Stable solid dispersions of salcaprozate with various active pharmaceutical ingredients

Abstract

The present invention relates to solid forms of N-(8-[2-Hydroxybenzoyl]-Amino) caprylic acid sodium, specifically solid dispersion of N-(8-[2-Hydroxybenzoyl]-Amino) caprylic acid sodium with one or more active pharmaceutical ingredients, its process of preparation and pharmaceutical compositions comprising the same. The present invention further relates to the process of preparing pure N-(8-[2-Hydroxybenzoyl]-Amino) caprylic acid sodium (Salcaprozate sodium / SNAC).

Description

“STABLE SOLID DISPERSIONS OF SALCAPROZATE WITH VARIOUS ACTIVEPHARMACEUTICAL INGREDIENTS”CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from Indian Patent Applications IN 202341047500 filed on July 14, 2023, IN 202341047499 filed on July 14, 2023, IN 202341052904 filed on August 7, 2023, and IN202341054830 filed on August 16, 2023.FIELD OF THE INVENTION

[0002] The present invention relates to stable solid dispersions of N-(8-[2- Hydroxybenzoyl] -Amino) caprylic acid sodium or Salcaprozate sodium with one or more active pharmaceutical ingredients, and processes from preparing the same.BACKGROUND OF THE INVENTION

[0003] N-(8-[2-Hydroxybenzoyl]-Amino) caprylic acid sodium is chemically known as Salcaprozate sodium and is represented by Formula (1) below, which is also known as SNAC sodium.Salcaprozate sodium(1)

[0004] US 6399798 patent discloses process for the preparation of Salcaprozate free base(la) as depicted in the following scheme:Scheme 1

[0005] US7659311 patent discloses an ethanol solvate or a monohydrate of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, and a process of preparation thereof.

[0006] US 7544833 patent discloses avoiding or reducing the production of a colour impurity therein comprising the step of hydrolyzing 2,4-dioxo-l,3-benzoxazinyloctanoic acid ethyl ester by admixing 2,4-dioxo-l,3-benzoxazinyloctanoic acid ethyl ester with sodium hydroxide, water, and a member selected from the group consisting of ethylenediamine tetra acetic acid (EDTA), ascorbic acid, sodium hydrosulfide, and triphenylphosphine.

[0007] US 10875826 patent also discloses a method of making the Salcaprozate free base or an anion or salt thereof.

[0008] US6900344 and US7169776 patents disclose a method of preparing a protected decarboxylated salicylamide from a protected and activated salicylamide. The purpose of protecting the hydroxyl group was to prevent the reaction at the hydroxy moiety and activate the Nitrogen atom of the amide group. The method comprising the step of (a) alkylating the protected and activated salicylamide at the amide group with a dicarboxylate alkylating agent to form the protected dicarboxylated salicylamide.

[0009] US8636996, US9321719 and US 11395809 patents disclose crystalline polymorphic forms of monosodium N-[8-(2 -hydroxybenzoyl) amino] caprylate (“SNAC”), including two hydrates, a crystalline anhydrous, a methanol solvates, and an ethanol solvate, of SNAC. More specifically, the disclosures provided six polymorphic forms of SNAC (referred to as Forms I- VI).

[0010] WO2022264166 discloses the process for the preparation of pure Salcaprozate sodium free of colour impurities.

[0011] WO2022162132 discloses a chemical process for the synthesis of the compound 8-[(2-hydroxybenzoyl) amino] octanoic acid or a derivative thereof useful in the process of making sodium 8-[(2-hydroxybenzoyl) amino] octanoate (SNAC). The invention provides an efficient synthesis using less hazardous chemicals and / or a reproducible process that is easier to handle on production scale.

[0012] US 11667614 patent discloses processes including hydrolysis of 8-(2,4-dioxo-l,3- benzoxazin-3-yl) octanoic acid ethyl ester in the presence of or by contacting it with benzotriazole, hydrazine and / or sodium borohydride.

[0013] WO2023285581 discloses a method of making sodium N-(8-2-Hydroxybenzoyl) amino caprylate form A, SNAC polymorphic form A having improved stability.

[0014] US9278123, US 10086047 and US 10278923 patents cover certain oral Semaglutide formulations containing N-(8-(2-hydroxybenzoyl) amino) caprylic acid salt and methods of using such formulations once daily to treat diabetes.

