Crystalline forms of aprocitentan
Novel crystalline forms of Aprocitentan, prepared via solvent-based crystallization, address stability and solubility issues, enhancing the drug's therapeutic potential as an endothelin receptor inhibitor.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- APITORIA PHARMA PTE LTD
- Filing Date
- 2025-12-12
- Publication Date
- 2026-06-18
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Abstract
Description
[0001] CRYSTALLINE FORMS OF APROCITENTAN
[0002] FIELD OF THE INVENTION
[0003] The present invention relates to crystalline forms of Aprocitentan, processes for the preparation thereof, and pharmaceutical composition thereof.
[0004] BACKGROUND OF THE INVENTION
[0005] Aprocitentan, also known under the name ACT-132577, is an endothelin receptor inhibitor and useful as endothelin receptor antagonist for treatment of endothelin related diseases. The chemical name of Aprocitentan is N-[5-(4- bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl) oxy]ethoxy]-4-pyrimidinyl]- sulfamide. Aprocitentan can be represented by the following chemical structure according to Formula (I).
[0006] Formula I
[0007] Aprocitentan and its preparation are disclosed in US 8,324,232. The US ‘232 patent also discloses crystallization of Aprocitentan from dichloromethane to obtain white crystalline powder.
[0008] US 9,938,244 discloses Variant I, Variant II, Variant III, Variant IV, Variant V, Variant VI and Variant VII of Aprocitentan and process for preparation thereof.
[0009] US 10,919,881 discloses Aprocitentan crystalline forms Form A, Form B, Form C, Form D, Form E, Form J, Form K and Form L. Further, this patent also describes the method of making these polymorphic forms. US 20230167090 discloses co-crystal of crystalline forms Form Pl & Form P2 of Aprocitentan: piperazine, co-crystal of crystalline Aprocitentan: methanesulfonic acid, anhydrous form of crystalline Aprocitentan: ethane sulfonic acid. This patent further discloses Aprocitentan crystalline Form T9, Form T10, Form T12, and Aprocitentan amorphous form and method of making thereof.
[0010] WO 2024140425 Al discloses Aprocitentan crystalline Form CSVI and method of making thereof. Also, CN 112679441 A discloses Aprocitentan crystalline Form I, Form II, Form III, Form IV, Form V & Form VI and method of making thereof.
[0011] Polymorphism, the phenomenon where a substance can exist in multiple crystalline forms, is a characteristic of certain molecules and these crystalline forms are known to exhibit different physical and chemical properties like stability, solubility and bioavailability. Therefore, for this reason, the inventors of the present application studied and identified new crystalline forms for Aprocitentan, which have improved physicochemical properties and thermodynamically stable.
[0012] OBJECTIVE OF THE INVENTION
[0013] The objective of the present invention is to provide novel crystalline forms of Aprocitentan, the process for preparing thereof, and pharmaceutical composition thereof.
[0014] SUMMARY OF THE INVENTION
[0015] In an aspect of the present invention provides crystalline forms Form APT-1, Form APT-2, Form APT-3, Form APT-4, Form APT-5 and Form APT-6 of Aprocitentan. In an embodiment, the present invention provides Aprocitentan Form APT-1 characterized by PXRD pattern comprising two or more peaks at about 9.4; 14.1; 14.9; 18.3 and 20.5 ± 0.2° 26.
[0016] In another embodiment, the present invention provides Aprocitentan Form APT-2 characterized by PXRD pattern comprising two or more peaks at about 8.1; 17.1; 18.3; 21.9 and 27.6 ± 0.2° 29.
[0017] In another embodiment, the present invention provides Aprocitentan Form APT-3 characterized by PXRD pattern comprising two or more peaks at about 7.8; 12.4; 14.9; 19.7 and 21.5 ± 0.2° 26.
[0018] In another embodiment, the present invention provides Aprocitentan Form APT-4 characterized by PXRD pattern comprising two or more peaks at about 11.0; 17.3; 21.7; 24.1 and 29.8 ± 0.2° 29.
[0019] In another embodiment, the present invention provides Aprocitentan Form APT-5 characterized by PXRD pattern comprising two or more peaks at about 6.7; 15.2; 16.2; 19.2 and 20.7 ± 0.2° 26.
