DESC:FIELD OF THE INVENTION

The present invention relates to process for the preparation of crystalline form I of Selexipag of compound of formula I. The present invention further relates to pharmaceutical compositions containing them, and method of treatment using the same.

Formula-I

BACKGROUND OF THE INVENTION

Selexipag, previously also known as NS-304 or ACT-293987, is a potent orally available and highly selective long acting non-prostanoid prostaglandin 12 (PGI-2) receptor agonist, and has been filed for approval in the E.U. and in the U.S. by Actelion for the treatment of pulmonary arterial hypertension. As a prodrug it is in vivo transformed by the liver to its active metabolite.

Selexipag and its synthesis are described in WO 2002/088084. In example 84 Selexipag is isolated after chromatographic purification.

WO 2010/150865 (IN2011CN09790A) discloses three crystalline Forms of Selexipag, designated Form I, Form II and form III. It is described that these forms were obtained either in pure form or as binary mixtures from a polymorph screening using 32 different solvents and 16 different solvent mixtures (see test example 4). The crystalline forms of WO 2010/150865 are described as useful for the preparation of pharmaceutical formulations and oral dosage forms, such as tablets comprising crystalline Selexipag, are described. It should be noted that amorphous Selexipag was only described in one single experiment using 1,3,5-trimethylbenzene as solvent (table 4, experiment 30) in WO 2010/150865.

WO 2016193994 (IN 2086/MUM/2015), WO 2017029594 (IN 4305/CHE/2015) and WO 2017109772 all of these applications disclose amorphous form of Selexipag and its preparation.
Another WO 2017040872 discloses crystalline forms of Selexipag, designated as form P, L and M and WO 2018008042 discloses crystalline forms of Selexipag, designated as form IV and form V.
Further WO 2018015974 discloses crystalline forms of Selexipag, designated as form V, form VII-1, IV and VI.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Selexipag, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g. measured by thermo gravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state ( C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Prior art processes for preparation of Form I of Selexipag do not possess desired repeatability and reproducibility of desired polymorphic purity. Hence there is a need to develop new robust process for preparation of Form I of Selexipag which produces desired polymorphic purity and can be used for commercial purposes.

Present inventors have identified novel process for the preparation of form I of Selexipag as disclosed in WO 2010/150865. The process as disclosed herein is highly reproducible and is suitable for scale up production.

SUMMARY OF THE INVENTION

In one aspect, the present application provides a process for the preparation of crystalline Selexipag Form I, comprising:
a) providing a reaction mixture of Selexipag in a suitable solvent;
b) heating the reaction mixture;
c) adding water to reaction mixture; and
d) isolating crystalline Selexipag Form I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

In one embodiment, the present application provides a process for the preparation of crystalline Selexipag Form I, comprising:
a) providing a reaction mixture of Selexipag in a suitable solvent;
b) heating the reaction mixture;
c) adding water to reaction mixture; and
d) isolating crystalline Selexipag Form I.

The suitable solvent used herein includes but not limited to such as water, DMSO (dimethyl sulfoxide), DMF (N, N-dimethyl formamide), DMA (N, N-dimethyl acetamide), carbon disulphide, acetic acid, acetonitrile, benzonitrile, propionitrile, NMP (N-methyl-2-pyrrolidone), sulfolane, 1-4-dioxane or their mixtures.

Heating of reaction mixture can be carried out at a suitable temperature range between 30 to 200oC, more preferably between 50 to 100 oC.
Cooling of reaction mixture can be carried out at a suitable temperature range between 0 to 30oC.

The crystalline form I of Selexipag obtained by the process disclosed in the present invention is substantially pure and stable.

As used herein, the term “substantially pure” with reference to a particular polymorphic form means that the polymorphic form includes less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% by weight of any other physical forms of the compound.

Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities absorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. 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 present invention adopts following general method for the isolation such as methods including cooling, crash cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization or evaporation or the like or combinations thereof. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.

Optionally, isolation may be effected by combining a suitable anti-solvent with the solution. Anti-solvent as used herein refers to a liquid in which Selexipag is less soluble or poorly soluble. An anti-solvent has no adverse effect on the quality of Selexipag and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: water, saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as hexanes, heptane, cyclohexane, or methyl cyclohexane, ethers, such as diethyl ether, diisopropyl ether, or mixtures thereof.

The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.

In one aspect, the present invention provides form I of Selexipag having particle size D90 =200µm; preferably, D90 =50µm, more preferably D90 =20µm.

In another embodiment, the present invention provides pharmaceutical compositions comprising crystalline form I of Selexipag.

The starting material “Selexipag” used for is prepared by known conventional method reported in the prior art either isolated product or the product /residue from the reaction mixture is used to prepare the crystalline form(s) of the present invention.

To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X-ray diffraction patterns, differential scanning calorimeter, thermogram, thermal gravimetric analyzers thermogram, melting point information, polarized light microscopy, hotstage microscopy, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra and hygroscopicity profile to name a few are used.

EXAMPLES

The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.

Example-1: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 4 ml of N, N-Dimethyl acetamide. The reaction mixture was heated at about 800C - 900C. Water (12 ml) was added to reaction mixture. The reaction mixture was cooled to ambient temperature and stirred for 1 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.70 g).

Example-2: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 4 ml of N-Methyl-2-pyrrolidone. The reaction mixture was heated at about 800C - 900C. Water (12 ml) was added to reaction mixture. The reaction mixture was cooled to ambient temperature and stirred for 1 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.40 g).
Example-3: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 4 ml of Dimethyl sulfoxide. The reaction mixture was heated at about 800C - 900C. Water (12 ml) was added to reaction mixture. The reaction mixture was cooled to ambient temperature and stirred for 1 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.50 g).
Example-4: Preparation of crystalline Form I of Selexipag
Selexipag (2.0 g) was charged in 4 ml of acetonitrile. The reaction mixture was heated at about 800C - 900C. Water (10 ml) was added to reaction mixture. The reaction mixture was cooled to ambient temperature and stirred for 1 hrs. The solid was filtered and dried to obtain crystalline form I of Selexipag (1.30 g).

Date this 24th day of May 2019.

,CLAIMS:We Claim:

1. A process for preparation of Form I of Selexipag comprising the steps of:
(a) providing a reaction mixture of Selexipag in a suitable solvent;
(b) heating the reaction mixture;
(c) adding water to the reaction mixture; and
(d) isolating crystalline Selexipag Form I.

2. The process as claimed in step (a) of claim 1 wherein suitable solvent is selected from N, N-Dimethyl acetamide, N-Methyl-2-pyrrolidone, Dimethyl sulfoxide, acetonitrile and mixtures thereof.

3. The process as claimed in step (b) of claim 1 wherein heating of reaction mixture is carried out between temperature range of 50-100oC.

4. The process as claimed in step (c) of claim 1 wherein water is added to the reaction mixture between temperature range of 50-100oC.

5. The process as claimed in step (c) of claim 1 further comprises cooling of reaction mixture between temperature range of 0 to 30oC.

Dated this 24th May 2019