[0015] US 11759501, US 11759502 and US 11759503 patents cover certain Semaglutide solid formulations containing N-(8-(2 -hydroxybenzoyl) amino) caprylic acid salt.

[0016] Existing reported literature discloses various processes of preparing Salcaprozate sodium, and different polymorphs of Salcaprozate sodium. The reported literature also discloses solid pharmaceutical compositions of a GLP-1 agonist and salt of N-(8-(2- hydroxybenzoyl) amino) caprylic acid, those compositions provided improved exposure and / or bioavailability of the GLP-1 agonist. However, still there is a long felt need to understand most effective ways to use or explore Salcaprozate sodium to improve solubility of a low solubility drug and / or to improve permeability of a low membrane permeability drug.OBJECTIVE OF THE INVENTION

[0017] The present invention provides a solid dispersion of N-(8-[2-Hydroxybenzoyl]- amino) caprylic acid sodium, which is also known as SNAC sodium or Salcaprozate sodium, with one or more active pharmaceutical ingredients.

[0018] In another objective, the present invention provides a stable solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients.

[0019] In another objective, the present invention provides a process of making a stable solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients.SUMMARY OF THE INVENTION

[0020] Certain embodiments of the present invention provide a solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients. In certain embodiments of the invention, the Active Pharmaceutical Ingredient (API) may fall within one or more groups as defined by the United States Pharmacopoeia’s Biopharmaceutics Classification System (BCS). More specifically, in said embodiments, the API may fall within the classification of BCS class I, II, III, IV, or combinations thereof.

[0021] In certain embodiments of the invention, the active pharmaceutical ingredient as described above is a therapeutically active peptide.

[0022] In certain embodiments of the invention, the solid dispersion as described above provides improved stability, or improved solubility, or improved membrane permeability.

[0023] Certain embodiments of the present invention relate to a process for the preparation of the solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients, said process comprising of:(a) dissolving Salcaprozate sodium with one or more active pharmaceutical ingredients in one or more solvents; and(b) isolating the solid dispersion comprising of Salcaprozate sodium and one or more active pharmaceutical ingredients.

[0024] In certain embodiments of the process as described above, the solvent is selected from the group consisting of: N, N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, l-methyl-2-pyrrolidone, l-methyl-2-piperidone, l,3-dimethyl-2- imidazolidinone, acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, methanol, ethanol, isopropanol and water. In certain embodiments, the solvent may be a combination of one of more of the solvents.

[0025] In certain embodiments of the process as described above, the isolating involve removal of solvent from the reaction is carried out by at least one of evaporation, spray drying, and freeze drying.

[0026] In certain embodiments, the solid dispersion as described above is a stable amorphous solid dispersion.

[0027] Certain embodiments of the present invention provide a pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion as described above.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Fig. 1: Illustrates characteristic Powder X-Ray Diffraction (PXRD) pattern of crystalline form of Salcaprozate sodium.

[0029] Fig. 2: Illustrates Differential scanning calorimetry (DSC) of crystalline form of Salcaprozate sodium.

[0030] Fig. 3: Illustrates Scanning Electron Microscopy (SEM) of crystalline form of Salcaprozate sodium.

[0031] Fig. 4: Illustrates characteristic Powder X-Ray Diffraction (PXRD) pattern of solid dispersion of Salcaprozate sodium with Suvorexant.

[0032] Fig. 5: Illustrates characteristic Powder X-Ray Diffraction (PXRD) pattern of solid dispersion of Salcaprozate sodium with Risdiplam.

[0033] Fig. 6: Illustrates characteristic Powder X-Ray Diffraction (PXRD) pattern of solid dispersion of Salcaprozate sodium with Asciminib Hydrochloride.

[0034] Fig. 7: Illustrates characteristic Powder X-Ray Diffraction (PXRD) pattern of solid dispersion of Salcaprozate sodium with Selexipag.

[0035] Fig. 8: Illustrates characteristic Powder X-Ray Diffraction (PXRD) pattern of solid dispersion of Salcaprozate sodium with Pitolisant hydrochloride.

[0036] Fig. 9: Illustrates characteristic Powder X-Ray Diffraction (PXRD) pattern of solid dispersion of Salcaprozate sodium with Olaparib.DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention provides a solid dispersion comprising Salcaprozate sodium with one or more active pharmaceutical ingredients. In one embodiment of the invention, the active pharmaceutical ingredient may have low solubility and / or low membrane permeability and / or a metastable polymorphic nature

[0038] In certain embodiments, the present invention provides a stable solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients. The solid dispersion may be obtained either in an amorphous form or in a crystalline form.