[0020] In another embodiment, the present invention provides Aprocitentan Form APT-6 characterized by PXRD pattern comprising two or more peaks at about 10.8; 14.9; 15.9; 21.0 and 26.5 ± 0.2° 29.
[0021] In another aspect of the present invention provides a process for the preparation of Aprocitentan Form APT-1 comprising: a) providing a solution or slurry of Aprocitentan in dimethyl sulfoxide (DMSO); b) adding the solution of step (a) to Isopropyl acetate or methyl tertiary butyl ether (MTBE); and c) isolating Aprocitentan Form APT - 1. In another aspect of the present invention provides a process for the preparation of crystalline form Aprocitentan Form APT-2 comprising: a) providing a solution of Aprocitentan in dimethyl acetamide (DMA); b) adding the solution of step (a) to Diisopropyl ether; and c) isolating Aprocitentan Form APT-2.
[0022] In another aspect of the present invention provides a process for the preparation of crystalline form Aprocitentan Form APT-3 comprising: a) providing a solution of Aprocitentan in acetone; b) removing the solvent from the solution of step (a); c) adding the reaction mixture to Di isopropyl ether; and d) isolating Aprocitentan Form APT-3.
[0023] In another aspect of the present invention provides a process for the preparation of crystalline form Aprocitentan Form APT-4 comprising: a) providing a solution of Aprocitentan in acetone; b) removing the solvent from the solution of step (a); c) adding the reaction mixture of step b) to toluene; and d) isolating Aprocitentan Form APT-4.
[0024] In another aspect of the present invention provides a process for the preparation of crystalline form Aprocitentan Form APT-5 comprising: a) providing a solution of Aprocitentan in cyclohexanone; b) adding the solution of step a) to n-heptane; and c) isolating Aprocitentan Form APT-5.
[0025] In another aspect of the present invention provides a process for the preparation of crystalline form Aprocitentan Form APT-6 comprising: a) providing a solution of Aprocitentan in tetrahydrofuran (THF); b) adding the solution of step a) to n-heptane; and c) isolating Aprocitentan Form APT-6.
[0026] BRIEF DESCRIPTION OF ABBREVIATIONS AND DEFINITIONS
[0027] BRIEF DESCRIPTION OF THE FIGURES
[0028] Figure 1: PXRD pattern of crystalline form of Aprocitentan Form APT-1.
[0029] Figure 2: PXRD pattern of crystalline form of Aprocitentan Form APT-2.
[0030] Figure 3: PXRD pattern of crystalline form of Aprocitentan Form APT-3.
[0031] Figure 4: PXRD pattern of crystalline form of Aprocitentan Form APT-4.
[0032] Figure 5: PXRD pattern of crystalline form of Aprocitentan Form APT-5.
[0033] Figure 6: PXRD pattern of crystalline form of Aprocitentan Form APT-6.
[0034] Figure 7: DSC curve of crystalline form of Aprocitentan Form APT-1.
[0035] Figure 8: TGA curve of crystalline form of Aprocitentan Form APT-1.
[0036] Figure 9: Single crystal diagram of Aprocitentan Form APT-1.
[0037] DETAILED DESCRIPTION OF THE INVENTION
[0038] The present invention relates to crystalline forms of Aprocitentan, a process for preparation thereof, and pharmaceutical composition thereof.
[0039] In an aspect of the present invention provides crystalline forms Form APT-1, Form APT-2, Form APT-3, Form APT-4, Form APT-5 and Form APT-6 of Aprocitentan.
[0040] In an embodiment, the present invention provides Aprocitentan Form APT-1 characterized by PXRD pattern comprising two or more peaks at about 9.4, 14.1, 14.9, 18.3 and 20.5 ± 0.2° 26. Aprocitentan Form APT-1 further comprising PXRD peaks at 11.1, 21.0, 21.5, 24.5 and 25.2 ± 0.2° 29. The process for the preparation of crystalline form Aprocitentan Form APT-1 comprising: a) providing a solution of Aprocitentan in dimethyl sulfoxide (DMSO); b) adding the solution of step (a) to Isopropyl acetate or methyl tertiary butyl ether (MTBE); and c) isolating Aprocitentan Form APT - 1.
