Claims:We Claim:
1. A stable and highly pure crystalline Form III of Selexipag having purity about 99.8% to about 99.99% as measured by HPLC, which is characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 9.33, 9.66, 16.82, 20.53 and 23.46 ±0.2 degrees substantially in accordance with Figure 1.

2. The highly pure crystalline Form III of Selexipag as claimed in claim 1, which is further characterized by: (i) an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 4.65, 8.84, 11.65, 14.00, 15.82, 17.18, 17.84, 19.61, 20.10, 21.56, 24.19 and 25.10 ± 0.2 degrees substantially in accordance with Figure 1; (ii) an infrared (FT-IR) spectrum comprising one or more main bands at about 3026, 2936, 2868, 1723, 1580, 1562, 1513, 1501, 1486, 1460, 1433, 1398, 1388, 1366, 1336, 1247, 1232, 1182, 1162, 1147, 1126, 1074, 1051, 1029, 967, 862, 765, 703 and 692 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram comprising a sharp endotherm peak at about 138.11ºC substantially in accordance with Figure 3.

3. A process for the preparation of the stable and highly pure crystalline Form III of Selexipag as claimed in claims 1 and 2, comprising:
(a) providing a suspension of Selexipag in an alcohol solvent at room temperature;
(b) heating the suspension obtained in step-(a) at a temperature of above about 60ºC to form a clear solution;
(c) allowing the solution obtained in step-(b) to cool slowly to room temperature;
(d) cooling the resulting solution obtained in step-(c) further to below about 20ºC to cause crystallization; and
(e) collecting the highly pure crystalline Form III of Selexipag essentially free of other crystalline forms obtained in step-(d).

4. The process as claimed in claim 3, wherein the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and mixtures thereof; wherein the suspension in step-(b) is heated while stirring at a temperature of about 60ºC to the reflux temperature of the solvent used for at least 5 minutes; wherein the solution in step-(c) is cooled to a temperature of about 25ºC to about 30ºC for about 20 minutes to 8 hours; wherein the resulting solution in step-(d) is cooled to a temperature of below about 15ºC while stirring for at least 10 minutes; and wherein the collection of the highly pure crystalline Form III of Selexipag in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

5. The process as claimed in claim 4, wherein the alcohol solvent used in step-(a) is methanol; wherein the suspension in step-(b) is heated while stirring at the reflux temperature of the solvent used for about 10 minutes to about 2 hours; wherein the solution in step-(c) is cooled to a temperature of about 25ºC to about 30ºC for about 1 hour to about 3 hours; and wherein the resulting solution in step-(d) is cooled to a temperature of about 0ºC to about 15ºC for about 20 minutes to 5 hours.

6. A stable and highly pure crystalline Form I of Selexipag having purity about 99.8% to about 99.99% as measured by HPLC, which is characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 9.39, 9.79, 15.56, 17.24, 18.93, 19.40 and 22.93 ± 0.2 degrees substantially in accordance with Figure 4.

7. The highly pure crystalline Form I of Selexipag as claimed in claim 6, wherein the stable and highly pure crystalline Form I of Selexipag is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 4.70, 8.64, 11.38, 14.13, 15.22, 16.85, 17.24, 17.97, 19.71, 20.26, 21.59, 23.78, 25.10 and 26.09 ± 0.2 degrees substantially in accordance with Figure 4; wherein the stable and highly pure crystalline Form I of Selexipag is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3027, 2936, 2865,1731, 1578, 1561, 1513, 1500, 1483, 1445, 1431, 1400, 1388, 1366, 1335, 1318, 1251, 1231, 1181, 1160, 1123, 1046, 1029, 970, 928, 890, 861, 765, 703 and 692 cm-1 ± 5 cm-1 substantially in accordance with Figure 5; and wherein the stable and highly pure crystalline Form I of Selexipag is further characterised by a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 139.35ºC substantially in accordance with Figure 6.

8. A process for the preparation of a stable and highly pure crystalline Form I of Selexipag as claimed in claims 6 and 7, comprising:
(a) providing a suspension of Selexipag in an alcohol solvent at room temperature;
(b) heating the suspension obtained in step-(a) at a temperature of above about 60ºC to form a clear solution; and
(c) substantially removing the solvent from the solution obtained in step-(b) to produce highly pure crystalline Form I of Selexipag essentially free of other crystalline forms.