[0039] In certain embodiments, the present invention provides a process for the preparation of a solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients.

[0040] In certain embodiments of the invention, the active pharmaceutical ingredient has a purity greater than 99.5% by HPLC. In a preferred embodiment, the API has a purity of greater than 99.9%. In said embodiments, the total impurities are controlled to less than 0.5% (w / w), more preferably to less than 0.15% (w / w). With respect to moisture content, any solvent impurities present are controlled as per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines (hereinafter “ICH guidelines”). Further, the presence of nitrosamine impurities is controlled to less than 0.10% (w / w) and shown absent as per the ICH guidelines.

[0041] In certain embodiments, the present invention provides a process for the preparation of pure Salcaprozate sodium, comprising the steps of:(a) providing monosodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) in a suitable solvent;(b) treating the reaction mixture with activated charcoal;(c) passing the reaction mixture through resin column; and(d) isolating pure monosodium N-[8-(2-hydroxybenzoyl) amino] caprylate.

[0042] Accordingly, the present invention uses resin columns for the purification of Salcaprozate sodium. In step (c) of the above-described process, the resin is either a basic resin or an acidic resin. Basic resins may be strong basic resins or weak basic resins. Examples of strong basic resins are Indion 810, Indion 820, Indion 830, Indion FFIP, Indion NIP. Examples of weak basic resins are Indion 850, Indion 860, Indion 860 S. Acidic resins may be strong acidic resins or weak acidic resins. Examples of strong acidic resins are Indion 220Na, Indion 225Na, Indion 225H+, Indion 3O3H+, Indion 720H+. Examples of weak acidic resin is Indion 236H+.

[0043] In one embodiment, the present invention provides a crystalline form of Salcaprozate sodium characterized by powder X-ray diffractogram as shown in Figure 1.

[0044] In another embodiment, the present invention provides a crystalline form of Salcaprozate sodium characterized by a Differential scanning calorimetry (DSC) pattern as illustrated in Figure 2.

[0045] In another embodiment, the present invention provides a crystalline form of Salcaprozate sodium characterized by a Scanning Electron Microscopy (SEM) pattern as illustrated in Figure 3.

[0046] In another embodiment, Salcaprozate sodium of the present invention has a purity of greater than 99.5% by HPLC.

[0047] In another embodiment, the Salcaprozate sodium of the present invention comprises one or more impurities such as impurity A, impurity B or impurity C at an amount of NMT 0.1% w / w. The structures of the impurities are shown below:Impurity C

[0048] In another embodiment, Salcaprozate sodium of the present invention has a water content value of NMT 1.0 % (w / w).

[0049] In another embodiment, Salcaprozate sodium of the present invention has a specific surface area (SSA) of <25 m2 / gm, preferably <20 m2 / gm.

[0050] In another embodiment, Salcaprozate sodium of the present invention comprises one or more metal impurities. The ICH specification of the metal impurities and the observed elemental results are shown in Table 1:

[0051] In another embodiment, Salcaprozate sodium of the present invention has a bulk density of less than 1.0 gm / ml, more preferably less than 0.5gm / ml.

[0052] In another embodiment, Salcaprozate sodium obtained by the present invention is having tap density less than 2.0 gm / ml, more preferably less than l.Ogm / ml.

[0053] In another embodiment, the absorbance and transmittance of 1% solution of the Salcaprozate sodium was checked at 400nm using UV-VIS spectrophotometer. The absorbance, transmittance, and purity of the Salcaprozate sodium prepared according to present invention is shown in Table 2:

[0054] UV absorbance of the Salcaprozate sodium at 270nm, 322nm & 350nm is shown inTable 3:

[0055] In one embodiment, the present invention provides a solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients, wherein the one or more active pharmaceutical ingredient has a low solubility, and / or a low membrane permeability, and / or a metastable polymorphic nature

[0056] In one embodiment, the present invention provides a stable solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients. The stable solid dispersion of the present invention is crystalline, or amorphous, or may be a substantially amorphous with certain degree of crystallinity, for example at an amount that is less than 20%, less than 10%, less than 5%, or less than 1%.

[0057] The Biopharmaceutics Classification System (BCS) is a system to differentiate active pharmaceutical ingredients because of their solubility and permeability. In one embodiment, one or more active pharmaceutical ingredients used in the present invention may be classified under the BCS system as Class-I, II, III or IV.