[0041] The process for preparing Form APT-1 according to the present invention comprises dissolution of Aprocitentan in DMSO at an elevated temperature or at reflux to obtain a clear solution, addition of this solution to isopropyl acetate or methyl tertiary butyl ether (MTBE) at an ambient temperature or vice-versa, slurry of the mixture for a suitable period of time and then isolation of the Form APT-1 by the methods known in the art, for example, fdtration, decantation and centrifugation. The isolation includes drying the solid.
[0042] According to the present invention, the Form APT-1 may be DMSO solvate. The Form APT-1 may be characterized by XPRD pattern substantially as illustrated in Figure 1. Further, the Form APT-1 may be characterized by DSC thermogram substantially as illustrated in Figure 7 and TGA substantially as illustrated in Figure 8.
[0043] Further, the X-ray single crystal of the present invention measured on Bruker D8 VENTURE and a PHOTON III C14 detector using SHELXL PLUS software program.
[0044] Further, the Form APT-1 characterized by X-ray single crystal having the following characteristics:
[0045] Crystal system: Monoclinic and Space Group: P2i / c
[0046] Unit cell dimensions: a = 18.773(3) A; b = 14.806(2) A; c = 8.8393(16) A a = 90°; p = 90.520(6)°; y = 90°.
[0047] Volume: 2456.8(7) A3 In another embodiment, the present invention provides Aprocitentan Form APT-2 characterized by PXRD pattern comprising two or more peaks at about 8.1, 17.1, 18.3, 21.9 and 27.6 ± 0.2° 26. Aprocitentan Form APT-2 further comprising PXRD peaks at 15.6, 17.8, 23.7, 24.6 and 25.3 ± 0.2° 26.
[0048] The process for the preparation of crystalline form Aprocitentan Form APT-2 comprising: a) providing a solution of Aprocitentan in dimethyl acetamide (DMA); b) adding the solution of step (a) to Diisopropyl ether; and c) isolating Aprocitentan Form APT-2.
[0049] The process for preparing Form APT-2 according to the present invention comprises dissolution of Aprocitentan in DMA at an elevated temperature or at reflux to obtain a clear solution, addition of this solution to diisopropylether at an ambient temperature or vice-versa, slurry the mixture for a suitable period of time and then isolation of the Form APT-2 by the methods known in the art, for example, filtration, decantation and centrifugation.
[0050] According to the present invention, the crystalline Form APT-2 may be DMA solvate of Aprocitentan.
[0051] In another embodiment, the present invention provides Aprocitentan Form APT-3 characterized by PXRD pattern comprising two or more peaks at about 7.8, 12.4, 14.9, 19.7 and 21.5 ± 0.2° 26. Aprocitentan Form APT-3 further comprising PXRD peaks at 8.7, 11.2, 15.6, 17.4 and 22.6 ± 0.2° 26.
[0052] The process for the preparation of crystalline form Aprocitentan Form APT-3 comprising: a) providing a solution of Aprocitentan in acetone; b) removing the solvent from the solution of step (a); c) adding the reaction mixture to Di isopropyl ether; and d) isolating Aprocitentan Form APT-3.
[0053] The process for preparing Form APT-3 according to the present invention comprises dissolution of Aprocitentan in acetone at an elevated temperature or at reflux to obtain a clear solution, removal of the solvent from the solution as slow mode or fast mode, addition of this mixture or solid to diisopropylether at less than 10°C or less than 0°C, slurry the mixture for a suitable period of time and then isolated the Form APT-3 by the methods known in the art, for example, fdtration, decantation and centrifugation. The addition encompasses charging of diisopropylether to the reaction mixture or solid.
[0054] According to the present invention, the crystalline Form APT-3 may be diisopropylether solvate of Aprocitentan.
[0055] In another embodiment, the present invention provides Aprocitentan Form APT-4 characterized by PXRD pattern comprising two or more peaks at about 11.0, 17.3, 21.7, 24.1 and 29.8 ± 0.2° 29. Aprocitentan Form APT-4 further comprising peaks at 12.1, 18.7, 21.0, 22.8 and 26.0 ± 0.2° 28.
[0056] The process for the preparation of crystalline form Aprocitentan Form APT-4 comprising: a) providing a solution of Aprocitentan in acetone; b) removing the solvent from the solution of step (a); c) adding the reaction mixture of step b) to toluene; and d) isolating Aprocitentan Form APT-4.