9. The process as claimed in claim 8, wherein the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and mixtures thereof; wherein the suspension in step-(b) is heated while stirring at a temperature of about 60ºC to the reflux temperature of the solvent used for at least 5 minutes; and wherein the removal of solvent in step-(c) is accomplished by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere to obtain stable and highly pure crystalline Form I of Selexipag.

10. The process as claimed in claim 9, wherein the alcohol solvent used in step-(a) is methanol; wherein the suspension in step-(b) is heated while stirring at the reflux temperature of the solvent used for about 10 minutes to about 2 hours; and wherein the removal of solvent in step-(c) is carried out by distillation.

11. A pharmaceutical composition comprising the stable and highly pure crystalline Form III of Selexipag obtained by the process as claimed in claims 3 to 5, and one or more pharmaceutically acceptable excipients.

12. A pharmaceutical composition comprising the stable and highly pure crystalline Form I of Selexipag obtained by the process as claimed in claims 8 to 10, and one or more pharmaceutically acceptable excipients.
13. A pharmaceutical composition comprising the stable and highly pure crystalline Form III of Selexipag having purity about 99.8% to about 99.99% as measured by HPLC, characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 9.33, 9.66, 16.82, 20.53 and 23.46 ±0.2 degrees.

14. The pharmaceutical composition as claimed in Claim 13, wherein the highly pure crystalline Form III of Selexipag has a D90 particle size of about 5 microns to about 150 microns.

15. A pharmaceutical composition comprising the stable and highly pure crystalline Form I of Selexipag having purity about 99.8% to about 99.99% as measured by HPLC, characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 9.39, 9.79, 15.56, 17.24, 18.93, 19.40 and 22.93 ± 0.2 degrees.

16. The pharmaceutical composition as claimed in Claim 15, wherein the highly pure crystalline Form I of Selexipag has a D90 particle size of about 5 microns to about 150 microns.
, Description:FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and consistently reproducible processes for the preparation of highly pure and stable crystalline forms of Selexipag (designated as Form I and Form III), which are free from other polymorphic forms.

BACKGROUND OF THE INVENTION
U.S. Patent No. 7,205,302 B2 discloses a variety of heterocyclic derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds have PGI2 receptor antagonist activity. Among them, Selexipag, chemically named 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide, is a prostaglandin I2 (PGI2) receptor antagonist used for treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Selexipag is represented by the following structural formula:

Selexipag is, a selective non-prostanoid IP prostacyclin receptor agonist, approved for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.
Selexipag was developed by Actelion. It is approved in the United States and European Union and is marketed under the trade name Uptravi®. It is orally administered as tablets containing 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1000 mcg, 1200 mcg, 1400 mcg, 1600 mcg of Selexipag.
Various processes for the preparation of Selexipag, its intermediates, and its polymorphic forms are described in U.S. Patent No. US 7,205,302B2, US 8,791,122B2 and US 10,188,648B2; European Patent No. EP 3344607B1; and PCT Publication No. WO 2017029594 A1.
The synthesis of Selexipag was first described in the US 7,205,302 patent (herein after referred to as the US’302 patent). As per the process exemplified in the US’302 patent, Selexipag is prepared by the following process steps: (a) the condensation of 2-chloro-5,6-diphenylpyrazine and 4-(isopropylamino)-1-butanol at 190°C for 10 hours. The resulting solution was air-cooled, poured into water, extracted with diethyl ether, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol as a colorless crystal having a melting point of 102-103°C; (b) reacting 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol with tert-butyl bromoacetate in presence of 40% potassium hydroxide and tetra-n-butylammonium hydrogen sulfate to produce a reaction mass, which was diluted with water and then extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-acetic acid tert-butyl ester; (c) deprotection of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-acetic acid tert-butyl ester using 1N sodium hydroxide in methanol as solvent to produce 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-acetic acid; (d) adding of 1,1’-carbonyl diimidazole to a solution of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-acetic acid in anhydrous tetrahydrofuran under argon atmosphere, after stirring at room temperature for 30 minutes, the mixture was heated at reflux for 30 minutes. After cooling to room temperature, methanesulfonamide was added. After stirring for 10 minutes, 1,8-diazabicyclo[5.4.0]-7-undecene was added drop-wise. After stirring at room temperature overnight, the reaction solution was diluted with water and then extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain Selexipag.
Selexipag is known to exhibit polymorphism and various crystalline forms are apparently disclosed in U.S Patent Nos. US 8,791,122 B2 and US 10,188,648 B2.
U.S Patent No. 8,791,122 B2 (herein after referred to as the US’122 patent), assigned to Nippon Shinyaku Co. Ltd., discloses three crystalline forms of Selexipag namely Form I, Form II and Form III, process for their preparation, and characterizes the crystalline forms by X-ray powder Diffractogram and scanning electron micrograph.
According to the US’122 patent, crystalline Form I of Selexipag is characterized by an X-ray powder diffraction spectrum having XRPD 2-theta peaks at about 9.4, 9.8, 17.2 and 19.4 ± 0.2 degrees; Crystalline Form II of Selexipag is characterized by an X-ray powder diffraction spectrum having XRPD 2-theta peaks at about 9.0, 12.9, 20.7 and 22.6 ± 0.2 degrees; and Crystalline Form III of Selexipag is characterized by X-ray powder diffraction spectrum having XRPD 2-theta peaks at about 9.3, 9.7, 16.8, 20.6 and 23.5 ± 0.2 degrees. The applicant of the US’122 patent has demonstrated, during the prosecution of the corresponding equivalent Indian patent Application No. IN2011CN09790A1 (hereinafter referred to as the IN’790 application), that Selexipag prepared in the product patent (US 7,205,302 B2) has the same X-Ray powder diffraction peaks as Form-III crystal reported in the IN’790 application.
As per the process reported in the US’122 patent, crystalline Form I of Selexipag is prepared by adding ethanol (440 ml) to Selexipag (40 g), and the mixture was stirred and heated in an oil bath at 100°C to 110°C. After Selexipag was dissolved, ethanol (280 ml) was removed. The obtained concentrate was stirred and heated under reflux in a water bath of 80°C for 1 hour. The solution was gradually cooled to 10°C in 20 hours while stirring, and the precipitated crystal was collected through filtration. The obtained crystal was washed with a small amount of ethanol (48 ml), and dried under reduced pressure at 60°C to give Form-I crystal of Selexipag [38.93 g, 97.3%; Mp: 140.4°C.; and HPLC Purity: 99.51%].
As per the process reported in the US’122 patent, crystalline Form I of Selexipag is also prepared by adding ethanol (99 g) and methylethylketone (11 g) to Selexipag (20 g), and heated at 77°C to dissolve Selexipag, and then the solution was gradually cooled to 10°C in 20 hours. During the cooling process, a small amount of Form-I crystal was added to the solution. After cooling, the precipitated crystal was collected through filtration, washed with ethanol, and then dried under reduced pressure to give Form-I crystal of Selexipag [Yield: 18.72 g, 93.6%].
