Polymorphs of iptacopan hydrochloride

Abstract

The present invention relates to novel polymorphic forms of Iptacopan hydrochloride and preparation thereof. The invention also relates to pharmaceutical composition comprising novel polymorphic forms of Iptacopan hydrochloride and their use in the treatment of paroxysmal nocturnal hemoglobinuria and proteinuria.

Description

[0001] POLYMORPHS OF IPTACOPAN HYDROCHLORIDE

[0002] This is a cognate application of the originally filed Indian patent application no.

[0003] 202521014942 dated February 21, 2025 and Indian patent application no.

[0004] 202521045882 dated May13, 2025.

[0005] TECHNICAL FIELD OF THE INVENTION

[0006] The present invention relates to novel polymorphs of Iptacopan hydrochloride and processes for preparation thereof. The invention also relates to pharmaceutical composition comprising novel polymorphic forms of Iptacopan hydrochloride and their use in the treatment of paroxysmal nocturnal hemoglobinuria and proteinuria.

[0007] BACKGROUND OF INVENTION

[0008] Iptacopan hydrochloride monohydrate is chemically known as (2S,4S)-2-(4-Carboxyphenyl)-4-ethoxy-l-[(5-methoxy-7-methyl-lH-indol-4-yl) methyl] piperidin-1-ium chloride — water (1 / 1).

[0009] Iptacopan hydrochloride monohydrate is represented as shown in Structure-I.

[0010]

[0011] Iptacopan hydrochloride is a small molecule inhibitor of complement factor B (FB) with potential immune modulatory activity. Iptacopan hydrochloride binds toFactor B, which prevents the activity of the AP C3 convertase and the formation of C5 convertase. This prevents the generation of C5a anaphylatoxins and the membrane attack complex, which suppresses inflammation, cell destruction, and excessive complement deposition. Iptacopan hydrochloride is used to treat complement-mediated diseases, such as paroxysmal nocturnal hemoglobinuria (PNH) and IgA nephropathy (IgAN).

[0012] US9682968B2 discloses Iptacopan hydrochloride, process for preparation of Iptacopan hydrochloride, pharmaceutical composition comprising Iptacopan hydrochloride and its use for treatment of the paroxysmal nocturnal hemoglobinuria and proteinuria. Further US ’968 disclose the crystalline form having a powder X-ray diffractogram comprising peaks at 2-Theta angles of 11.6±0.2°, 15.3±0.2°, 16.5±0.2°, 21.0±0.2°. Example 26d of US ’968 discloses the preparation of Iptacopan hydrochloride as a crystalline solid by recrystallization of amorphous material. The crystalline form is referred to as anhydrous Form A.

[0013] US11603363B2 discloses crystalline hydrate form of Iptacopan hydrochloride (Form HB) having a powder X-ray diffractogram comprising peaks at 2-Theta angles of 4.6±0.2°, 9.2±0.2° and 19.1±0.2°. This patent further discloses the process for preparation of Form HB, pharmaceutical composition comprising the crystalline hydrate form of Iptacopan hydrochloride and its use for treatment of the paroxysmal nocturnal hemoglobinuria and proteinuria.

[0014] Developing new polymorphs of the pharmaceutical actives possessing desirable properties such as ease of handling, ease of processing, improved stability, ease of purification provides an opportunity to improve the pharmaceutical activity of the drugs.

[0015] The drug substances can exist in multiple crystalline forms, known as polymorphs, possessing different properties. This difference in the physicochemical properties of the various crystalline solid forms of the API canimpact the key aspects in drug formulation and its performance such as solubility, stability, dissolution rates and bioavailability.

[0016] In view of the same, there remains a scope in the art to provide novel polymorphs of Iptacopan hydrochloride, which are having greater stability, flowability, dissolution properties; thereby increasing the bioavailability as well as to enhance the efficacy of the drug.

[0017] OBJECTIVE OF THE INVENTION

[0018] The primary objective of the present invention is to provide novel polymorphs of Iptacopan Hydrochloride.

[0019] The other objective of the present invention is to provide processes for the preparation of polymorphs of Iptacopan Hydrochloride.

[0020] Another objective of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of novel polymorphs of Iptacopan hydrochloride with pharmaceutically acceptable carrier, diluent or excipients.

[0021] Yet another objective of the present invention is to provide method of treatment of the paroxysmal nocturnal hemoglobinuria and proteinuria, wherein novel polymorphic forms of Iptacopan hydrochloride are useful.

[0022] SUMMARY OF THE INVENTION

[0023] In a first aspect, the present invention provides novel polymorphic forms of Iptacopan hydrochloride, hereinafter referred to as Form Cl, Form C2, Form C3, Form C4, Form C5, Form C6, Form C7 and Form C8.The crystalline nature of novel polymorphic Form Cl, Form C2, Form C3, Form C4, Form C5, Form C6, Form C7 and Form C8 according to the present invention is characterized by X-ray powder diffraction pattern (XRPD) as depicted in Fig 1, Fig 2, Fig 3, Fig 4, Fig 5, Fig 6, Fig 7, Fig 10, Fig 11, Fig 14; Form C7 is characterized by thermogravimetric analysis curve (TGA) as depicted in Fig 8, Fig 12 and Form C7 is further characterized by Differential Scanning Calorimetry (DSC) thermogram as depicted in Fig 9, Fig 13.

[0024] In a second aspect, the present invention relates to processes for preparing novel polymorphic Form Cl, Form C2, Form C3, Form C4, Form C5, Form C6, Form C7 and Form C8 of Iptacopan hydrochloride thereof.

[0025] In a third aspect, the present invention provides a pharmaceutical composition comprising novel polymorphic forms of Iptacopan hydrochloride along with pharmaceutically acceptable carrier, diluent or excipients.

[0026] In a fourth aspect, the present invention is directed to methods of treating and / or preventing paroxysmal nocturnal hemoglobinuria and proteinuria by administering a therapeutically effective amount of novel polymorphic forms of Iptacopan hydrochloride thereof.

[0027] In a fifth aspect, the present invention is directed to the use of novel polymorphic forms of Iptacopan hydrochloride in the manufacture of a medicament for treating and / or preventing paroxysmal nocturnal hemoglobinuria and proteinuria.

