DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
PROCESS FOR MAKING FINER CRYSTALS OF RIVAROXABAN BY SONOCRYSTALLIZATION

INTRODUCTION
The present application relates to a sonocrystallization process for the preparation of crystalline rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm.

Rivaroxaban is described chemically as 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide and is represented structurally by formula I.

Formula I
Rivaroxaban of formula (I) is a low molecular weight, orally administrable anticoagulant drug. The pharmaceutical directly inhibits the active form of serine protease Factor Xa (FXa). Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris, reocclusions and restenosis after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
Rivaroxaban is pharmacologically active in humans and are thus useful as anticoagulant agent. Rivaroxaban is commercially available as Xarelto® in Europe and Canada. U.S. Patent No. 7,157,456 discloses Rivaroxaban, its pharmaceutically acceptable salts. Rivaroxaban is categorized as BCS class II drug and has low aqueous solubility; hence the formulator may be required to have the finer particle size of API for the formulation development.

The traditional methods 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 disclose 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 a process for the preparation of rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm.

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

Yet another aspect of the present invention relates to an oral pharmaceutical composition comprising rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm, prepared by sonocrystallization technique, and one or more pharmaceutically acceptable excipient.

DETAILED DESCRIPTION
One aspect of the present application relates to a process for the preparation of rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm.

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

The present application relates to a process for the preparation of rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm comprising sonocrystallizing a solution of rivaroxaban.

The process for the preparation of rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm comprising sonocrystallizing a solution of rivaroxaban may optionally be performed in presence of an anti-solvent.

Any crystalline or amorphous or solvate form of rivaroxaban may be used as input material for sonocrystallizing a solution of rivaroxaban of the present application. Specifically, rivaroxaban crystalline form I or crystalline form II or amorphous or mixture thereof may be used for making the solution to perform sonocrystallization to get the desired particle size of rivaroxaban.

Any solvent capable of dissolving rivaroxaban may be used for sonocrystallizing a solution of rivaroxaban of the present application. Specifically, the solvent may include but not limited to, glacial acetic acid; alcohols like methanol, ethanol, isopropyl alcohol, butanol and the like; ketones like acetone, methyl isobutyl ketone and the like. More specifically, the solvent that may be used in the present application is glacial acetic acid.

Rivaroxaban may be dissolved in a suitable solvent at a temperature of about 20 °C to about boiling point of the solvent. Specifically, rivaroxaban may be dissolved at about 110°C to about 120°C in acetic acid.

The present invention also includes that the solution may be obtained directly from the reaction after performing the necessary work up procedure. The resulted solution may be used for sonocrystallization by adopting the method described in the present application.

The process of sonocrystallizing a solution of rivaroxaban of the present application may optionally be performed in presence of an anti-solvent. Suitable anti-solvent includes but not limited to water; aliphatic hydrocarbons such as n-pentane, n-hexane, n-heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like.

It has been observed that the process for the preparation of rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm comprising sonocrystallizing a solution of rivaroxaban 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 rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm comprising sonocrystallizing a solution of rivaroxaban depends on the sonication time. The sonication time may be from about 15 minutes to about 5 hours. Specifically, the sonication time may be from about 30 minutes to about 3 hours.

It has been further observed that the process for the preparation of rivaroxaban having a particle size D90 of about 1 µm to about 10 µm comprising sonocrystallizing a solution of rivaroxaban 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 rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm comprising sonocrystallizing a solution of rivaroxaban depends on the temperature. The temperature of sonocrystallization may be about of 10 °C to about boiling point of the solution. Specifically, the temperature may be about 10 °C to about 70 °C and more specifically the temperature may be about 25 °C to about 60 °C.

It has been observed that the polymorphic form of rivaroxaban obtained after sonocrystallization process has remained same to that of its initial crystalline form in the present invention. In one particular embodiment, the polymorphic form of rivaroxaban obtained in the present application after sonocrystallization process appears to be substantially similar to the crystalline Form-I.