[0057] The process for preparing Form APT-4 according to the present invention comprises dissolution of Aprocitentan in acetone at an elevated temperature or at reflux to obtain a clear solution, removal of the solvent from the solution as slow mode or fast mode, addition of this mixture or solid to toluene at less than 10°C or less than 0°C, slurry the mixture for a suitable period of time and then isolated the Form APT-4 by the methods known in the art, for example, fdtration, decantation and centrifugation. The addition encompasses charging of toluene to the reaction mixture or solid.
[0058] In another embodiment, the present invention provides Aprocitentan Form APT-5 characterized by PXRD pattern comprising two or more peaks at about 6.7, 15.2, 16.2, 19.2 and 20.7 ± 0.2° 29. Aprocitentan Form APT-5 further comprises PXRD peaks at 10.2, 13.4, 20.1, 21.8 and 26.0 ± 0.2°29.
[0059] The process for the preparation of crystalline form Aprocitentan Form APT-5 comprising: a) providing a solution of Aprocitentan in cyclohexanone; b) adding the solution of step a) to n-heptane; and c) isolating Aprocitentan Form APT-5.
[0060] The process for preparing Form APT-5 according to the present invention comprises dissolution of Aprocitentan in cyclohexanone at an ambient temperature or at reflux to obtain a clear solution, addition of this solution to n- heptane at less than 10°C or less than 0°C, slurry the mixture for a suitable period of time and then isolated the Form APT-5 by the methods known in the art, for example, filtration, decantation and centrifugation. The addition encompasses charging of toluene to the reaction mixture or solid.
[0061] In another embodiment, the present invention provides Aprocitentan Form APT-6 characterized by PXRD pattern comprising two or more peaks at about 10.8, 14.9, 15.9, 21.0 and 26.5 ± 0.2° 26. Aprocitentan Form APT-6 further comprises PXRD peaks at 6.6, 10.2, 13.3 and 18.4 ± O.2°20.
[0062] The process for the preparation of crystalline form Aprocitentan Form APT-6 comprising: a) providing a solution of Aprocitentan in tetrahydrofuran (THF); b) mixing the solution of step a) to n-heptane; and c) isolating Aprocitentan Form APT-6.
[0063] The process for preparing Form APT-6 according to the present invention comprises dissolution of Aprocitentan in THF at an ambient temperature to obtain a clear solution, addition of this solution to n-heptane at less than 10°C or less than 0°C, slurry the mixture for a suitable period of time and then isolated the Form APT-6 by the methods known in the art, for example, fdtration, decantation and centrifugation. The addition encompasses charging of toluene to the reaction mixture or solid.
[0064] According to the present invention, the solution that stated above can be prepared at ambient temperature or elevated temperature. For the elevated temperature, the reaction mixture may be dissolved by heating the contents at a temperature of less than 100°C or less than about 50°C or less than 40°C or at reflux temperature of the solvents used. For ambient temperature, the reaction mixture may be dissolved at 20°C to about 35 °C.
[0065] Aprocitentan used for preparing solution can be in crystalline form or amorphous form or semi-solid or oily liquid. The obtained solution optionally fdtered to remove undissolved particles, if any, suitably by fdtration, centrifugation, decantation, and any other known techniques. The solution can be fdtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the fdtration apparatus may need to be preheated to avoid premature crystallization.
[0066] According to the present invention, the removal of solvent may be carried out by distillation, open-dish evaporation, or reduced pressure evaporation. The addition of the reaction suspension or solution into another solvent or mixtures thereof may be performed at a temperature of less than about 100°C or less than about 50° C or less than about 40°C or less than 30°C or less than 20°C or less than 10°C or less than 0°C.
[0067] The slurry used in the present invention may be performed for a period of about 60 hours or for about 50 hours or about 40 hours or about 30 hours or about 20 hours or less than 10 hours to obtain desired crystalline form and to enhance precipitation of the solid. The slurry is performed at a temperature of 20 °C to about 100°C or less than 50° C or less than 40°C or less than 30°C or less than 20°C or less than 0°C.
[0068] The isolated crystalline forms of the present invention are dried. The drying may be suitably carried out using equipment such as a tray dryer, suck dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than about 100°C, less than about 60°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve the desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
[0069] The term "about" when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1. The ratio of the solvent system is in the range of 1: 1 to 1: 10. The X-ray powder diffraction paterns of the present invention are measured by Bruker D8 advance-Eco with lynex detector equipped with Cu source (Z=I .5 A). Before analysis, the small quantity of sample was gently grounded using Motor-pastel to prepare uniform sample and then the sample placed directly on low background silicon holder with cavity and pressed with glass slide to make flat surface.