[0028] DESCRIPTION OF THE FIGURES

[0029] Figure 1 depicts X-ray powder diffraction spectrum (XRPD) of Iptacopan Hydrochloride Form Cl as per example 1.

[0030] Figure 2 depicts X-ray powder diffraction spectrum (XRPD) of Iptacopan Hydrochloride Form C2 as per example 3.Figure 3 depicts the Powder X-ray Diffraction (PXRD) of Iptacopan hydrochloride Form C3.

[0031] Figure 4 depicts the Powder X-ray Diffraction (PXRD) of Iptacopan hydrochloride Form C4.

[0032] Figure 5 depicts the Powder X-ray Diffraction (PXRD) of Iptacopan hydrochloride Form C5.

[0033] Figure 6 depicts the Powder X-ray Diffraction (PXRD) of Iptacopan hydrochloride Form C6.

[0034] Figure 7 depicts the Powder X-ray Diffraction (PXRD) of Iptacopan hydrochloride Form C7 according to example 10.

[0035] Figure 8 depicts a Thermogravimetric Analysis curve (TGA) of Iptacopan hydrochloride Form C7 according to example 10.

[0036] Figure 9 depicts a Differential Scanning Calorimetry (DSC) thermogram of Iptacopan hydrochloride Form C7 according to example 10.

[0037] Figure 10 depicts the Powder X-ray Diffraction (PXRD) of Iptacopan hydrochloride Form C7 before MTBE slurry according to example 9.

[0038] Figure 11 depicts the Powder X-ray Diffraction (PXRD) of Iptacopan hydrochloride Form C7 after MTBE slurry according to example 9.

[0039] Figure 12 depicts a Thermogravimetric Analysis curve (TGA) of Iptacopan hydrochloride Form C7 according to example 9.

[0040] Figure 13 depicts a Differential Scanning Calorimetry (DSC) thermogram of Iptacopan hydrochloride Form C7 according to example 9.

[0041] Figure 14 depicts the Powder X-ray Diffraction (PXRD) of Iptacopan hydrochloride Form C8.Fig 15 depicts Comparative powder dissolution data of Iptacopan Hydrochloride (C7) vs Form HB (Note: Form HB & Form C7: 200 mg equivalent Iptacopan filled in Size ‘0’ hard gelatin capsule).

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. However, any skilled person will appreciate the extent to which such embodiments could be extrapolated in practice.

[0044] Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

[0045] Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention.

[0046] Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.

[0047] Polymorphs are solid substances that can exist in different crystallographic structures with varying crystal lattice arrangements. Therefore, a solid chemical substance exists in more than one crystalline form. Different polymorphs of onemolecule have distinct physical properties such as X-ray powder diffraction, Differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA), Infrared absorption (IR), Nuclear magnetic resonance spectroscopy etc.

[0048] In an embodiment, the present invention relates to Iptacopan hydrochloride Form Cl.

[0049] In another embodiment, the present invention discloses Iptacopan hydrochloride Form Cl characterized by X-ray powder diffraction pattern (XRPD) with peaks at 9.98, 10.40, 11.53, 16.55, 17.61, 21.05, 23.15 and 25.45 ± 0.2°2θ.

[0050] Iptacopan hydrochloride Form Cl of the present invention is characterized by X-ray diffraction as depicted in Figure 1.

[0051] In an embodiment, the present invention relates to Iptacopan hydrochloride Form C2.

[0052] In another embodiment, the present invention discloses Iptacopan hydrochloride Form C2 characterized by X-ray powder diffraction pattern (XRPD) with peaks at 9.66, 15.93, 18.97, 24.92 and 27.34 ± 0.2°2θ.

[0053] Iptacopan hydrochloride Form C2 of the present invention is characterized by X-ray diffraction as depicted in Figure 2.

[0054] In an embodiment, the present invention relates to Iptacopan hydrochloride polymorph Form C3.

[0055] In another embodiment, the Iptacopan hydrochloride Polymorph Form C3 is characterized by PXRD peaks at 3.94, 7.86, 10.95, 14.56, 17.28. 18.98, 20.075, 25.22 and 27.10 ± 0.2°2θ

[0056] Iptacopan hydrochloride Form C3 of the present invention is characterized by X-ray diffraction as depicted in Figure 3.In yet another embodiment, the present invention relates to Iptacopan hydrochloride polymorph Form C4.

[0057] In another embodiment, the Iptacopan hydrochloride Polymorph Form C4 is characterized by PXRD peaks at 10.49, 11.06, 13.46, 14.57, 17.43, 17.97, 21.37 and 27.05± 0.2°2θ

[0058] Iptacopan hydrochloride Form C4 of the present invention is characterized by X-ray diffraction as depicted in Figure 4.

[0059] In an embodiment, the present invention relates to Iptacopan hydrochloride polymorph Form C5.

[0060] In another embodiment, the Iptacopan hydrochloride Polymorph Form C5 is characterized by PXRD peaks at 10.11, 12.39, 13.05, 15.46, 17.34, 21.06, 23.61, 26.95 and 27.57± 0.2°2θ.

[0061] Iptacopan hydrochloride Form C5 of the present invention is characterized by X-ray diffraction as depicted in Figure 5.

[0062] In another embodiment, the present invention relates to Iptacopan hydrochloride polymorph Form C6.

[0063] In yet another embodiment, the Iptacopan hydrochloride Polymorph Form C6 is characterized by PXRD peaks at 6.88, 9.07, 10.33, 12.49, 13.81, 14.69, 17.93, 23.42 and 25.04± 0.2°2θ.

[0064] Iptacopan hydrochloride Form C6 of the present invention is characterized by X-ray diffraction as depicted in Figure 6.

[0065] In a preferred embodiment, the present invention relates to Iptacopan hydrochloride polymorph Form C7.Accordingly, the Iptacopan hydrochloride Polymorph Form C7 is characterized by PXRD peaks at 7.77, 9.77, 12.09, 15.24, 18.17, 21.04 and 22.74± 0.2°2θ.