As per the process reported in the US’122 patent, crystalline Form II of Selexipag is prepared by adding ethanol (550 g) and methyl ethyl ketone (55 g) to Selexipag (100 g), heated at 77°C., and filtered under pressure while kept heated. With stirring, the resulting filtrate was cooled from 70°C to 0°C., taking 30 minutes, and after reaching 0°C., this was stirred at 0°C for 2.5 hours. The precipitated crystal was collected through filtration, washed with ethanol (200 ml), and dried under reduced pressure. Ethanol (99 g) and methyl ethyl ketone (11 g) were added to the obtained crystal (20 g), heated at 70°C., then kept at 70°C for 1 hour, and gradually cooled to 10°C., taking 20 hours; and after reaching 10°C., this was stirred at 10°C for 1 hour. The precipitated crystal was collected through filtration, washed with ethanol (40 ml), and then dried under reduced pressure to give Form-II crystal of Selexipag [Yield: 18.73 g, 93.7%; Mp: 135.2°C; HPLC Purity: 99.33%].
As per the process reported in the US’122 patent, crystalline Form II of Selexipag is also prepared by adding ethanol (99 g) and methylethylketone (11 g) to Selexipag (20 g), and the resulting mixture was heated at 77°C to dissolve Selexipag, and then the solution was gradually cooled to 10°C in 20 hours. During cooling, to the solution was added a small amount of Form-II crystal. After cooling, the precipitated crystal was collected through filtration, washed with ethanol, and then dried under reduced pressure to give Form-II crystal of Selexipag [Yield: 19.70 g, 98.5%].
As per the process reported in the US’122 patent, crystalline Form III of Selexipag is prepared by adding n-butyl acetate (500 ml) to Selexipag (36.7 g), and heated at 75°C to dissolve Selexipag, and then cooled to 5°C. Then, a process of heating to 60°C and cooling to 5°C was carried out, and the process was repeated. The precipitated crystal was collected through filtration, washed with a small amount of isopropyl acetate (50 ml), and dried under reduced pressure to give Form-III crystal of Selexipag [Yield: 29.0 g, 79.0%; Mp: 138.0°C; HPLC Purity: 98.97%].
U.S. Patent No. 10,188,648 (hereinafter referred to as the US’648 patent), assigned to Teva Pharmaceuticals, discloses two additional crystalline forms of Selexipag namely Form IV and Form V, and process for their preparation. The US’648 patent characterizes the crystalline form IV of Selexipag with X-ray powder diffractogram (XRPD), Lattice parameters, FT-IR spectrum, Raman Spectrum, Differential Scanning Calorimetric (DSC) thermogram and Themorgravimetric analysis (TGA) thermogram. The US’648 patent characterizes the crystalline form V of Selexipag with X-ray powder diffractogram (XRPD).
According to the US’648 patent, crystalline Form IV of Selexipag is characterized by an X-ray powder diffraction spectrum having XRPD 2-theta peaks at about 4.4, 6.6, 12.0, 16.3 and 21.1 ± 0.2 degrees; and the crystalline Form V of Selexipag is characterized by an X-ray powder diffraction spectrum having XRPD 2-theta peaks at about 3.8, 11.5, 13.0, 17.9, 20.7, 21.1, 22.4, 22.7, 24.7 and 27.0 ± 0.2 degrees.
Further, according to the US’648 patent, crystalline Form IV of Selexipag is characterized by the following lattice parameters: a = 41.231 Å, b = 14.486 Å, c = 8.863 Å, cell volume = 5393.47 Å3; Symmetry cell setting = orthorhombic; and symmetry space group name: Pccn. Crystalline Form IV of Selexipag is further characterized by and FTIR spectrum having main bands at about 3059, 3025, 2980, 2956, 2876, 2711, 1722, 1600, 1583, 1566, 1514, 1470, 1444, 1401, 1365, 1344, 1325, 1298, 1265, 1235, 1180, 1153, 1111, 1073, 1060, 1027, 1008, 997, 975, 946, 915, 873, 803, 770, 756, 699, 629, 586, 527, 510, 496 and 460 ± 1 cm-1 and DSC thermogram having a melting peak at 93±4°C.
However, the processes described in the aforementioned prior art have failed to consistently produce highly pure crystalline Form I and crystalline Form III of Selexipag essentially free of other polymorphic forms. The prior art processes suffer from several disadvantages such as lack of reproducibility, low purity and low quality of the product. The main drawback of the processes for the preparation of the crystalline forms (Form I, Form II and Form III) as described in the US’122 patent is that the purities of the said crystalline forms obtained are very low, for example, the reported purity of the crystal Form-I of Selexipag is only 99.51% measured by HPLC, the reported purity of the crystal Form-II of Selexipag is 99.33% measured by HPLC, and the reported purity of the crystal Form-III of Selexipag is 98.97% measured by HPLC.
Hence, a need still remains for simple, cost effective, consistently reproducible and industrially advantageous processes for preparing highly pure crystalline Form I and crystalline Form III of Selexipag.

