DESC:PROCESS FOR THE PREPARATION OF AMORPHOUS SELEXIPAG

FIELD OF THE INVENTION

The present invention relates to an amorphous solid dispersion comprising selexipag and corn starch and process for preparation thereof.

BACKGROUND OF THE INVENTION

Selexipag chemically known as 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl) amino]butoxy}-N(methylsulfonyl)acetamide, is represented by the compound of Formula I:

Selexipag is selective non-prostanoid IP prostacyclin receptor agonist, approved in December 2015 in the United States and marketed under the brand name UPTRAVI® as oral tablets. UPTRAVI® is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

The United States patent No. 7,205,302 discloses selexipag and process for preparation thereof. Selexipag is reported to be present in various polymorphic forms in the literature. The United States patent No. 8,791,122 (the ‘122 patent) discloses polymorphic forms I, II and III of selexipag.

SUMMARY OF THE INVENTION
The present invention provides an amorphous solid dispersion comprising selexipag and corn starch.
The present invention also provides a process for the preparation of amorphous solid dispersion comprising selexipag and corn starch, wherein the process comprises:
(a) dissolving selexipag in an aqueous solution of a base,
(b) adding an acid sufficient to neutralize the base, to the solution of step a,
(c) adding corn starch, and
(d) isolating amorphous solid dispersion comprising selexipag and corn starch.

The amorphous solid dispersion of selexipag of the present invention is free flowing, easy to handle which makes it suitable for manufacturing of pharmaceutical finished dosage formulations.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: XRPD (X-ray powder diffraction) graph of amorphous solid dispersion of selexipag with corn starch (1:2) obtained in example 1.

Figure 2: XRPD graph of amorphous solid dispersion of selexipag with corn starch (1:5) obtained in example 2.

Figure 3: XRPD graph of amorphous solid dispersion of selexipag with corn starch (1:5) after 6 months storage at 25 °C to 30 °C.

DETAILED DESCRIPTION OF THE INVENTION

Thus in one aspect, the present invention provides an amorphous solid dispersion
comprising selexipag and corn starch.

In one embodiment, the present invention provides an amorphous solid dispersion comprising selexipag and corn starch, wherein the ratio of selexipag to corn starch is 1:1 to 1:100. In another embodiment, the ratio selexipag to corn starch is 1:2 to 1:100. In a preferred embodiment, the ratio of selexipag to corn starch is 1:2. In yet another preferred embodiment, the ratio of selexipag to corn starch is 1:5.

In another embodiment, the present invention provides an amorphous solid dispersion comprising selexipag and corn starch characterized by X-ray powder diffraction pattern as shown in figure 1, figure 2 or figure 3.

In another embodiment, the present invention provides an uniform amorphous solid dispersion comprising selexipag and corn starch, wherein the ratio of selexipag to corn starch is 1:2 to 1:100 and wherein the said amorphous solid dispersion is stable when stored at 25 °C to 30 °C for at least 6 months.

The term “stable” as used herein refers to a state of a solid phase of a material, which is stable in terms of chemical stability and polymorphic form stability for atleast a period as described herein.

The amorphous solid dispersion comprising selexipag and corn starch of the present invention was found to be stable during storage. For instance, the XRPD of the amorphous solid dispersion of the present invention does not change significantly when it was stored at 25 °C to 30 °C for more than 6 months (Figure 3), i.e. no crystallinity was detected by X-ray analysis method. Even there was no significant change in the HPLC purity of the amorphous solid dispersion after 6 months of storage.

In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion comprising selexipag and corn starch, wherein the process comprises:
(a) dissolving selexipag in an aqueous solution of a base,
(b) adding an acid sufficient to neutralize the base to the solution of step a,
(c) adding corn starch, and
(d) isolating amorphous solid dispersion comprising selexipag and corn starch.
A suspension of selexipag in water is prepared, to which an aqueous solution of a base is added to dissolve selexipag. Alternatively, selexipag as such can be added to an aqueous solution of a base to prepare the aqueous solution comprising selexipag and the base. The base can be selected from inorganic or organic bases. The inorganic base can be selected from a group comprising hydroxides and carbonates of alkali metals or alkali earth metals, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or a mixture thereof. The organic base can be selected from a group comprising of triethylamine, diisopropylamine, diisopropylethylamine (DIPEA), pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) or a mixture thereof. The preferred base is sodium hydroxide.

The acid used in the above process may be selected from organic or inorganic acids such as hydrochloric acid, sulfuric acid, acetic acid, formic acid and the like. The preferred acid is hydrochloric acid. The acid may be diluted with the water or it may be used without dilution. The acid may be added at a temperature ranging from 0 ºC to 35 ºC. Alternatively, the aqueous solution comprising of selexipag and the base may be added to the acid. The acid is used in a quantity sufficient enough to neutralize the base and precipitate the selexipag from the solution to form a suspension of selexipag in water; more preferably it is used in a quantity to adjust the pH of the solution from 5 to 7. Selexipag is used in amounts such that it is precipitated out of the solution. In one embodiment, the amount of selexipag is 0.2 g to about 10 g per 100 mL of solution. In another embodiment, the amount of selexipag is about 1 g to about 8 g per 100 mL of the solution. In yet another embodiment, the amount of selexipag is about 2 g to about 5 g per 100 mL of solution.