[0066] Iptacopan hydrochloride Form C7 of the present invention is characterized by X-ray diffraction as depicted in Figure 7 according to example 10, Figure 10 according to example 9 and Figure 11 according to example 9.

[0067] In another embodiment, the Iptacopan hydrochloride Polymorph Form C7 according to example 10 is characterized by thermogravimetric analysis curve (TGA) with a weight loss of approximately 0.531% at temperature about 150°C.

[0068] Iptacopan hydrochloride Form C7 according to example 10 of the present invention is characterized by thermogravimetric analysis curve (TGA) as depicted in Figure 8.

[0069] In yet another embodiment, the Iptacopan hydrochloride Polymorph Form C7 according to example 10 is characterized by differential scanning calorimetry (DSC) thermogram with an exothermic peak with an onset temperature at about 199.40±10°C and a peak maximum at about 202.79±5°C.

[0070] Iptacopan hydrochloride Form C7 according to example 10 of the present invention is characterized by differential scanning calorimetry (DSC) thermogram as depicted in Figure 9.

[0071] In another embodiment, the Iptacopan hydrochloride Polymorph Form C7 according to example 9 is characterized by thermogravimetric analysis curve (TGA) with a weight loss of approximately 1.652% at temperature about 150°C.

[0072] Iptacopan hydrochloride Form C7 according to example 9 of the present invention is characterized by thermogravimetric analysis curve (TGA) as depicted in Figure 12.In yet another embodiment, the Iptacopan hydrochloride Polymorph Form C7 according to example 9 is characterized by differential scanning calorimetry (DSC) thermogram with an exothermic peak with an onset temperature at about 200.62±10°C and a peak maximum at about 204.91±5°C.

[0073] Iptacopan hydrochloride Form C7 according to example 9 of the present invention is characterized by differential scanning calorimetry (DSC) thermogram as depicted in Figure 13.

[0074] In an embodiment, the present invention relates to Iptacopan hydrochloride polymorph Form C8.

[0075] In another embodiment, the Iptacopan hydrochloride Polymorph Form C8 is characterized by PXRD peaks at 7.92, 10.07, 15.21, 20.24, 21.00 and 25.27± 0.2°2θ.

[0076] Iptacopan hydrochloride Form C8 of the present invention is characterized by X-ray diffraction as depicted in Figure 8.

[0077] In yet another embodiment, the present invention discloses a process for the preparation of Iptacopan hydrochloride Form Cl comprising:

[0078] a. Dissolving Iptacopan hydrochloride in a suitable solvent or mixture of solvents;

[0079] b. Stirring the above mixture; and

[0080] c. Filtering and drying to obtain Iptacopan hydrochloride Form Cl.

[0081] The starting material can be obtained by any method known in art, such as the one described in US9682968B2 which is incorporated herein by reference.

[0082] In an embodiment, suitable solvent used in step a, is selected from but not limited to the group comprising of polar aprotic solvents such as aromatic hydrocarbon, aliphatic hydrocarbon, nitriles, ketones, and such like or mixture thereof.The temperature of the reaction ranges from 0°C to 50°C, preferably 10°C to 40° C, more preferably 15°C to 35°C.

[0083] The reaction mass was stirred for 1 to 30 hours, preferably for 5 to 25 hours.

[0084] The solid obtained was filtered and dried at a temperature ranging from 10°C to 80°C, preferably at 30°C to 60°C for a period ranging from 1 minute to 4 hours, more preferably 30 minutes to 3 hours.

[0085] In an alternate embodiment, Iptacopan hydrochloride Form Cl may be prepared by the process comprising:

[0086] a. Dissolving Iptacopan hydrochloride in a first solvent and concentrating the resultant solution;

[0087] b. Charging the above Iptacopan hydrochloride mass to a second solvent; c. Stirring the reaction mass of step b; and

[0088] d. Filtering and drying to obtain Iptacopan hydrochloride Form Cl.

[0089] In an embodiment, first solvent used in step a, is selected from but not limited to the group comprising of polar or non-polar, protic or aprotic solvents such as aromatic hydrocarbon, aliphatic hydrocarbon, nitriles, ketones, alcohols, acids, water and such like or mixture thereof.

[0090] The temperature of step a. ranges from 10° C to 90° C, preferably 30° C to 70° C, more preferably 40° C to 60° C.

[0091] Second suitable solvent used in step b, is selected from but not limited to the group comprising of polar or non-polar, protic or aprotic solvents such as hydrocarbon, nitriles, ketones, alcohols, acids, water etc. or mixture thereof.

[0092] The reaction mass is stirred for 1 to 30 hours, preferably for 5 to 25 hours.

[0093] The temperature in step c. ranges from 0° C to 50° C, preferably 10° C to 40° C, more preferably 15° C to 35° C.The solid obtained was filtered and dried at a temperature ranging from 10°C to 80°C, preferably at 30°C to 60°C for a period ranging from 1 minute to 4 hours, more preferably 30 minutes to 3 hours.

[0094] In another embodiment, the present invention discloses a process for the preparation of Iptacopan hydrochloride Form C2 comprising:

[0095] a. Dissolving Iptacopan hydrochloride in a suitable solvent followed by cooling;

[0096] b. Stirring the reaction mass;

[0097] c. Filtering and drying to obtain Iptacopan hydrochloride Form C2.

[0098] In an embodiment, the suitable solvent used in step a, is selected from but not limited to the group comprising of polar or non-polar, protic or aprotic solvents such as aromatic hydrocarbon, aliphatic hydrocarbon, nitriles, ketones, alcohols, acids, water etc. or mixture thereof.

[0099] The temperature in step a. ranges from -15°C to 20°C, preferably -10° C to 15° C, more preferably -5°C to 10°C.

[0100] The reaction mass stirred for 1 to 7 hours, preferably for 1 to 5 hours.

[0101] The temperature in step b. ranges from -15°C to 20° C, preferably -10° C to 15° C, more preferably -5°C to 10°C.

[0102] The solid obtained was filtered and dried for a period ranging from 1 minute to 4 hours, preferably 30 minutes to 3 hours.