[0058] BCS CLASSCIFICATIONS:Below are the non-limiting examples of various Active pharmaceutical ingredients falling under four BCS classifications:

[0059] CLASS I (includes APIs that have high permeability & high solubility): Acetylsalicylic acid, Viloxazine HC1, Pitolisant hydrochloride, Chloroquine, Amlodipine,Amoxicillin, Ascorbic acid, Doxycycline HC1, Levofloxacin, Metronidazole, Prednisolone, Prednisone, Primaquine, Propranolol, Quinidine, Quinine, Stavudine, Warfarin sodium, Verapamil, Biperiden HC1, Quinidine, Levodopa, Carbidopa.

[0060] CLASS II (includes APIs that have higher permeability & lower solubility): Diclofenac, Suvorexant, Asciminib Hydrochloride, Bempedoic acid, Cariprazine hydrochloride, Selexipag, Cannabidiol, Apalutamide, Ibuprofen, Ketoprofen, Mefloquine, Quinine, Rifampicin, Phenytoin sodium, Carbamazepine, Dapsone, Griseofulvin, lopanoic acid, Nevirapine, Nitrofurantoin, Praziquantel, Trimethoprim, Sulfamethoxazole, Trimethoprim, Diazepam, Nicotinamide, Ciomifene citrate, Ibuprofen, Ciomifene citrate, Hydrochlorothiazide, Nifurtimox, Albendazole, Glibenclamide Clofazimine, Efavirenz, Niclosamide, Haloperidol, Ivermectin, Spironolactone, Valproic acid sodium, Artemether, Risdiplam.

[0061] CLASS III (includes APIs having lower permeability & high solubility): Acetaminophen, Eluxadoline, Betrixaban, Abacavir, Amodiaquine, Atenolol, Benznidazole, , Chloramphenicol, Chlorpromazine HC1, Ciprofloxacin HC1, Cioxacillin sodium, Cimetidine, Ethambutol, Enalapril, Ergocalciferol, Ethambutol HCL, Ferrous salt, Carbidopa, Levothyroxine sodium, Metformin HC1, Isoniazid, Lamivudine, Metaclopramide, Pyrazinamide, Ranitidine, Methyldopa, Penicillamine, Zinc sulfate, Thiamine hydrochloride. Amiloride hydrochloride, Metaclopramide, Salbutamol sulfate, Abemaciclib, Azithromycin, Pyrimethamine.

[0062]

[0004] CLASS IV (includes APIs having less permeability & less solubility):Acetazolamide, Relugolix, Ribociclib, Venetoclax, Lumefantrine, Cefixime, Diloxanide furoate, Erythromycin stearate, Erythromycin ethyl succinate, Furosemide, Lopinavir, Ritonavir, Indinavir sulfate, Mebendazole, Mefloquine HC1 , Nelfinavir mesylate, Pyrantel embonate, Retinol palmitate, Ritonavir, Saquinavir, Sulfasalazine, Triclabendazole, Allopurinol, Ciprofloxacin HC1, Venetoclax, Folic acid, Digoxin, Olaparib.”

[0063] In one embodiment, the present invention provides a solid dispersion of Salcoprazate sodium with one or more active pharmaceutical ingredients wherein the active pharmaceutical ingredients is a therapeutically active peptide, for e.g.; a GLP-1 agonist like Semaglutide or a GLP-1 analogue, optionally comprising one substituent.

[0064] In some embodiments, a simple nomenclature is used to describe the GLP-1 agonist, e.g., [Aib8] GLP-l(7-37) designates an analogue of GLP-l(7-37) wherein the naturally occurring Ala in position 8 has been substituted with Aib. In some embodiments the GLP-1 agonist comprises a maximum of twelve, such as a maximum of 10, 8 or 6, amino acids which have been altered, e.g., by substitution, deletion, insertion and / or modification, compared to e.g. GLP-l(7-37).

[0065] The term “analogue” as used herein refers to a GLP-1 peptide (hereafter “peptide”) means a peptide wherein at least one amino acid residue of the peptide has been substituted with another amino acid residue and / or wherein at least one amino acid residue has been deleted from the peptide and / or wherein at least one amino acid residue has been added to the peptide and / or wherein at least one amino acid residue of the peptide has been modified. Such addition or deletion of amino acid residues may take place at the N-terminal of the peptide and / or at the C-terminal of the peptide.

