DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL CRYSTALLINE FORM OF ELIGLUSTAT TARTRATE (1:1) AND PROCESS FOR THE PREPARATION THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to a stable & non-hygroscopic crystalline form of Eliglustat Tartrate (1:1) and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Eliglustat, chemically known as N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4] -dioxin-6-yl)-1-hydroxy-3-(pyrrolidine-1-yl)propan-2-yl)-octanamide (2R,3R)-2,3-dihydoxysuccinate (compound of Formula 1), which is a small molecule inhibitor of glycosylceramide synthase that resembles substrate for the enzyme.
Formula 1
Eliglustat (1) along with its pharmaceutically acceptable salts was disclosed in US 7,196,205. The ‘205 patent also disclosed a process for the preparation of Eliglustat.
US 11,458,119 disclosed crystalline form of Eliglustat Hemitartrate. However, this patent did not describe crystalline form of Eliglustat Tartrate (1:1). Moreover, in the summary of the invention of the ‘119 patent, it describes Eliglustat Tartrate (1:1) as neither crystalline nor non-hygroscopic for formulation.

IN 201621009771 disclosed amorphous and crystalline form of Eliglustat tartrate (1:1) and process for the preparation thereof. However, this application has failed to provide non-hygroscopic and compatible API towards formulated product.
Considering the importance of Eliglustat Tartrate (1:1), nevertheless, besides the known solid forms of Eliglustat Tartrate (1:1), there is still the need for further polymorphs, which are non-hygroscopic, stable in formulation, reproducible, and a process which involves the use of reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly, and/or provide a product of higher purity.

In view of the above, our inventors have developed crystalline Form ET1 of Eliglustat Tartrate (1:1), which is stable and non-hygroscopic in nature. Further, the present inventors developed a process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1).

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a crystalline Form ET1 of Eliglustat Tartrate (1:1) and a process for the preparation thereof.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a crystalline Form ET1 of Eliglustat Tartrate (1:1).

In another embodiment, the present application provides a crystalline Form ET1 of Eliglustat Tartrate (1:1) characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 3.7, 4.5, 5.5, 7.3 and 12.6 ± 0.2° 2?. In embodiments, the present application provides crystalline Form ET1 of Eliglustat Tartrate (1:1) characterized by its PXRD pattern having additional peaks at about 6.9, 8.4, 10.0, 11.0, and 14.5 ± 0.2° 2?.

In another embodiment the present invention provides a process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1)
which comprises;
a) dissolving Eliglustat hemitartrate in acetic acid to obtain a solution;
b) adding the above solution to isobutyl acetate; and
c) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).
In another embodiment the present invention provides a process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1)
which comprises;
a) dissolving Tartaric acid in acetic acid to obtain a solution;
b) adding Eliglustat to the solution of step a);
c) adding the solution of step b) to isobutyl acetate; and
d) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).

In another embodiment the present invention provides a process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1)
which comprises;
a) dissolving Tartaric acid in methanol to obtain a solution;
b) adding Eliglustat and acetic acid to the solution of step a);
c) adding the solution of step b) to isobutyl acetate; and
d) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).

In another embodiment, the present invention provides a crystalline Form ET1 of Eliglustat Tartrate (1:1) having a Powder X-ray Diffraction (PXRD) pattern shown in Figure-1.

In another embodiment, the present invention provides a crystalline Form ET1 of Eliglustat Tartrate (1:1) characterized by an DSC thermogram comprising an endotherm onset peak temperature at 115.25°C as shown in Figure.2.

In another embodiment, the present application provides crystalline Form ET1 of Eliglustat Tartrate (1:1) characterized by a TGA pattern substantially as illustrated in Figure 3.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: PXRD pattern of crystalline Form ET1 of Eliglustat Tartrate (1:1)
Figure 2: DSC pattern of crystalline Form ET1 of Eliglustat Tartrate (1:1)
Figure 3: TGA pattern of crystalline Form ET1 of Eliglustat Tartrate (1:1)

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides crystalline Form ET1 of Eliglustat Tartrate (1:1).

In another embodiment, present application provides crystalline Form ET1 of Eliglustat Tartrate (1:1) characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 3.7, 4.5, 5.5, 7.3 and 12.6 ± 0.2° 2?. In embodiments, the present application provides crystalline form ET1 of Eliglustat Tartrate (1:1) characterized by its PXRD pattern having additional peaks at 6.9, 8.4, 10.0, 11.0, and 14.5 ± 0.2° 2?.

In another embodiment present application provides crystalline form ET1 of Eliglustat Tartrate (1:1) characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 3.7, 4.5, 5.5, 6.9, 7.3, 8.4, 9.1, 10.0, 11.0, 12.6, 14.5, 18.0, 19.1, 20.3, 20.8, 22.3 and 23.7± 0.2° 2?.

In another embodiment the present invention provides a process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1)
which comprises;
a) dissolving Eliglustat hemitartrate in acetic acid to obtain a solution;
b) adding the above solution to isobutyl acetate; and
c) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).

In another embodiment, the present invention provides a process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1)
which comprises;
a) dissolving Tartaric acid in acetic acid to obtain a solution
b) adding Eliglustat to the solution of step a).
c) adding the solution of step b) to isobutyl acetate; and
d) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).

In another embodiment the present invention provides a process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1)
which comprises;
e) dissolving Tartaric acid in methanol to obtain a solution;
f) adding Eliglustat and acetic acid to the solution of step a);
g) adding the solution of step b) to isobutyl acetate; and
h) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).

In another embodiment, the present invention provides a process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1) which comprises addition of seed crystal optionally.