[0103] In an embodiment, the present invention relates to a process for preparation of Iptacopan hydrochloride Polymorph Form C3 comprising;

[0104] (i) Dissolving or suspending the amorphous Iptacopan hydrochloride in a suitable solvent or solvent mixture and stirring to obtain the wet material;(ii) Filtering and washing the wet material obtained in step (i) and resuspending in a suitable solvent or solvent mixture and stirring; and (iii) Filtering and drying to obtain the desired product.

[0105] The solvent for the process is selected from lower C1-C5 alcohols, ketones, ethers, aliphatic or aromatic hydrocarbons and the like alone or combination thereof.

[0106] The reaction temperature is maintained between 25-30°C.

[0107] The reaction mixture in step (i) is stirred for a period of about 24 hours.

[0108] The reaction mixture in step (ii) is stirred for a period of 30-40 minutes.

[0109] The drying is carried out at a temperature in the range of 45-55°C for 10-15 hours.

[0110] In another embodiment, the present invention relates to a process for preparation of Iptacopan hydrochloride Polymorph Form C4 comprising;

[0111] (i) Dissolving or suspending Iptacopan hydrochloride Polymorph Form C3 in a suitable solvent or solvent mixture;

[0112] (ii) Filtering, washing the solid in a suitable solvent or solvent mixture and drying under vacuum to obtain the desired product.

[0113] The solvent for the process is selected from alcohols, ketones, ethers, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons and the like alone or combination thereof.

[0114] The process is carried out at room temperature for about 1-3 hours.

[0115] The drying is carried out at a temperature in the range of 45-55°C for about 2-3 hours.

[0116] In yet another embodiment, the present invention discloses the process for preparation of Iptacopan hydrochloride Polymorph Form C5 comprising;(i) Dissolving or suspending Iptacopan hydrochloride in a suitable solvent or solvent mixture and stirring followed by adding water to the mixture to get a clear solution;

[0117] (ii) Dissolving or suspending Iptacopan hydrochloride Form C4 in a solvent or solvent mixture and cooling to a temperature in the range of 0-5°C;

[0118] (iii) Adding the clear solution of step (i) to the pre-cooled solution of step (ii), stirring, separating the layers, decanting the pre-chilled solvent layer to obtain the reaction mass;

[0119] (iv) Adding a solvent or solvent mixture to the reaction mass of step (iii), filtering the resultant slurry, washing and drying to obtain the product.

[0120] The solvent for the process is selected from alcohols, ketones, ethers, aliphatic or aromatic hydrocarbons, halogenated hydrocarbons and the like alone or combination thereof.

[0121] The temperature of the reaction to obtain the clear solution is in the range of 45-55°C and the reaction mixture is stirred for a period of 5-15minutes.

[0122] The mixture of step (iii) of the process is stirred for about an hour at 0-5°C.

[0123] The mixture of step (iv) after adding the solvent to the reaction mass of step (iii) is stirred at a temperature in the range of 25-30°C for a period of about 30minutes.

[0124] The resulting product was suck dried for about 30minutes followed by drying at a temperature in the range of 35-45°C for 15-20 hours to obtain polymorph C5.

[0125] In an embodiment, the present invention relates to a process for preparation of Iptacopan hydrochloride Polymorph Form C6, comprising;

[0126] i. Dissolving Iptacopan hydrochloride in a solvent or mixture of solvents to obtain a clear solution;

[0127] ii. Suspending Iptacopan hydrochloride Form C5 in a solvent or mixture of solvents and cooling the mixture;iii. Adding slowly the clear solution of step (i) to the prechilled solution of step (ii) and seed suspension at a temperature of 0-5°C and stirring at said temperature to obtain a slurry;

[0128] iv. Filtering the slurry of step (iii) followed by washing to obtain the desired product.

[0129] The solvent for the process is selected from C1-C5 alcohols, aliphatic or aromatic hydrocarbons such as hexane, heptane, toluene and the like; ethers such as diethyl ether, 1,4 dioxane, THF and the like; alone or mixtures thereof.

[0130] The temperature for reaction step (i) is maintained at 55-75°C.

[0131] The mixture of step (iii) is stirred for about 2-3 hours.

[0132] In another preferred embodiment, the present invention relates to a process for preparation of Iptacopan hydrochloride Polymorph Form C7 comprising;

[0133] i. Dissolving Iptacopan hydrochloride in a solvent or mixture of solvents to obtain a clear solution;

[0134] ii. Suspending Iptacopan hydrochloride Form C5 or Form C6 in a solvent or mixture of solvents and cooling the mixture;

[0135] iii. Adding slowly the clear solution of step (i) to the prechilled solution of step (ii) and seed suspension at a temperature of 0-5°C and stirring at said temperature to obtain a slurry;

[0136] iv. Filtering the slurry of step (iii) followed by washing to obtain the desired product.

[0137] The solvent for the process is selected from C1-C5 alcohols, aliphatic or aromatic hydrocarbons such as hexane, heptane, toluene and the like; ethers such as diethyl ether, 1,4 dioxane, THF and the like; halogenated hydrocarbons such as methylene dichloride alone or mixtures thereof.

[0138] The temperature for reaction step (i) is maintained at 55-75°C.The mixture of step (ii) is cooled to a temperature of 0-5°C.

[0139] The mixture of step (iii) is stirred for about 2-5 hours.

[0140] The residue obtained after filtration and washing is suck dried and further may be dried at a temperature in the range of 45-55°C for a period of 25-30hours to obtain the product.

[0141] In an alternate embodiment, the present invention relates to a process for preparation of Iptacopan hydrochloride Polymorph Form C7 comprising;

[0142] i. Suspending Iptacopan hydrochloride in a solvent or mixture of solvents to obtain a clear solution;

[0143] ii. Suspending Iptacopan hydrochloride Form C7 in a solvent or mixture of solvents at a suitable temperature;

[0144] iii. Adding slowly the clear solution of step (i) to the solution of step (ii) and seed suspension at a temperature of 20-25°C and stirring at said temperature to obtain a slurry;

[0145] iv. Filtering the slurry of step (iii) followed by drying to obtain the desired product.

[0146] The solvent for the process is selected from C1-C5 alcohols, aliphatic or aromatic hydrocarbons such as hexane, heptane, toluene and the like; ethers such as diethyl ether, 1,4 dioxane, 2-MeTHF, MTBE and the like; halogenated hydrocarbons such as methylene dichloride alone or mixtures thereof.