Another aspect of the present invention relates to a pharmaceutical composition comprising rivaroxaban having a particle size, D90 of about 1 µm to about 10 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 get the compound with the desired particle size.

The PXRD conditions for the measurement of PXRD peaks of rivaroxaban 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 PSD conditions for the measurement of PSD of rivaroxaban of the present application are as follows:
Method: 1
Instrument: Malvern Morphologi G3S

Instrument ID: AA279
Analysis Model: Number Distribution (CE diameter)
Light Source: Diascopic
Calibration Intensity: 80%
Intensity Tolerance: 0.2
Optics: 20X
Trash Size: 10
Method: Wet using wet cell

Method: 2
Instrument: Malvern mastersizer 2000
Instrument ID: AA136
Analysis Model: General purpose
Light Source: LASER Source
Method: Wet using wet cell HYDRO 2000 S(A)
Dispersant: Water
Instrument measurement range: 0.02-2000 microns.
In one of the preferred embodiments, the particle size of rivaroxaban obtained in the present application by using the instrument, Malvern G3S with the above described conditions is as follows:
D10 (µm) D50 (µm) D90 (µm)
1.85 3.17 5.23

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 rivaroxaban by sonocrystallization:
Example 1:
Rivaroxaban (25 g) was charged in glacial acetic acid (142.5 mL) and heated to reflux (110-120oC). The clear solution was charged in a jacketed reactor vessel at a temperature of 50-55oC. The inside temperature of the reactor vessel is maintained by means of a julabo chiller set to 20°C. The delta T between the set value of the julabo chiller and the process value of the reactor vessel is 20±5 °C. A sonotrode (34 mm diameter) was introduced inside the reactor vessel and the sonication was started at 75% amplitude. Sonication was given in short bursts for this process. After about 140 minutes of sonication, the slurry from the reactor vessel was collected and filtered under vacuum. The solids were dried for 10 hours in a vacuum tray drier at 500mbar vacuum and the particle size was analyzed by both Malvern G3 analyzer as well as Malvern mastersizer.
PSA by Malvern G3 analyzer: D10: 1.60 µm; D50: 3.28 µm; D90: 6.09 µm.
PSA by Malvern mastersizer: D10: 1.26 µm; D50: 3.44 µm; D90: 6.49 µm.

Example 2:
Rivaroxaban (15 g) was charged in glacial acetic acid (150 mL) and heated to reflux (110-120oC). The clear solution was charged in a beaker and kept in an ice bath to cool the solution to 50-60OC. The sonication was started at 75% amplitude and at a temperature of 55°C. Thereafter, the temperature of the reaction mass was allowed to cool down to 32°C and maintained between 30-35oC until sonication is completed. Sonication was given continuously in this process. After about 180 minutes of sonication, the obtained slurry was filtered under vacuum. The wet solid was dried for 10 hours in a vacuum tray drier at 550 mbar pressure and the particle size was analyzed by Malvern G3 analyzer.
PSA by Malvern G3 analyzer: D10: 1.85 µm; D50: 3.17 µm; D90: 5.23 µm
,CLAIMS:WE CLAIM:
1. A process for the preparation of rivaroxaban having a particle size D90 of about 1 µm to about 10 µm comprising sonocrystallizing a solution of rivaroxaban.

2. A process for the preparation of rivaroxaban having a particle size D90 of about 1 µm to about 5 µm comprising sonocrystallizing a solution of rivaroxaban.

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

4. The process of claim 3, wherein the anti-solvent is selected from water, n-pentane, n-hexane, n-heptane, toluene, xylene and mixtures thereof.

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

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

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

8. An oral pharmaceutical composition comprising rivaroxaban having a particle size, D90 of about 1 µm to about 10 µm, prepared by sonocrystallization technique, and one or more pharmaceutically acceptable excipient.

9. An oral pharmaceutical composition comprising rivaroxaban having a particle size, D90 of about 1 µm to about 5 µm, prepared by sonocrystallization technique, and one or more pharmaceutically acceptable excipient.