CLIAMS:
1. A stable amorphous palonosetron hydrochloride, compound of formula I

Formula I
has purity more than 99% when measured by HPLC.

2. The stable amorphous form of palonosetron hydrochloride of claim 1, characterized by powder X-ray diffraction pattern in accordance of Figure 1.

3. A process for the preparation of amorphous form of palonosetron hydrochloride using spray dryer, which comprises step of,
a) dissolving palonosetron hydrochloride in organic solvent,
b) removing the solvent from the solution obtained in step a) by using spray drying techniques ,
c) isolating amorphous palonosetron hydrochloride.

4. The process of claim 3, wherein organic solvent is selected from group comprises one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, water, propylene glycol and mixtures thereof.

5. The process of claim 3, wherein the organic solvent is methanol.

6. The process of claim 3, wherein the step c) is carried out at temperature in between range of 40 to 120 ºC for inlet temperature and outlet temperature in between the range of 30 to 100 ºC.
7. The process of claim 3, wherein the step c) is carried out at minimum feed rate about 3 ml/min.

8. The process of claim 3, wherein the step c) is carried out with the atomization pressure of about Maximum10 Kg/cm2
,TagSPECI:Field of Invention

The present invention relates to the stable amorphous palonosetron hydrochloride, has purity more than 99 % when measured by HPLC. In particular of the present invention relates to the process for the preparation of stable amorphous palonosetron hydrochloride, using spray dryer, has purity more than 99 % by HPLC.

Background of the invention

Palonosetron hydrochloride is chemically known as (3aS)-2-[(S)-1-azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1H-benz[de]isoquinoline hydrochloride of Formula I, having the structure as depicted below

Formula I
Palonosetron hydrochloride is a potent 5-hydroxytryptamine 3 receptor (5-HT 3 receptor) antagonist, and is used as an antiemetic and antinauseant agent. Palonosetron hydrochloride is marketed under the brand name Aloxi®.

U.S. Patent No. 5,202,333 describes the palonosetron hydrochloride salt and its process for preparation. There are several processes described in the various patents and patent applications, including U.S Pat. Nos. 5,510,486; 5,567,818; 8,304,544; U.S application No. 2012/0267533 A1 and Chinese Patent application CN 1768750A.

The U.S application No. 2014/0171646 A1 describes amorphous palonosetron hydrochloride and its process of preparation by means of lyophilization in water. The amorphous palonosetron hydrochloride obtained from the process of US ‘646 is unstable and hygroscopic in nature, which is not suitable for formulation. The ‘646 described process involves the use of lyophilization technique, which requires heavy investments in machines and equipments and product output comparatively slow, which in turn making it industrially uneconomical.

Therefore, there is a need to provide an improved process for preparation of stable amorphous palonosetron hydrochloride, which is economical, industrially feasible and provides high yield.

Summary of the Invention

The one aspect of the present invention relates to the stable amorphous palonosetron hydrochloride, compound of formula I

Formula I
has purity more than 99 % when measured by HPLC.

The one another aspect of the present invention relates to the process for the preparation of stable amorphous palonosetron hydrochloride, using spray drying technique.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of stable amorphous form of palonosetron hydrochloride, prepared according to Example 1.

Description of the Invention

For purposes of the present invention, the following terms are defined below.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Kα radiation, having the wavelength 1.54 Å.

In one aspect of the present invention provides a stable amorphous form of palonosetron hydrochloride, compound of Formula I,

Formula I
has purity more than 99 % when measured by HPLC.

In another aspect of the present invention provides a stable amorphous form of palonosetron hydrochloride, having an X-ray diffraction pattern as depicted in Figure 1.

The stable amorphous form of palonosetron hydrochloride obtained according to Example 1 of the present invention was stored at 2-8°C for a period of 3 months and no conversion in the amorphous form was observed and even on subsequent storage at a temperature 25° C and relative humidity in between range of 25 to 40 % for a time period of at least 1 month.

In one another aspect of the present invention provides a process for the preparation of the amorphous form of palonosetron hydrochloride compound of Formula I,

Formula I
the process includes step of
a) dissolving palonosetron hydrochloride in organic solvent,
b) removing the solvent from the solution obtained in step a) using spray drying techniques,
c) isolating amorphous palonosetron hydrochloride,

The step a) of the present invention involves the dissolution of palonosetron hydrochloride in organic solvent at temperature in between range of 25 °C to 30°C, wherein organic solvent is selected from group comprises one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, water, propylene glycol and mixtures thereof.

The solution obtained in step (a) is stirred at temperature in between range of 25 °C to 30°C to get clear solution. The solution obtained may be filtered to remove any undissolved particles, prior to further processing. The undissolved particles may be removed suitably by filtration, centrifugation, decantation, and other techniques. The solution may be filtered by passing through paper (for example, Whatman filter paper), buckner filter, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The step b) of the present invention involves the removing the solvent from the solution obtained in step a) by using spray drying techniques at temperature in between range of 40°C to 120°C The step b) of the present invention may be carried out with any other suitable techniques to remove solvent from the solution such as rotary evaporation under vacuum, freeze drying, spray drying and lyophilization, agitated thin film drying (ATFD) and the like.

The step c) of the present invention involves the isolation of the amorphous palonosetron hydrochloride carried out by means of drying at temperature in between range of 40°C to 120°C and the collection of amorphous palonosetron hydrochloride from spray dryer, under inert atmosphere, wherein amorphous material can be collected from the spray dryer by using techniques such as scraping, or by shaking the container, or using techniques specific to the particular apparatus.

Evaporation of the solvent may be conducted under a vacuum at temperatures such as about -20°C to about 170°C. Any temperature and vacuum conditions may be used as long as there is no increase in the impurity levels of the product. For example, spray drying is more suitable for industrial scale production with batch sizes of about 100 g or about 1 Kg, or greater at about 50 °C to 100 °C.

The desired temperatures for the step (a) to (c) can be modified, depending on type of solvent and its boiling point. Any other temperature is also acceptable as long as a clear solution of palonosetron hydrochloride is provided.

In one another embodiment the present invention provides process for the preparation of palonosetron hydrochloride, which includes the dissolving palonosetron hydrochloride in methanol at temperature in between range of 25 °C to 30°C, followed by spray drying of obtained solution, wherein spray drying carried out at minimum feed rate 3ml/minute at inlet at temperature in between range of 40±120 ºC and out let at temperature in between range 30±100 ºC, wherein at temperature in between range of spray dryer can be modified depending on solvent boiling point.

Palonosetron hydrochloride used as a starting material may be obtained according to the procedure provided in the prior art, for example U.S. Pat. Nos. 5,202,333; 5,567,818; and 5,510,486.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Process of preparation of Amorphous Palonosetron hydrochloride

The palonosetron hydrochloride (5.0 gm) was dissolved in methanol (80 ml) and stirred for 15-20 minutes at temperature in between range of 25 to 30 ºC. The mass was filtered and washed with methanol (20ml). The filterate is collected and spray dried at temperature in between range of 95±1.5°C After the completion of spray drying, the amorphous material is collected under nitrogen atmosphere.
Set Parameter for spray drying
a) Inlet temperature : 95±1.5°C
b) Outlet temperature : 62 ± 1.5 °C
c) Feed rate : 600 ± 10 ml/hr
d) Atomization pressure (Nitrogen) : 10 Kg/cm2
e) Vacuum in system : 50 ± 5 mbar
Percentage Yield: 80 %
Yield: 4.0 gm
XRPD showed Amorphous Nature of material