[0147] The temperature for reaction step (i) is maintained at 25-45°C.

[0148] The mixture of step (ii) is maintained at a temperature of 10-35°C.

[0149] The mixture of step (iii) is stirred for about 2-5 hours.

[0150] The residue obtained after filtration and washing is suck dried and further may be dried at a temperature in the range of 25-60°C for a period of 30 minutes to 40 hours to obtain the product.In yet another embodiment, the present invention discloses a process for preparation of Iptacopan hydrochloride Polymorph Form C8 comprising;

[0151] i. Dissolving Iptacopan hydrochloride in a solvent or mixture of solvents to obtain a clear solution;

[0152] ii. Suspending Iptacopan hydrochloride Form C5 in a solvent or mixture of solvents and cooling the mixture;

[0153] iii. Adding slowly the clear solution of step (i) to the prechilled solution of step (ii) and seed suspension at a temperature of 0-5°C and stirring at said temperature;

[0154] iv. Optionally decanted the solvent layer and to the residue is added a solvent or mixture of solvents and stirred the reaction mixture to obtain a slurry; v. Filtering and drying to obtain the desired product.

[0155] The solvent for the process is selected from C1-C5 alcohols, aliphatic or aromatic hydrocarbons such as hexane, heptane, toluene and the like; ethers such as diethyl ether, 1,4 dioxane, THF and the like; halogenated hydrocarbons such as methylene dichloride; ketones such as acetone, ethylmethylketone, diethyl ketone alone or mixtures thereof.

[0156] The temperature for reaction step (i) is maintained at 40-65°C.

[0157] The mixture of step (ii) is cooled to a temperature of 0-5°C.

[0158] The mixture of step (iii) and (iv) is stirred for about 1-7 hours.

[0159] The residue obtained after filtration and washing is suck dried and further may be dried at a temperature in the range of 45-55°C for a period of 25-40hours to obtain the product.

[0160] In an embodiment, Iptacopan Hydrochloride Form C7 is stable and does not degrade at accelerated temperature and pressure as depicted in Table 1 below. Iptacopan Hydrochloride Form C7 is stable for a period of up to 6 months as indicated in table 2 below.In another embodiment, Iptacopan Hydrochloride Form C7 exhibited superior dissolution over Iptacopan Hydrochloride Form HB as shown in Table 3 below. Iptacopan Hydrochloride Form C7 exhibited enhanced dissolution in a period of 15-30 minutes as compared to Iptacopan Hydrochloride Form HB wherein about 98% dissolution was observed after 60minutes.

[0161] In an embodiment, the present invention relates to pharmaceutical composition comprising novel polymorphs of Iptacopan Hydrochloride Form Cl, Form C2, Forms C3, Form C4, Form C5, Form C6, Form C7 or Form C8 or mixture thereof along with pharmaceutically acceptable carrier, diluent or excipients.

[0162] In another embodiment, the present invention is directed to methods of treating and / or preventing paroxysmal nocturnal hemoglobinuria and proteinuria by administering a therapeutically effective amount of novel polymorphs Form Cl, Form C2, Forms C3, Form C4, Form C5, Form C6, Form C7 or Form C8 of Iptacopan hydrochloride thereof.

[0163] In yet another embodiment, the present invention is directed to the use of novel polymorph Form Cl, Form C2, Forms C3, Form C4, Form C5, Form C6, Form C7 or Form C8 of Iptacopan hydrochloride in the manufacture of a medicament for treating and / or preventing paroxysmal nocturnal hemoglobinuria and proteinuria.

[0164] The examples set below are to aid in understanding the disclosure but are not limited to and should not be construed to limit the scope of the invention in any way.

[0165] EXAMPLES

[0166] Example 1: Process for the preparation of Iptacopan Hydrochloride Form Cl1.0 mL of 5% Water in acetonitrile and 0.5 g of Iptacopan hydrochloride were charged in a clean round bottom flask (RBF) at 20-25°C. The reaction mass was stirred for 12 to 16 hours at 20-25°C. The resulting solid material was filtered and dried at 40-50°C under vacuum in VTD for 1-2 hours to obtain Iptacopan Hydrochloride Form Cl.

[0167] Yield: 0.3 g

[0168] Example 2: Process for the preparation of Iptacopan Hydrochloride Form Cl

[0169] 1.5g of Iptacopan hydrochloride was dissolved in 20 ml of methanol, and the resultant solution was concentrated under vacuum at 50°C.

[0170] 5.0 mL of 5% water in acetone and 1.6 g of above Iptacopan hydrochloride were charged in a clean round bottom flask (RBF). The reaction mass was stirred for 12-16 hours at 20-25°C. The resulting solid material was filtered and dried at 40-50°C under vacuum in VTD for 1-2 hour to obtain Iptacopan Hydrochloride Form Cl.

[0171] Yield: 1.1 g

[0172] Example 3: Process for the preparation of Iptacopan Hydrochloride Form C2

[0173] 0.5 mL of 5% Water in Ethanol was charged in a clean round bottom flask (RBF) and cooled to 0-5°C. 200.0 mg of Iptacopan hydrochloride was added into it. The reaction mass was stirred for 3 hours at 0-5°C. The resulting solid material was filtered and suck dried the material for 1-2 hours to obtain the Iptacopan Hydrochloride Form C2.

[0174] Yield: 0.25 g

[0175] Example 4: Preparation of Iptacopan hydrochloride polymorphic Form C3 Iptacopan hydrochloride (5.0 g, amorphous form) was suspend in 75.0 ml of tertiary butanol at 30°C and stirred for 24 hours. The resultant slurry was filtered and washed with heptane. The resulted wet material was suspend in 50ml of heptane and stirred at 30°C for 30minutes and filtered the material in pressurenutsche filter under nitrogen pressure, washed with 10.0 ml of heptane, dried the material under nitrogen pressure for 30 min followed by drying at 50°C for 12 hours to obtain the title compound.