In another embodiment, the present invention provides a crystalline Form ET1 of Eliglustat Tartrate (1:1) having a Powder X-ray Diffraction (PXRD) pattern shown in Figure-1.

In another embodiment, the present invention provides a crystalline Form ET1 of Eliglustat Tartrate (1:1) characterized by DSC thermogram comprising an endotherm onset peak temperature at 115.25°C as shown in Figure 2.

In another embodiment, the present application provides crystalline Form ET1 of Eliglustat Tartrate (1:1) characterized by a TGA pattern substantially as illustrated in Figure 3.

In another embodiment, the present application provides crystalline Form ET1 of Eliglustat Tartrate (1:1) which is stable and non-hygroscopic in nature.

The hygroscopicity test is carried by weighing 0.1 gm of sample in a glass weighing vessel (50 mm diameter and 15 mm high) and placed in unstoppered vessel in a desiccator at 25ºC containing a saturated solution of ammonium chloride or ammonium sulphate or placed in a climatic cabinet set at 25±1ºC and 80±2 % relative humidity and allowed to stand for 24 hours and calculated the percentage increase in the mass of the sample.

The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (instrument name Bruker D8 Advance with lynex detector equipped with Cu source (? = 1.54Aº) measured using CuKa radiation. Methodology of X-ray diffraction is as follows:
Scanning Type: Continuous scan; Scan range: at least 3-40° 2theta; Step size: 0.5°; Time/Step: 0.05 sec; Divergence slit: V20; Rotation: 30 rpm

The Differential Scanning Calorimetry (DSC) thermograms were obtained on a DSC Q2000. Methodology of DSC is as follows:
Mass flow: 50.0 ± 10 mL/min; Equilibrate: 25.00°C; Ramp: 10.00°C/min to 300.00°C.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example 1: Preparation of Eliglustat Tartrate (1:1) From Eliglustat Hemitartrate:
In a 100mL glass vessel reactor, 3.4 gm. Eliglustat hemitartrate and 7 ml. acetic acid was added at room temperature. The solution was added to 80 ml. isobutyl acetate and stirred for 10-12 hrs. at room temperature, the obtained solid was filtered and washed with 5 ml isobutyl acetate and suck dried under nitrogen atmosphere for 5 minutes and dried at 40±5ºC under vacuum for 3-4 hrs. to get 1.7 gm. of Crystalline Eliglustat tartrate (1:1). Dried material analyzed by PXRD.
Example 2: Preparation of Eliglustat Tartrate (1:1) From Eliglustat:
In a 50mL glass vessel reactor, 0.183 gm L-Tartaric acid was dissolved in 2 ml acetic acid at 80ºC and was cooled to room temperature. 0.5 gm. Eliglustat was added to the above solution. This solution was added to 15 ml Isobutyl acetate and a seed of Crystalline Form ET1 Eliglustat Tartrate (1:1) was added and stirred for 10-15 hours at room temperature. The obtained solid was filtered and washed with 5 ml isobutyl acetate and suck dried under nitrogen atmosphere for 5 minutes and dried at 40±5ºC under vacuum for 3-4 hrs. to get 0.44 gm. of Crystalline Eliglustat tartrate (1:1). Dried material analyzed by PXRD.

Example 2: Preparation of Eliglustat Tartrate (1:1) From Eliglustat:
In a 50mL glass vessel reactor, 0.366 g L-Tartaric acid was dissolved in 0.5 ml methanol at reflux temperature and was cooled to room temperature. 1 gm. Eliglustat is added to the above solution and 2 ml acetic acid was added. This solution was added to 15 ml isobutyl acetate and stirred for 10-15 hrs. at room temperature. The obtained solid was filtered and washed with 5 ml isobutyl acetate and suck dried under nitrogen atmosphere for 5 minutes and dried at 40±5ºC under vacuum for 3-4 hrs. to get 1.08 gm. of Crystalline Eliglustat tartrate (1:1). Dried material analyzed by PXRD. ,CLAIMS:WE CLAIM:

1. A Crystalline Form ET1 of Eliglustat Tartrate (1:1) characterized by XRPD pattern having 2? values 3.7, 4.5, 5.5, 7.3 and 12.6 (± 0.2 degrees 2 theta).

2. The Crystalline form according to claim 1, characterized by XRPD pattern having 2? values 6.9, 8.4, 10.0, 11.0, and 14.5 (± 0.2 degrees 2 theta).

3. Crystalline form according to claim 1, characterized by XRPD pattern having 2? values 3.7, 4.5, 5.5, 6.9, 7.3, 8.4, 9.1, 10.0, 11.0, 12.6, 14.5, 18.0, 19.1, 20.3, 20.8, 22.3 and 23.7(± 0.2 degrees 2 theta).

4. Crystalline form according to claim 1 characterized by XRPD pattern depicted in Figure 1.

5. A process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1), which comprises;
a) dissolving Eliglustat hemitartrate in acetic acid to obtain a solution;
b) adding the above solution to isobutyl acetate; and
c) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).

6. A process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1), which comprises;
a) dissolving Tartaric acid in acetic acid to obtain a solution
b) adding Eliglustat to the solution of step a).
c) adding the solution of step b) to isobutyl acetate; and
d) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).

7. A process for the preparation of the crystalline Form ET1 of Eliglustat Tartrate (1:1), which comprises;
a) dissolving Tartaric acid in methanol to obtain a solution;
b) adding Eliglustat and acetic acid to the solution of step a);
c) adding the solution of step b) to isobutyl acetate; and
d) obtaining the crystalline Form ET1 of Eliglustat Tartrate (1:1).