[0070] Scanning parameters:
[0071] Scan type: Continuous scan
[0072] Scan range: 3-40 deg.
[0073] Time / step: 0.8 sec
[0074] Step size: 0.05°
[0075] Divergence slit: V20
[0076] Rotation: 30 rpm
[0077] The crystalline form of the present invention can be used for the preparation of amorphous form, solid dispersions thereof, and pharmaceutical compositions thereof.
[0078] Suitable pharmaceutically acceptable excipients, which may be used include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystal line cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC -Phthalate, HPMC- AS, HPMC- 15 CPS, and the like.
[0079] 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
[0080] Example 1: Preparation of crystalline Aprocitentan Form-APT-1
[0081] Aprocitentan (2.0gm) was dissolved in dimethyl sulfoxide (DMSO) (5ml) at 50- 60°C to obtain a clear solution. The clear solution was added to isopropyl acetate at RT and stirred for 18-20 hours to obtain the solid. The solid was filtered and suck dried for 5-10 minutes and then dried at 70°C for 24 hours to obtain Aprocitentan Form-APT-1.
[0082] PXRD pattern showed as Figure 1. DSC showed Sharp endothermic peak at about 120.35°C and TGA showed a loss of 8.64% up to 200°C.
[0083] Stability of crystalline Aprocitentan Form-APT-1 under different conditions tabulated as below:
[0084] Example 2: Preparation of crystalline Aprocitentan Form-APT-1
[0085] Aprocitentan (3.0gm) was dissolved in dimethyl sulfoxide (DMSO) (7.5 ml) at 30-40°C to obtain a clear solution which was added to methyl tertiary butyl ether (MTBE) at 2-5 °C followed by solution was seeded with Aprocitentan Form -APT 1 and solution was stirred for 4-5 hours to obtain solid. The solid was fdtered and suck dried for 10 minutes and then further dried at 40°C for 18 hours to obtain Aprocitentan Form-APT-1.
[0086] Example 3: Preparation of crystalline Aprocitentan Form-APT-2
[0087] Aprocitentan (250mg) was dissolved in dimethyl acetamide (0.5ml) at 50-60°C to obtain a clear solution. This was added to diisopropylether at RT and stirred for 15-20 hours and then filtered the solid. The solid obtained was suck dried for 5- lOmins and dried at 70°C for 24 hours to obtain Aprocitentan Form-APT-2. PXRD pattern showed as Figure 2. Example 4: Preparation of crystalline Aprocitentan Form-APT-3
[0088] Aprocitentan (l.Ogm) was dissolved in Acetone (70.0ml) at 50-60°C to obtain a clear solution. The total solvent was distilled off under vacuum at 50°C and dried for 1 hour at 50°C under vacuum. The solid obtained was added to pre-cool Diisopropylether 30ml at -5°C to -8°C and stirred for 18-20 hours at -5 to -8°C and then fdtered. The solid obtained was suck dried for 5-10mins and then dried at 40°C for 4-6hrs to obtain Aprocitentan Form-APT-3. PXRD pattern showed as Figure 3.
[0089] Example 5: Preparation of Aprocitentan Form-APT-4:
[0090] Aprocitentan (300mg) was dissolved in Acetone (30ml) at 50-60°C to obtain a clear solution. The total solvent was distilled off at 50°C under vacuum and dried for 1 hour at 50°C under vacuum. The obtained solid was added to pre-cooled toluene 4ml at -5 °C to -10°C and stirred for 15-20 hours at -5 °C to -10°C and then fdtered. The solid obtained was suck dried for 5-10mins and then dried at 40°C for 4-6 hours to obtain Aprocitentan Form-APT-4. PXRD pattern showed as Figure 4.
[0091] Example 6: Preparation of Aprocitentan Form-APT-5:
[0092] Aprocitentan (500mg) was dissolved in cyclohexanone (4.0ml) at 30°C to obtain a particle free clear solution which was added to n-heptane 10ml at 1°C - 3°C and stirred for 18-20 hours. The obtained suspension was fdtered and suck dried for 5- lOmins and further dried at 70°C for 18 hours under vacuum to obtain Aprocitentan Form-APT-5. PXRD showed as Figure 5.
