIPTION
One aspect of the present application relates to aprepitant having a particle size, D90 of about 1 µm to about 5 µm.

Another aspect of the present application relates to a process for the preparation of aprepitant having a particle size D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant. The process for the preparation of aprepitant having a particle size D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant may optionally be performed in presence of an anti-solvent.

Any crystalline form of aprepitant may be used as input material for sonocrystallizing a solution of aprepitant of the present application. Specifically, aprepitant crystalline form I or crystalline form II or mixture thereof may be used for sonocrystallizing a solution of aprepitant of the present application.

Any solvent capable of dissolving aprepitant may be used for sonocrystallizing a solution of aprepitant of the present application. Specifically, the solvent may include but not limited to, alcohols like methanol, ethanol, isopropyl alcohol, butanol and the like; ketones like acetone, methyl isobutyl ketone and the like. More specifically, the solvent is an alcoholic solvent selected from a group of methanol and isopropyl alcohol. Most specifically, the alcoholic solvent is isopropyl alcohol. Aprepitant may be dissolved in a suitable solvent at a temperature of about 10 °C to about boiling point of the solvent. Specifically, aprepitant may be dissolved at about 20 °C to about 70 °C.

The process of sonocrystallizing a solution of aprepitant of the present application may optionally be performed in presence of an anti-solvent. Suitable anti-solvent includes but not limited to water; hydrocarbon solvent such as toluene, xylene and the like. More specifically, the anti-solvent is water. It has been found that the particle size of the product depends on the ratio of solvent:anti-solvent and on the rate of mixing solvent and anti-solvent. The process of sonocrystallizing a solution of aprepitant of the present application involves a ratio of solvent:anti-solvent from about 1:1 to about 1:20. Specifically, the ratio of solvent:anti-solvent is from about 1:2 to about 1:10. More specifically, the ratio of solvent:anti-solvent is from about 1:3 to about 1:5.
It has been observed that the process for the preparation of aprepitant having a particle size, D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant depends on the rate of addition of solution comprising aprepitant and anti-solvent in the flow cell. The rate of addition may be from about 1 to about 20 mL/min for solution comprising aprepitant and from about 40 mL/min to about 800 mL/min for anti-solvent. Specifically, the rate of addition may be from about 2 to about 7 mL/min for solution comprising aprepitant and from about 50 mL/min to about 400 mL/min for anti-solvent. More specifically, the rate of addition may be from about 4 mL/min to about 5 mL/min for solution comprising aprepitant and from about 65 mL/min to about 75 mL/min for anti-solvent.

It has been observed that the process for the preparation of aprepitant having a particle size, D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant depends on the frequency of ultrasound. The frequency of ultrasound is from about 20 KHz to about 50 KHz. Specifically, the frequency of ultrasound is about 20 kHz.

It has also been observed that the process for the preparation of aprepitant having a particle size, D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant depends on the sonication time. The sonication time may be from about 15 minutes to about 15 hours. Specifically, the sonication time may be from about 30 minutes to about 5 hours.

It has been observed that the process for the preparation of aprepitant having a particle size D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant depends on the power of ultrasound. The power of the ultrasound may be from about 50 W to about 1000 W. Specifically, the power of ultrasound may be from about 100 W to about 500 W. More specifically, the power of ultrasound may be about 120W.
It has been observed that the process for the preparation of aprepitant having a particle size D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant depends on the temperature. The temperature of sonocrystallization may be about of 0 °C to about boiling point of the solution. Specifically, the temperature may be about 5 °C to about 70 °C and more specifically the temperature may be about 10 °C to about 60 °C.

Another aspect of the present invention relates to a pharmaceutical composition comprising aprepitant having a particle size, D90 of about 1 µm to about 5 µm, prepared by sonocrystallization technique and one or more pharmaceutically acceptable excipient.

The process of the present application may be scaled up accordingly involving the use of suitable equipment depending on the batch size. The parameters described above may be adopted as such to afford the compound with the desired particle size.

The PXRD conditions for the measurement of PXRD peaks of aprepitant of the present application are as follows:
Range: 3o 2? to 40o 2? in conventional reflection mode
Instrument: PANalytical X-ray Diffractometer
Detector: X’celerator
Source: Copper K-alpha radiation (1.5418 Angstrom).

The particle size is measured by using a Malvern G3 analyzer.

Certain specific aspects and embodiments of the present disclosure will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present disclosure. While particular embodiments of the present disclosure have been illustrated and described, those skilled in the art will recognize that various other changes and modifications can be made without departing from the spirit and scope of the disclosure.

EXAMPLES
Preparation of aprepitant by sonocrystallization technique
Example 1:
Demineralized water (750 mL) was circulated in a flow cell by means of a peristaltic pump. The temperature inside the flow cell is maintained by means of a julabo chiller to 10 °C. A sonotrode (34 mm diameter) was introduced inside the flow cell and the sonication was started at 70% amplitude. After 5 minutes, a solution of aprepitant (4 g) in IPA (250 mL) at 60 °C was injected at a flow rate of 4.5 mL/min into the flow cell by means of a peristaltic pump. After about 30 minutes of sonication, a sample of the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 0.78 µm; D50: 1.27 µm; D90: 1.97 µm.
Crystalline form (by PXRD): Form I

Example 2:
Demineralized water (700 mL) was circulated in a flow cell by means of a peristaltic pump at a rate of 180 mL/min. The temperature inside the flow cell is maintained by means of a julabo chiller to 10 °C. A sonotrode (34 mm diameter) was introduced inside the flow cell and the sonication was started at 60% amplitude. After 10 minutes, a solution of aprepitant (3 g) in IPA (100 mL) at 60 °C was injected at a flow rate of 1 mL/min into the flow cell by means of a peristaltic pump. After about 45 minutes of sonication, the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 2.04 µm; D50: 2.82 µm; D90: 4.32 µm.