Corn starch is added to the suspension formed in step b and the resultant suspension may be stirred at 0 ºC to 35 ºC to form a suspension of amorphous solid dispersion of selexipag with corn starch in water. The corn starch is used in a quantity wherein the ratio of selexipag to corn starch is 1:1 to 1:100. In another embodiment, corn starch is used in a quantity wherein the ratio of selexipag to corn starch is 1:2 to 1:100. In a preferred embodiment, corn starch is used in a quantity wherein the ratio of selexipag to corn starch is 1:2. In yet another preferred embodiment, corn starch is used in a quantity wherein the ratio of selexipag to corn starch is 1:5. The amorphous solid dispersion comprising selexipag and corn starch may be isolated from the above suspension by well-known techniques in the art such as filtration or centrifugation. The obtained amorphous dispersion may be additionally washed with water and dried under vacuum at a temperature of 40 ºC to 50 ºC.

Selexipag used as a starting material for the process for the preparation of amorphous solid dispersion of selexipag can be prepared by any of the processes known in the art, for instance, by the process reported in United States patent No. 7,205,302.

In another aspect, the present invention provides a pharmaceutical composition comprising amorphous solid dispersion of selexipag with corn starch and one or more pharmaceutically acceptable excipient.

The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.

EXAMPLES
Instrument details:
X-ray powder diffraction analyses were carried out on a PANalytical Empyrean X-ray powder diffractometer using Cu K alpha radiation. The instrument was equipped with a line focus X-ray tube, and the voltage and amperage were set to 45 kV and 40 mA respectively. The scanning rate was set as 10 second per step and step size is set as 0.01º. The diffractometer was equipped with Pixcel1D solid state detector and rotating sample stage. X-ray diffractometer was used to record diffractogram from 4º to 40º (2-theta).

Example 1: Preparation of amorphous solid dispersion of selexipag with corn starch (1:2)
Aqueous sodium hydroxide solution (prepared by dissolving 42.2 mg sodium hydroxide in 4.2 mL of water) was added to a suspension selexipag (500 mg) in water (20 mL) at room temperature to get clear solution. The solution was cooled to 0 ºC to 5 ºC and then aqueous hydrochloric acid solution (prepared by adding 0.11 mL concentrated HCl in 1.1 mL of water) was added to get a suspension. Corn starch (1g, Unipure FL) was added and the resultant suspension was stirred for about 1 hour at room temperature. The solid was filtered and washed with water. The obtained amorphous solid dispersion was dried under vacuum at 50 ºC. XRPD graph is shown in Figure 1.

Example 2: Preparation of amorphous solid dispersion of selexipag with corn starch (1:5)
Aqueous sodium hydroxide solution (prepared by dissolving 4.2 g sodium hydroxide in 42 mL of water) was added to a suspension selexipag (50 g) in water (2.50 L) at room temperature to get clear solution. The solution was cooled to 5 ºC to 10 ºC and then aqueous hydrochloric acid solution (prepared by adding 12.85 mL concentrated HCl in 65 mL of water) was added to get a suspension. Corn starch (250 g, Unipure FL) was added and the resultant suspension was stirred for about 1 hour at room temperature. The solid was filtered and washed with water. The obtained amorphous solid dispersion was dried under vacuum at 45 ºC. XRPD graph is shown in Figure 2.
HPLC purity: 99.67 %.
Total Impurity content: 0.33 %.
HPLC purity of amorphous solid dispersion was determined by using:
Column: Agilent Poroshell® 120 EC C-18, (150 x 4.6) mm, 2.7µm;
Mobile phase: Mobile phase A- buffer preparation: methanol: acetonitrile (70:20:10); Mobile phase B- buffer preparation: acetonitrile (30:70).
Buffer preparation was prepared by dissolving potassium dihydrogen orthophophosphate (3.4 g) in 1000 mL of water, followed by addition of triethylamine (10 mL) and adjusting the pH to 3.0 ± 0.05 with orthophosphoric acid.
The above amorphous solid dispersion of selexipag with corn starch (1:5) was stored at 25 °C to 30 °C for 6 months.
XRPD graph after 6 months of storage is shown in Figure 3.
HPLC purity after 6 months of storage: 99.47 %.
Total impurity content after 6 months of storage: 0.53 %.

,CLAIMS:1. An amorphous solid dispersion comprising selexipag and corn starch.

2. The amorphous solid dispersion as claimed in claim 1, wherein the ratio of selexipag to corn starch is 1:2 to 1:100.

3. An uniform amorphous solid dispersion comprising selexipag and corn starch, wherein the ratio of selexipag to corn starch is 1:2 to 1:100 and wherein the said amorphous solid dispersion is stable when stored at 25 °C to 30 °C for at least 6 months.

4. A process for the preparation of amorphous solid dispersion comprising selexipag and corn starch, wherein the process comprises:
(a) dissolving selexipag in an aqueous solution of a base,
(b) adding an acid sufficient to neutralize the base, to the solution of step a,
(c) adding corn starch, and
(d) isolating amorphous solid dispersion comprising selexipag and corn starch.

5. The process as claimed in claim 4, wherein the ratio of selexipag to corn starch is 1:2 to 1:100.