SUMMARY OF THE INVENTION
Provided herein are commercially viable, consistently reproducible and industrially advantageous processes for the preparation of stable and highly pure crystalline forms of Selexipag (Form I and Form III).
In one aspect, disclosed herein is a stable and highly pure crystalline Form III of Selexipag having purity greater than about 99.8%, specifically greater than about 99.9%, and most specifically greater than about 99.95%, as measured by HPLC, which is characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 9.33, 9.66, 16.82, 20.53 and 23.46 ±0.2 degrees substantially in accordance with Figure 1.
In one embodiment, the stable and highly pure crystalline Form III of Selexipag is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 4.65, 8.84, 11.65, 14.00, 15.82, 17.18, 17.84, 19.61, 20.10, 21.56, 24.19 and 25.10 ± 0.2 degrees substantially in accordance with Figure 1.
In another embodiment, the stable and highly pure crystalline Form III of Selexipag is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3026, 2936, 2868, 1723, 1580, 1562, 1513, 1501, 1486, 1460, 1433, 1398, 1388, 1366, 1336, 1247, 1232, 1182, 1162, 1147, 1126, 1074, 1051, 1029, 967, 862, 765, 703 and 692 cm-1 ± 5 cm-1 substantially in accordance with Figure 2.
In another embodiment, the stable and highly pure crystalline Form III of Selexipag is further characterised by a Differential Scanning Calorimetric (DSC) thermogram comprising a sharp endotherm peak at about 138.11°C substantially in accordance with Figure 3.
The highly pure crystalline Form III of Selexipag is consistently reproducible and it does not have the tendency to convert to other forms and found to be more stable.
The present inventors have surprisingly and unexpectedly found that highly pure crystalline Form III of Selexipag essentially free of other crystalline forms can be produced by a novel, consistently reproducible, industrially advantageous and commercially viable process which comprises: (a) providing a suspension of Selexipag in an alcohol solvent, preferably ethanol, at room temperature; (b) heating the suspension obtained in step-(a) at a temperature of about 60ºC to the reflux temperature of the solvent used to produce a clear solution; (c) allowing the solution obtained in step-(b) to cool slowly to room temperature; (d) cooling the resulting solution obtained in step-(c) further to below about 20ºC, preferably about 5-10ºC; and (e) collecting the highly pure crystalline Form III of Selexipag essentially free of other crystalline forms obtained in step-(d).
In one embodiment, the highly pure crystalline Form III of Selexipag obtained by the processes disclosed herein is essentially free from other crystalline forms of Selexipag detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The term “highly pure crystalline Form III of Selexipag essentially free of other crystalline forms” means that no other polymorphic forms of Selexipag can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Selexipag” is intended to mean the polymorphic forms of Selexipag other than crystalline Form III.
In another aspect, provided also herein is a novel, cost effective and consistently reproducible process for the preparation of highly pure crystalline Form III of Selexipag essentially free of other crystalline forms.
The highly pure crystalline Form III of Selexipag obtained by the process disclosed herein has a purity of greater than about 99.8%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure crystalline Form III of Selexipag obtained by the processes disclosed herein is about 99.8% to about 99.99% as measured by HPLC.
In another aspect, disclosed herein is a stable and highly pure crystalline Form I of Selexipag having purity greater than about 99.8%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC, which is characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 9.39, 9.79, 15.56, 17.24, 18.93, 19.40 and 22.93 ± 0.2 degrees substantially in accordance with Figure 4.
In one embodiment, the stable and highly pure crystalline Form I of Selexipag is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 4.70, 8.64, 11.38, 14.13, 15.22, 16.85, 17.24, 17.97, 19.71, 20.26, 21.59, 23.78, 25.10 and 26.09 ± 0.2 degrees substantially in accordance with Figure 4.
In another embodiment, the stable and highly pure crystalline Form I of Selexipag is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3027, 2936, 2865,1731, 1578, 1561, 1513, 1500, 1483, 1445, 1431, 1400, 1388, 1366, 1335, 1318, 1251, 1231, 1181, 1160, 1123, 1046, 1029, 970, 928, 890, 861, 765, 703 and 692 cm-1 ± 5 cm-1 substantially in accordance with Figure 5.
In another embodiment, the stable and highly pure crystalline Form I of Selexipag is further characterised by a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 139.35ºC substantially in accordance with Figure 6.
The crystalline Form I of Selexipag is consistently reproducible does not have the tendency to convert to other forms and found to be thermally more stable.
The present inventors also found that highly pure crystalline Form I of Selexipag essentially free of other crystalline forms can be produced by an improved, consistently reproducible, industrially advantageous and commercially viable process which comprises: (a) providing a suspension of Selexipag in an alcohol solvent, preferably ethanol, at room temperature; (b) heating the suspension obtained in step-(a) at reflux temperature to produce a clear solution; and (c) substantially removing the solvent from the solution obtained in step-(b) to produce highly pure crystalline Form I of Selexipag essentially free of other crystalline forms.
In one embodiment, the crystalline Form I of Selexipag obtained by the processes disclosed herein is essentially free from other crystalline forms of Selexipag detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The term “crystalline Form I of Selexipag essentially free of other crystalline forms” means that no other polymorphic forms of Selexipag can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Selexipag” is intended to mean the polymorphic forms of Selexipag other than crystalline Form I.