[0176] Yield: 3.5 g

[0177] Example 5: Preparation of Iptacopan hydrochloride polymorphic Form C4 Iptacopan hydrochloride (100 mg, Form C3) was suspended in 4.0 ml of methylene di chloride (MDC) at room temperature and stirred for 1-2 hours. The resulting suspension was filtered, washed the solid with 5ml of MDC and suck dried the material under vacuum for 30 minutes, followed by drying at 50°C for 2 hours to obtain the title compound.

[0178] Yield: 90 mg

[0179] Example 6: Preparation of Iptacopan hydrochloride polymorphic Form C4 Iptacopan hydrochloride (1.0 g, Form C3) was suspended in 24.0 ml of MDC and 0.2 ml of water at 0-5°C and stirred for 1-2 hours. The resulting suspension was filtered and washed the solid with 5 ml of MDC and suck dried the material under vacuum for 30 minutes, followed by drying at 50°C for 3 hours to obtain the title compound.

[0180] Yield: 0.9g

[0181] Example 7: Preparation of Iptacopan hydrochloride polymorphic Form C5 Iptacopan hydrochloride (2.0 g) was suspended in 4.0 ml of MDC and 4.0 ml of acetone and stirred for 5mins at 30°C. Charged 3.5ml of water and stirred for 10mins at 50°C to get the clear solution. In another clean RBF suspend 200mg of Iptacopan hydrochloride Form C4 in 60 ml of heptane and cooled to 0-5°C. Slowly added above prepared clear solution into the prechilled heptane and seed suspension at 0-5°C, stirred for 1 hour at 0-5°C, later two layers were formed, decant the heptane solvent layer and kept aside, Into the remaining reaction mass charged 50 ml of MDC and stirred the reaction mass at 25-30°C for 30 minutes. The resulted slurry was filtered and washed with 10.0 ml of MDC suck dried thematerial for 30 min followed by drying at 40°C for 16 hours to obtain the title compound.

[0182] Yield: 1.8 g

[0183] Example 8: Preparation of Iptacopan hydrochloride polymorphic Form C6 Iptacopan hydrochloride (5.0 g) was dissolved in 20.0 ml of Methanol and 180.0 ml of THF mixture at 60°C to get the clear solution. In another clean RBF suspend 100mg of Iptacopan hydrochloride Form C5 in 75 ml of heptane and cooled to 0-5°C. Slowly added the above prepared clear solution into the prechilled heptane and seed suspension at 0-5°C and stirred for 2 hours at 0-5°C. The resulted slurry was filtered and washed with 30.0 ml of Heptane, suck dried to get the title compound.

[0184] Yield: 4.9 g

[0185] Example 9: Process for the preparation of Iptacopan hydrochloride Form C7 Iptacopan hydrochloride (125.0 g) was suspended in 1000 ml of 30 % Methanol in 2 -Methyl THF mixture and 6.25 ml of water and stirred for 10mints at 35°C to get the clear solution. In another reactor, suspend 6.25 g of Iptacopan hydrochloride Form C7 in 2000 ml of Heptane, 2-Methyl THF and MTBE (8:1:1 ratio) mixture at 20-25°C. Slowly added above prepared clear solution into the Heptane, 2-Methyl THF and MTBE (8:1:1 ratio) mixture and seed suspension at 20-25°C, stirred for 2 hours at 20-25°C. The resulted slurry was filtered and washed with 250.0 ml of Heptane, suck dried the material for 30 min followed by drying at 30°C for 2 hours, 40°C for 4 hours and 50°C for 35 hours to obtain the title compound.

[0186] Yield: 113 g

[0187] MTBE slurry:

[0188] Iptacopan hydrochloride C7 (5.0 g) was suspend in 50.0 ml of MTBE and stirred for 120 minutes at 23-25°C. The resulted slurry was filtered and washed with 10.0 ml of MTBE, suck dried the material for 10 min followed by VTD drying at 30°Cfor 1 hour, at 40°C for 4 hours and at 50°C for 18 hours to obtain the title compound.

[0189] Yield: 4.3 g

[0190] Example 10: Preparation of Iptacopan hydrochloride polymorphic Form C7 Iptacopan hydrochloride (5.0 g) was dissolved in 20.0 ml of Methanol and 180.0 ml of THF mixture at 60°C to get the clear solution. In another clean RBF suspend 100mg of Iptacopan hydrochloride Form C5 in 75 ml of heptane and cooled to 0-5°C. Slowly added the above prepared clear solution into the prechilled heptane and seed suspension at 0-5°C and stirred for 2 hours at 0-5°C. The resulted slurry was filtered and washed with 30.0 ml of Heptane suck the material for 30 min followed by drying at 50°C for 26 hours to obtain the title compound.

[0191] Yield: 4.5 g

[0192] Example 11: Preparation of Iptacopan hydrochloride polymorphic Form C7 Iptacopan hydrochloride (5.0 g) was dissolved in 20.0 ml of Methanol and 180.0 ml of THF mixture at 60°C to get the clear solution. In another clean RBF suspend 100mg of Iptacopan hydrochloride Form C6 in 75 ml of heptane and cooled to 0-5°C. Slowly added the above prepared clear solution into the prechilled heptane and seed suspension at 0-5°C and stirred for 2 hours at 0-5°C. The resulted slurry was filtered and washed with 30.0 ml of Heptane, suck dried the material for 30 min followed by drying at 50°C for 26 hours to obtain the title compound.

[0193] Yield: 4.5 g

[0194] Example 12: Preparation of Iptacopan hydrochloride polymorphic Form C7 Iptacopan hydrochloride (5.0 g) was dissolved in 3.0 ml of Methanol and 57.0 ml of MDC at 40°C to get the clear solution. In another clean RBF suspend 100mg of Iptacopan hydrochloride Form C5 in 75 ml of heptane and cooled to 0-5°C. Slowly added the above prepared clear solution into the prechilled heptane and seed suspension at 0-5°C and stirred for 4 hours at 0-5°C. The resulted slurry was filtered and washed with 30.0 ml of Heptane, suck dried the material for 30 min followed by drying at 50°C for 26 hours to obtain the title compound.