Example 3:
Demineralized water (700 mL) was circulated in a flow cell by means of a peristaltic pump at a rate of 360 mL/min. The temperature inside the flow cell is maintained by means of a julabo chiller to 10 °C. A sonotrode (34 mm diameter) was introduced inside the flow cell and the sonication was started at 60% amplitude. After 10 minutes, a solution of aprepitant (3 g) in IPA (100 mL) at 62 °C was injected at a flow rate of 1 mL/min into the flow cell by means of a peristaltic pump. After about 100 minutes of sonication, the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 1.55 µm; D50: 2.15 µm; D90: 3.52 µm.
Example 4:
Demineralized water (450 mL) was circulated in a flow cell by means of a peristaltic pump at a rate of 70 mL/min. The temperature inside the flow cell is maintained by means of a julabo chiller to 10 °C. A sonotrode (34 mm diameter) was introduced inside the flow cell and the sonication was started at 70% amplitude. After 5 minutes, a solution of aprepitant (3 g) in IPA (150 mL) at 60 °C was injected at a flow rate of 4.5 mL/min into the flow cell by means of a peristaltic pump. After about 1 hour of sonication, the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 0.85 µm; D50: 1.47 µm; D90: 2.7 µm.

Example 5:
Demineralized water (450 mL) was circulated in a flow cell by means of a peristaltic pump at a rate of 180 mL/min. The temperature inside the flow cell is maintained by means of a julabo chiller to 10 °C. A sonotrode (34 mm diameter) was introduced inside the flow cell and the sonication was started at 70% amplitude. After 5 minutes, a solution of aprepitant (3 g) in IPA (150 mL) at 60 °C was injected at a flow rate of 4.5 mL/min into the flow cell by means of a peristaltic pump. After about 45 minutes of sonication, the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 1.18 µm; D50: 2.56 µm; D90: 3.9 µm.

Example 6A:
Demineralized water (750 mL) was circulated in a flow cell by means of a peristaltic pump at a rate of 70 mL/min. The temperature inside the flow cell is maintained by means of a julabo chiller to 10 °C. A sonotrode (34 mm diameter) was introduced inside the flow cell and the sonication was started at 70% amplitude. After 5 minutes, a solution of aprepitant (4 g) in IPA (250 mL) at 60 °C was injected at a flow rate of 4.5 mL/min into the flow cell by means of a peristaltic pump. After about 35 minutes of sonication, a sample of the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 0.78 µm; D50: 1.27 µm; D90: 1.97 µm.

Example 6B:
Water (300 mL) was charged into the flow cell of example 6A by means of a peristaltic pump at a rate of 70 mL/min. and the amplitude was changed to 90%. The sonication was continued with the remaining amount of aprepitant solution from example 6A. After about 25 minutes of sonication, the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 0.74 µm; D50: 2.34 µm; D90: 4.44 µm.
Crystalline form (by PXRD): Form I

Example 7A:
Demineralized water (900 mL) was circulated in a flow cell by means of a peristaltic pump at a rate of 70 mL/min. The temperature inside the flow cell is maintained by means of a julabo chiller to 10 °C. A sonotrode (34 mm diameter) was introduced inside the flow cell and the sonication was started at 70% amplitude. After 5 minutes, a solution of aprepitant (4 g) in IPA (300 mL) at 60 °C was injected at a flow rate of 4.5 mL/min into the flow cell by means of a peristaltic pump. After about 30 minutes of sonication, a sample of the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 0.99 µm; D50: 1.45 µm; D90: 2.47 µm.
Example 7B:
Water (500 mL) was charged into the flow cell of example 7A by means of a peristaltic pump at a rate of 180 mL/min. The sonication was continued with the same amplitude with the remaining amount of aprepitant solution from example 7A. After about 45 minutes of sonication, the reaction mass from the flow cell was collected and filtered under vacuum. The solids were dried in a vacuum tray drier and analyzed by Malvern G3 analyzer.
Particle size: D10: 0.88 µm; D50: 2.14 µm; D90: 3.95 µm.
,CLAIMS:1. A process for the preparation of aprepitant having a particle size D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of aprepitant.

2. The process of claim 1, wherein the sonocrystallization of a solution of aprepitant is performed in presence of an anti-solvent.

3. The process of claim 2, wherein the anti-solvent is water.

4. The process of claim 1, wherein the solvent for dissolving aprepitant is an alcoholic solvent.

5. The process of claim 2, wherein the ratio of solvent:anti-solvent is from about 1:2 to about 1:10.

6. The process of claim 1, wherein the frequency of ultrasound is about 20 kHz.

7. The process of claim 1, wherein the power of ultrasound is from about 100 W to about 500 W.

8. The process of claim 1, wherein the sonication time is from about 15 minutes to about 5 hours.

9. The process of claim 1, wherein the rate of addition of solution comprising aprepitant is from about 4 mL/min to about 5 mL/min.

10. The process of claim 1, wherein the rate of addition of anti-solvent is from about 65 mL/min to about 75 mL/min.