The highly pure crystalline Form I of Selexipag obtained by the process disclosed herein has a purity of greater than about 99.8%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure crystalline Form I of Selexipag obtained by the processes disclosed herein is about 99.8% to about 99.99% as measured by HPLC.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form III of Selexipag essentially free of other crystalline forms as disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form I of Selexipag essentially free of other crystalline forms as disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form III of Selexipag essentially free of other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form I of Selexipag essentially free of other crystalline forms made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form III of Selexipag essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form I of Selexipag essentially free of other crystalline forms made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In another aspect, the highly pure crystalline Form III of Selexipag essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 5 microns to about 150 microns, and most specifically about 10 microns to about 100 microns.
In another aspect, the highly pure crystalline Form I of Selexipag essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 5 microns to about 150 microns, and most specifically about 10 microns to about 100 microns.
The processes for the preparation of highly pure crystalline Forms of Selexipag provided herein have the following advantages:
(i) The process disclosed herein consistently produce the highly pure crystalline Form III of Selexipag essentially free of other crystalline forms with high yield and high purity; and
(ii) The process disclosed herein consistently produces the highly pure crystalline Form I of Selexipag essentially free of other crystalline forms with high yield and high purity.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form III of Selexipag.
Figure 2 is a characteristic infra-red (IR) spectrum of crystalline Form III of Selexipag.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form III of Selexipag.
Figure 4 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form I of Selexipag.
Figure 5 is a characteristic infra-red (IR) spectrum of crystalline Form I of Selexipag.
Figure 6 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form I of Selexipag.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, provided herein is a stable and highly pure crystalline Form III of Selexipag having purity about 99.8% to about 99.99% as measured by HPLC, which is characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 9.33, 9.66, 16.82, 20.53 and 23.46 ±0.2 degrees substantially in accordance with Figure 1.
In one embodiment, the stable and highly pure crystalline Form III of Selexipag is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 4.65, 8.84, 11.65, 14.00, 15.82, 17.18, 17.84, 19.61, 20.10, 21.56, 24.19 and 25.10 ± 0.2 degrees substantially in accordance with Figure 1.
In another embodiment, the stable and highly pure crystalline Form III of Selexipag is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3026, 2936, 2868, 1723, 1580, 1562, 1513, 1501, 1486, 1460, 1433, 1398, 1388, 1366, 1336, 1247, 1232, 1182, 1162, 1147, 1126, 1074, 1051, 1029, 967, 862, 765, 703 and 692 cm-1 ± 5 cm-1 substantially in accordance with Figure 2.
In another embodiment, the stable and highly pure crystalline Form III of Selexipag is further characterised by a Differential Scanning Calorimetric (DSC) thermogram comprising a sharp endotherm peak at about 138.11ºC substantially in accordance with Figure 3.
The highly pure crystalline Form III of Selexipag is consistently reproducible and it does not have the tendency to convert to other forms and found to be more stable.
According to another aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form III of Selexipag comprising:
(a) providing a suspension of Selexipag in an alcohol solvent at room temperature;
(b) heating the suspension obtained in step-(a) at a temperature of above about 60ºC to form a clear solution;
(c) allowing the solution obtained in step-(b) to cool slowly to room temperature;
(d) cooling the resulting solution obtained in step-(c) further to below about 20ºC to cause crystallization; and
(e) collecting the highly pure crystalline Form III of Selexipag essentially free of other crystalline forms obtained in step-(d).
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC, and specifically to a temperature of about 25ºC to about 30ºC.
In one embodiment, the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and mixtures thereof. A most specific alcohol solvent used in step-(a) is ethanol.
Usually, the amount of alcohol solvent employed in step-(a) is about 8 volumes to about 12 volumes, specifically about 9 volumes to about 11 volumes, and most specifically about 10 volumes, with respect to the quantity of Selexipag used.
Step-(a) of providing a suspension of Selexipag includes suspending Selexipag in the alcohol solvent while stirring at temperature room temperature, specifically at a temperature of about 25-30ºC, or obtaining an existing suspension from a previous processing step.
In one embodiment, the Selexipag used as a starting material in step-(a) is having purity less than or equal to about 99.5% as measured by HPLC.
Unless otherwise specified, the Selexipag as used herein as starting material in step-(a) can be obtained by the processes known in the prior art, for example, as per the processes described in the US 7,205,302B2, and Indian Patent Application No. IN202041010268.