[0195] Yield: 4.8 g

[0196] Example 13: Preparation of Iptacopan hydrochloride polymorphic Form C8 Dissolved Iptacopan hydrochloride (0.2 g) in 50.0 µL of Methanol and 0.95 ml of MDC at 40°C to get the clear solution. In another clean RBF suspend 200mg of Iptacopan hydrochloride Form C5 in 30 ml of heptane and cooled to 0-5°C. Slowly added the above prepared clear solution into the prechilled heptane and seed suspension at 0-5°C and stirred for 7 hours at 0-5°C. The resulted slurry was filtered and washed with 30.0 ml of Heptane, suck dried the material for 30 min followed by drying at 50°C for 29 hours to obtain the title compound.

[0197] Yield: 110 mg

[0198] Example 14: Preparation of Iptacopan hydrochloride polymorphic Form C8 Dissolved Iptacopan hydrochloride (0.2 g) in 0.5 ml of Methanol and 1.5 ml of Acetone at 50-55°C to get the clear solution. In another clean RBF suspend 20mg of Iptacopan hydrochloride Form C5 in 30 ml of heptane and cooled to 0-5°C. Slowly added above prepared clear solution into the prechilled heptane and seed suspension at 0-5°C, stirred for 1 hour at 0-5°C, later two layers were formed, decant the heptane solvent layer and kept aside, Into the remaining reaction mass charged 5 ml of MDC and 5ml of acetone stirred the reaction mass at 25-30°C for 30 minutes. The resulted slurry was filtered, and suck dried the material for 30 min followed by drying at 50°C for 40 hours to obtain the title compound.

[0199] Yield: 90 mg

[0200] Example 15: Forced degradation data of Iptacopan Hydrochloride (C7). Table 1:Forced degradation of Iptacopan Hydrochloride (C7)

[0201] Condition XRD Water content Purity Iptacopan Hydrochloride

[0202] 2.10% 99.86% Initial

[0203] (C7)

[0204] Comparable with initial - °C / 60%RH Open cup 7D 99.85% Comparable with initial - 99.85%°C / 60%RH Closed cup 7D

[0205] - 99.86% Comparable with initial°C / 75%RH Open cup 7D

[0206] - 99.85% Comparable with initial°C / 75%RH Closed cup 7D

[0207] 2.12% 99.81% Comparable with initial°C / 60%RH Open cup 15D

[0208] 2.12% 99.84% Comparable with initialC / 60%RH Closed cup 15D

[0209] 1.83% 99.85% Comparable with initial°C / 75%RH Open cup 15D

[0210] 1.92% 99.84% Comparable with initialC / 75%RH Closed cup 15 D

[0211] - 99.82% Comparable with initial 105°C 6 Hours

[0212] 2.32% 99.85% Comparable with initial 25°C / 90%RH 5D

[0213] 1.46% 99.84% Comparable with initial 60°C / 80%RH 5D

[0214] - 99.85% Comparable with initial UV protected

[0215] - 99.85% Comparable with initial VISIBLE protected

[0216] - 99.80% Comparable with initial 10 TORR

[0217]

[0218] Example 16: Indicative stability data of Iptacopan Hydrochloride (C7)

[0219] Table 2:

[0220] Iptacopan Hydrochloride (C7)- 6 months indicative stability

[0221] Water

[0222] Total Description XRD SMI Limits content (%

[0223] impurities w / w)

[0224] Off-white colored

[0225] powder Form C7 0.09 0.18 Initial

[0226] 2.16

[0227] Form C7 Off-white colored

[0228] °C / 60%RH (6

[0229] powder 0.10 0.28 months)

[0230] 1.91

[0231] Form C7 Off-white colored

[0232] powder 2.15 0.10 0.28°C (6 months)

[0233]

[0234] Table 3: Comparative dissolution data of Iptacopan Hydrochloride (C7) with Form HB

[0235] Dissolution Method

[0236] Dissolution Media 0.01 N HCl (pH 2.0)

[0237] Apparatus USP Apparatus I (Basket)

[0238] Media Volume 500 mL

[0239] Rotation speed 100 RPM

[0240] Temperature 37°C

[0241]

[0242] Dissolution Data

[0243] % Drug Release

[0244] Time point (min)

[0245] Form HB Form C7

[0246] 10 91.85 97.73

[0247] 15 97.78 100.76⁵

[0248] 20 98.52 100.00

[0249] 30 99.26 100.00

[0250] 45 98.52 98.48

[0251] 60 98.52 98.48₂₀

[0252]

[0253] Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.

Claims

We claim:

1. A crystalline Iptacopan hydrochloride Form C7.

2. The crystalline Iptacopan hydrochloride Form C7 as claimed in claim 1, characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2θ angle values: 7.77, 9.77, 12.09, 15.24, 18.17, 21.04 and 22.74± 0.2°2θ.

3. The crystalline Form C7 as claimed as claimed in claim 1, characterized by a differential scanning calorimetry (DSC) curve comprising an exothermic peak with an onset temperature at about 200.62±10°C and a peak maximum at about 204.91±5°C.

4. The crystalline Form C7 as claimed as claimed in claim 1, characterized by TGA with a weight loss of approximately 1.652% at temperature about 150°C.

5. A crystalline Iptacopan hydrochloride Form Cl characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2θ angle values: 9.98, 10.40, 11.53, 16.55, 17.61, 21.05, 23.15 and 25.45 ± 0.2°2θ.

6. A crystalline Iptacopan hydrochloride Form C2 characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2θ angle values: 9.66, 15.93, 18.97, 24.92 and 27.34 ± 0.2°2θ.

7. A crystalline Iptacopan hydrochloride Form C3 characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2θ angle values: 3.94, 7.86, 10.95, 14.56, 17.

28. 18.98, 20.075, 25.22 and 27.10 ± 0.2°2θ.

8. A crystalline Iptacopan hydrochloride Form C4 characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2θ angle values: 10.49, 11.06, 13.

46. 14.57, 17.43, 17.97, 21.37 and 27.05± 0.2°2θ.

9. A crystalline Iptacopan hydrochloride Form C5 characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2θ angle values: 10.11, 12.39, 13.05, 15.46, 17.34, 21.06, 23.61, 26.95 and 27.57± 0.2°2θ.