[0093] Example 7: Preparation of Aprocitentan Form-APT-6:
[0094] Aprocitentan (lOgm) was dissolved in tetrahydrofuran (120.0ml) at 45-50°C to obtain a particle free clear solution which was added to pre-cooled n-heptane 240ml at -5°C to -7°C and stirred for 30min to 60mins. The solid obtained was suck dried for 5-10mins and further dried at at 50°C for 2 hours to obtain Aprocitentan Form-APT-6. PXRD pattern showed as Figure 6.
Claims
WE CLAIM:
1. A crystalline form of Aprocitentan, selected from: crystalline Form APT-1 of Aprocitentan, characterized by PXRD pattern comprising two or more peaks at about 9.4; 14.1; 14.9; 18.3 and 20.5 ± 0.2° 20. crystalline Form APT-3 of Aprocitentan, characterized by PXRD pattern comprising two or more peaks at about 7.8; 12.4; 14.9; 19.7 and 21.5 ± 0.2° 29. crystalline Form APT-4 of Aprocitentan, characterized by PXRD pattern comprising two or more peaks at about 11.0; 17.3; 21.7; 24.1 and 29.8 ± 0.2° 29. crystalline Form APT-5 of Aprocitentan, characterized by PXRD pattern comprising two or more peaks at about 6.7; 15.2; 16.2; 19.2 and 20.7 ± 0.2° 29. crystalline Form APT-6 of Aprocitentan, characterized by PXRD pattern comprising two or more peaks at about 10.8; 14.9; 15.9; 21.0 and 26.5 ± 0.2° 29.
2. The crystalline form as claimed in claim 1, wherein the preparation of crystalline Form APT-1 of Aprocitentan comprising: a. providing a solution of Aprocitentan in dimethyl sulfoxide (DMSO); b. adding the solution of step (a) to Isopropyl acetate or methyl tertiary butyl ether (MTBE); and c. isolating crystalline Form APT-1 of Aprocitentan.
3. The crystalline form as claimed in claim 1, wherein the preparation of crystalline Form APT-3 of Aprocitentan comprising: a. providing a solution of Aprocitentan in acetone; b. removing the solvent from the solution of step (a); c. adding the reaction mixture to Di isopropyl ether; and d. isolating crystalline Form APT-3 of Aprocitentan.
4. The crystalline form as claimed in claim 1, wherein the preparation of crystalline Form APT-4 of Aprocitentan comprising: a. providing a solution of Aprocitentan in acetone; b. removing the solvent from the solution of step (a); c. adding the reaction mixture of step b) to toluene; and d. isolating crystalline Form APT-4 of Aprocitentan.
5. The crystalline form as claimed in claim 1, wherein the preparation of crystalline Form APT-5 of Aprocitentan comprising: a. providing a solution of Aprocitentan in cyclohexanone; b. adding the solution of step a) to n-heptane; and c. isolating crystalline Form APT-5 of Aprocitentan.
6. The crystalline form as claimed in claim 1, wherein the preparation of crystalline Form APT-6 of Aprocitentan comprising: a. providing a solution of Aprocitentan in tetrahydrofuran (THF); b. mixing the solution of step a) to n-heptane; and c. isolating crystalline Form APT-6 of Aprocitentan.
7. The crystalline form as claimed in claim 1, wherein the crystalline Form APT-1 of Aprocitentan characterized by single crystal X-ray data comprising:Crystal system: Monoclinic and Space Group: P2i / cUnit cell dimensions: a = 18.773(3) A; b = 14.806(2) A; c = 8.8393(16) A a = 90°; p = 90.520(6)°; y = 90° and Volume: 2456.8(7) A3.
8. The crystalline form as claimed in claim 1, wherein the crystalline Form APT-1 of Aprocitentan characterized by PXRD pattern comprising two or more peaks at about 11.1, 21.0, 21.5, 24.5 and 25.2 ± 0.2° 26.
9. The process as claimed in claim 2, wherein the ratio of the solvent system is in the range of 1 : 1 to 1: 10.
10. Use of the crystalline Aprocitentan of claims 1, for the preparation of pharmaceutical composition in combination with a pharmaceutically acceptable excipient.