In one embodiment, the suspension in step-(b) is heated while stirring at a temperature of about 60ºC to the reflux temperature of the solvent used for at least 5 minutes, and more specifically at the reflux temperature of the solvent used for about 10 minutes to about 2 hours to form a clear solution.
In one embodiment, the solution obtained in step-(b) is optionally subjected to carbon treatment. The carbon treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of about 50ºC to the reflux temperature of the solvent used for at least 5 minutes, specifically for about 10 minutes to about 2 hours, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Selexipag by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In another embodiment, the solution in step-(c) is cooled to a temperature of about 25ºC to about 30ºC for about 20 minutes to 8 hours, and most specifically for about 1 hour to about 3 hours.
In another embodiment, the resulting solution in step-(d) is cooled to a temperature of below about 15ºC while stirring for at least 10 minutes, specifically at a temperature of about 0ºC to about 15ºC for about 20 minutes to 5 hours, and most specifically at a temperature of about 5ºC to about 10ºC for about 30 minutes to about 3 hours.
The collection of the highly pure crystalline Form III of Selexipag in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
The highly pure crystalline Form III of Selexipag obtained by the process described herein is found to be more stable.
The highly pure crystalline Form III of Selexipag obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 40°C to about 85°C and most preferably at about 60°C to about 70°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 25 hours, and more preferably about 4 hours to 15 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
The purity of the highly pure crystalline Form III of Selexipag obtained by the processes disclosed herein is, for example, about 99.8% to about 99.99% as measured by HPLC.
The stable and highly pure crystalline Form III of Selexipag obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The stable and highly pure crystalline Form III of Selexipag obtained by the process disclosed herein exhibits properties making it suitable for formulating Selexipag.
Further encompassed herein is the use of the stable and highly pure crystalline Form III of Selexipag obtained by the process disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of stable and highly pure crystalline Form III of Selexipag obtained by the processes disclosed herein is selected from a solid dosage forms and liquid dosage formulations.
In one embodiment, the stable and highly pure crystalline Form III of Selexipag obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 5 microns to about 150 microns, and most specifically about 10 microns to about 100 microns.
In another embodiment, the particle sizes of the stable and highly pure crystalline Form III of Selexipag obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
According to another aspect, provided herein is a stable and highly pure crystalline Form I of Selexipag having purity about 99.8% to about 99.99% as measured by HPLC, which is characterized by an X-ray powder diffraction (XPRD) pattern comprising 2-theta peaks at about 9.39, 9.79, 15.56, 17.24, 18.93, 19.40 and 22.93 ± 0.2 degrees substantially in accordance with Figure 4.
In one embodiment, the stable and highly pure crystalline Form I of Selexipag is further characterized by an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 4.70, 8.64, 11.38, 14.13, 15.22, 16.85, 17.24, 17.97, 19.71, 20.26, 21.59, 23.78, 25.10 and 26.09 ± 0.2 degrees substantially in accordance with Figure 4.
In another embodiment, the stable and highly pure crystalline Form I of Selexipag is further characterised by an infrared (FT-IR) spectrum comprising one or more main bands at about 3027, 2936, 2865,1731, 1578, 1561, 1513, 1500, 1483, 1445, 1431, 1400, 1388, 1366, 1335, 1318, 1251, 1231, 1181, 1160, 1123, 1046, 1029, 970, 928, 890, 861, 765, 703 and 692 cm-1 ± 5 cm-1 substantially in accordance with Figure 5.
In another embodiment, the stable and highly pure crystalline Form I of Selexipag is further characterised by a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 139.35ºC substantially in accordance with Figure 6.
The highly pure crystalline Form I of Selexipag is consistently reproducible and it does not have the tendency to convert to other forms and found to be more stable.
According to another aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form I of Selexipag comprising:
(a) providing a suspension of Selexipag in an alcohol solvent at room temperature;
(b) heating the suspension obtained in step-(a) at a temperature of above about 60ºC to form a clear solution; and
(c) substantially removing the solvent from the solution obtained in step-(b) to produce highly pure crystalline Form I of Selexipag essentially free of other crystalline forms.
In one embodiment, the alcohol solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and mixtures thereof. A most specific solvent used in step-(a) is ethanol.
Usually, the amount of alcohol solvent employed in step-(a) is about 8 volumes to about 12 volumes, and most specifically about 9 volumes to about 11 volumes with respect to the quantity of Selexipag used.
Step-(a) of providing a suspension of Selexipag includes suspending Selexipag in the alcohol solvent while stirring at temperature room temperature, specifically at a temperature of about 25-30ºC, or obtaining an existing suspension from a previous processing step.
In one embodiment, the Selexipag used as a starting material in step-(a) is having purity less than or equal to about 99.5% as measured by HPLC.
Unless otherwise specified, the Selexipag as used herein as starting material in step-(a) can be obtained by the processes known in the prior art, for example, as per the processes described in the US 7,205,302B2, and Indian Patent Application No. IN202041010268.