10. A crystalline Iptacopan hydrochloride Form C6 characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2θ angle values: 6.88, 9.07, 10.33, 12.49, 13.81, 14.69, 17.93, 23.42 and 25.04± 0.2°2θ.

11. A crystalline Iptacopan hydrochloride Form C8 characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 2θ angle values: 7.92, 10.07, 15.21, 20.24, 21.00 and 25.27± 0.2°2θ.

12. A process for preparing crystalline Iptacopan hydrochloride Form C7 as claimed in claims 1, comprising:a) Suspending Iptacopan hydrochloride in a solvent or mixture of solvents to obtain a clear solution;b) Suspending Iptacopan hydrochloride Form C7 in a solvent or mixture of solvents at 10-35°C;c) Adding slowly the clear solution of step (i) to the solution of step (ii) and seed suspension at a temperature of 20-25°C and stirring at said temperature to obtain a slurry;d) Filtering the slurry of step (iii) followed by drying to obtain the desired product.

13. A process for preparing crystalline Iptacopan hydrochloride Form C7 as claimed in claims 1, comprising:a) Dissolving Iptacopan hydrochloride in a solvent or mixture of solvents to obtain a clear solution;b) Suspending Iptacopan hydrochloride Form C5 or Form C6 in a solvent or mixture of solvents and cooling the mixture to 0-5°C;c) Adding slowly the clear solution of step (i) to the prechilled solution of step (ii) and seed suspension at a temperature of 0-5°C and stirring at said temperature to obtain a slurry;d) Filtering the slurry of step (iii) followed by washing to obtain the desired product.

14. A process for preparing crystalline Iptacopan hydrochloride Form Cl as claimed in claim 5, comprising:a) Dissolving Iptacopan hydrochloride in a suitable solvent or mixture of solvents;b) Stirring the above mixture; andc) Filtering and drying to obtain Iptacopan hydrochloride Form Cl.

15. A process for preparing crystalline Iptacopan hydrochloride Form Cl as claimed in claim 5, comprising:a) Dissolving Iptacopan hydrochloride in a first solvent and concentrating the resultant solution;b) Charging the above Iptacopan hydrochloride mass to a second solvent; c) Stirring the reaction mass of step b; andd) Filtering and drying to obtain Iptacopan hydrochloride Form Cl.

16. A process for preparing crystalline Iptacopan hydrochloride Form C2 as claimed in claim 6, comprising:a) Dissolving Iptacopan hydrochloride in a suitable solvent followed by cooling to -5°C to 10°C;b) Stirring the reaction mass;c) Filtering and drying to obtain Iptacopan hydrochloride Form C2.

17. A process for preparing crystalline Iptacopan hydrochloride Form C3 as claimed in claim 7, comprising:a) Dissolving or suspending the amorphous Iptacopan hydrochloride in a suitable solvent or solvent mixture and stirred to obtain the wet material; b) Filtering and washing the wet material obtained in step (i) and resuspending in a suitable solvent or solvent mixture and stirring; and c) Filtering and drying to obtain the desired product.

18. A process for preparing crystalline Iptacopan hydrochloride Form C4 as claimed in claim 8, comprising:a) Dissolving or suspending Iptacopan hydrochloride Polymorph Form C3 in a suitable solvent or solvent mixture;b) Filtering, washing the solid in a suitable solvent or solvent mixture and drying under vacuum to obtain the desired product.

19. A process for preparing crystalline Iptacopan hydrochloride Form C5 as claimed in claim 9, comprising:a) Dissolving or suspending Iptacopan hydrochloride in a suitable solvent or solvent mixture and stirring followed by adding water to the mixture to get a clear solution;b) Dissolving or suspending Iptacopan hydrochloride Form C4 in a solvent or solvent mixture and cooling to a temperature in the range of 0-5°C;c) Adding the clear solution of step (i) to the pre-cooled solution of step (ii), stirring, separating the layers, decanting the pre-chilled solvent layer to obtain the reaction mass;d) Adding a solvent or solvent mixture to the reaction mass of step (iii), filtering the resultant slurry, washing and drying to obtain the product.

20. A process for preparing crystalline Iptacopan hydrochloride Form C6 as claimed in claim 10, comprising:a) Dissolving Iptacopan hydrochloride in a solvent or mixture of solvents to obtain a clear solution;b) Suspending Iptacopan hydrochloride Form C5 in a solvent or mixture of solvents and cooling the mixture;c) Adding slowly the clear solution of step (i) to the prechilled solution of step (ii) and seed suspension at a temperature of 0-5°C and stirring at said temperature to obtain a slurry;d) Filtering the slurry of step (iii) followed by washing to obtain the desired product.

21. A process for preparing crystalline Iptacopan hydrochloride Form C8 as claimed in claim 11, comprising:a) Dissolving Iptacopan hydrochloride in a solvent or mixture of solvents to obtain a clear solution;b) Suspending Iptacopan hydrochloride Form C5 in a solvent or mixture of solvents and cooling the mixture to 0-5°C;c) Adding slowly the clear solution of step (i) to the prechilled solution of step (ii) and seed suspension at a temperature of 0-5°C and stirring at said temperature;d) Optionally decanted the solvent layer and to the residue is added a solvent or mixture of solvents and stirred the reaction mixture to obtain a slurry; e) Filtering and drying to obtain the desired product.

22. The process as claimed in any one of the preceding claims 12 to 21, wherein the solvent is selected from polar or non-polar, protic or aprotic solvents, ethers such as diethyl ether, 1,4 dioxane, THF, 2-MeTHF, MTBE and the like, aliphatic or aromatic hydrocarbon such as hexane, heptane, toluene and the like, halogenated hydrocarbons such as methylene dichloride, nitriles, ketones such as acetone, ethylmethylketone, diethyl ketone, alcohols, acids, water etc. or mixture thereof, either alone or in mixtures thereof.

23. A pharmaceutical composition comprising the crystalline Iptacopan hydrochloride Form C7 or Form Cl or Form C2 or Form C3 or Form C4 or Form C5 or Form C6 or Form C8 or mixture thereof together with pharmaceutically acceptable carrier, diluent or excipients.

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