In one embodiment, the suspension in step-(b) is heated while stirring at a temperature of about 60ºC to the reflux temperature of the solvent used for at least 5 minutes, and more specifically at the reflux temperature of the solvent used for about 10 minutes to about 2 hours to form a clear solution.
In one embodiment, the solution obtained in step-(b) is optionally subjected to carbon treatment. The carbon treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of about 50ºC to the reflux temperature of the solvent used for at least 5 minutes, specifically for about 10 minutes to about 2 hours, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Selexipag by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
Removal of solvent in step-(c) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere to obtain stable and highly pure crystalline Form I of Selexipag.
In one embodiment, the removal of solvent in step-(c) is carried out by distillation. The distillation process can be performed at atmospheric pressure or at reduced pressure.
Specifically, the distillation process is performed at reduced pressure. In one embodiment, the solvent is removed at a pressure of about 760 mm Hg or less, specifically at about 400 mm Hg or less, more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.
In a preferred embodiment, the distillation process is performed under reduced pressure and at a temperature of about 50ºC to about 120ºC, and most specifically at a temperature of about 60ºC to about 90ºC.
The highly pure crystalline Form I of Selexipag obtained by the process described herein is found to be more stable.
The highly pure crystalline Form I of Selexipag obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 40ºC to about 85ºC and most preferably at about 60ºC to about 70ºC. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 25 hours, and more preferably about 4 hours to 15 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
The purity of the highly pure crystalline Form I of Selexipag obtained by the processes disclosed herein is, for example, about 99.8% to about 99.99% as measured by HPLC.
Further encompassed herein is the use of the stable and highly pure crystalline Form I of Selexipag obtained by the process disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of stable and highly pure crystalline Form I of Selexipag obtained by the processes disclosed herein is selected from a solid dosage forms and liquid dosage formulations.
In one embodiment, the stable and highly pure crystalline Form I of Selexipag obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 5 microns to about 150 microns, and most specifically about 10 microns to about 100 microns.
In another embodiment, the particle sizes of the stable and highly pure crystalline Form I of Selexipag obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there is provided a pharmaceutical composition comprising stable and highly pure crystalline Form III of Selexipag obtained by the process disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining the stable and highly pure crystalline Form III of Selexipag obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a pharmaceutical composition comprising stable and highly pure crystalline Form I of Selexipag obtained by the process disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining the stable and highly pure crystalline Form I of Selexipag obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form III of Selexipag or highly pure crystalline Form I of Selexipag obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, parenteral, ophthalmic, or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, suspensions, powders, and the like.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650 cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 200°C.
Particle Size Method of Analysis (PSD):
Particle Size Distribution (PSD) is determined by laser diffraction in a Malvern Mastersizer 2000 (Ver. 5.60) equipment or its equivalent under the following conditions: Accessory Name = Scirocco 2000; Dispersant = Dry dispersion; Dispersant Refractive Index = 1; Absorption = 1; Obscuration limit = 2.72; Measurement time = 10 seconds; Background time = 10 seconds.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = X-Bridge C18, (150 × 4.6) mm, 3.5 µm; Detector wavelength = 298 nm; Flow Rate = 1.0 ml/minute; Injection volume = 20 µL; Oven temperature = 40°C; Run time = 50 minutes; Diluent = Acetonitrile: water (80:20); Elution = Gradient; and Sample Concentration: 0.4 mg/ml.
Mobile Phase-A: buffer
Mobile Phase-B: Methanol.
The following example is given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of pure crystalline Form III of Selexipag
Ethanol (440 ml) was added to crude Selexipag (40 g) at 25-30°C, the resulting suspension was heated to reflux temperature (75-80°C) and then stirred for 5-10 minutes at the same temperature. The resulting hot solution was allowed to cool slowly to 25-30°C for 1 hour 30 minutes. The resulting mass was further cooled to 5-10°C for 1 hour and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with ethanol (40 ml) and then dried the material at 60-65°C for 4 to 5 hours to produce 38 g of pure crystalline Form III of Selexipag [Purity by HPLC: 99.9%].

Example 2
Preparation of pure crystalline Form I of Selexipag
Ethanol (330 ml) was added to crude Selexipag (30 g) at 25-30°C and then stirred for 5 to 10 minutes. The resulting suspension was heated to reflux temperature (75-80°C) and then stirred for 10 to 15 minutes at the same temperature to form a clear solution. The resulting solution was distilled under vacuum to remove the solvent and the resulting solid was dried at 60-65°C for 4 to 5 hours to produce 29 g of pure crystalline Form I of Selexipag [Purity by HPLC: 99.9%].
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.