[0066] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium with suvorexant.

[0067] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium with suvorexant, wherein the solid dispersion is characterized by powder X-ray diffractogram as shown in Figure 4.

[0068] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium with Risdiplam.

[0069] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium with Risdiplam, wherein the solid dispersion is characterized by powder X-ray diffractogram as shown in Figure 5.

[0070] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium and Asciminib hydrochloride.

[0071] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium and Asciminib hydrochloride, wherein the solid dispersion is characterized by powder X-ray diffractogram as shown in Figure 6.

[0072] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium and Selexipag.

[0073] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium and Selexipag, wherein the solid dispersion is characterized by powder X-ray diffractogram as shown in Figure 7.

[0074] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium and Pitolisant hydrochloride.

[0075] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium and Pitolisant hydrochloride, wherein the solid dispersion is characterized by powder X-ray diffractogram as shown in Figure 8.

[0076] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium and Olaparib.

[0077] In another embodiment, the present invention provides a solid dispersion of Salcaprozate sodium and Olaparib, wherein the solid dispersion is characterized by powder X- ray diffractogram as shown in Figure 9.

[0078] In another embodiment, the present invention provides a process for the preparation of solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients, wherein the process comprises:(a) dissolving Salcaprozate sodium and one or more active pharmaceutical ingredients in one or more solvents selected from the group comprising of: N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, l-methyl-2-pyrrolidone, l-methyl-2-piperidone, 1,3- dimethyl-2-imidazolidinone, acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, methanol, ethanol, isopropanol, water, or a combination thereof;(b) removing the solvent from the reaction mass by at least one of evaporation, spray drying, and freeze drying; and(c) isolating the solid dispersion comprising of Salcaprozate sodium and one or more active pharmaceutical ingredients.

[0079] The suitable techniques used for isolating the desired product may be selected from but not limited to filtration, solvent evaporation, hot melt extrusion, lyophilization or freeze drying, spray drying, agitated thin film drying (ATFD), air tray drying (ATD), Vacuum tray dryer (VTDR), vacuum drying, cooling the solvent, adding anti-solvent to the reaction mixture and combination thereof. Preferably, solvent evaporation, Vacuum tray dryer (VTDR) and free drying and spray drying were used in the present invention. The drying can be carried out at a suitable temperature ranging from about 40°C to about 70°C, preferably from about 60°C to about 65°C.

[0080] In one embodiment, the amorphous solid dispersion comprises Salcaprozate sodium and one or more active ingredient in a ratio from 0.1: 1 to 100: 1. In a preferred embodiment, the ratio of Salcaprozate sodium and one or more active ingredient is from 0.1: 1 to 20: 1.

[0081] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients.

[0082] In another embodiment, the present invention provides a process for the preparation of solid dispersions of Salcaprozate sodium with one or more active pharmaceutical ingredients, which comprises:(a) dissolving or suspending Salcaprozate sodium in one or more suitable solvent;(b) mixing suitable quantity of active pharmaceutical ingredient with the obtained solution or suspension; or vice versa.(c) stirring the suspension or solution for a sufficient period of time; and(d) isolating the solid dispersions of Salcaprozate sodium and a active pharmaceutical ingredient.

[0083] In step (a) of the above-described process, the solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like;preferably methanol. In step (b), the active pharmaceutical ingredient is selected from Suvorexant, Risdiplam, Asciminib Hydrochloride, Mitapivat, Relugolix, Bempedoic acid, Cariprazine hydrochloride, Selexipag, Pimavanserin, Tavaborole, Crisaborole, Cannabidiol, Viloxazine hydrochloride, Tafamidis, Pitolisant hydrochloride, Ribociclib, Rucaparib, Eluxadoline, Abemaciclib, Venetoclax, Roxadustat, Apalutamide, Betrixaban or the like.

[0084] In step (d) of the above described process, isolating the solid dispersion of Salcaprozate sodium involves removal of solvent by suitable techniques which include but are not limited to evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture or by any other suitable techniques known in the art.

[0085] In the process of the present invention, drying the amorphous solid dispersion of Salcaprozate sodium involves using suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressure at temperature of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperature. The drying can be carried out for any time period required for obtaining a desired quality, such as from a few minutes to 10 hours or longer.

[0086] In a preferred embodiment, a process for the preparation of solid dispersion of Salcaprozate sodium with suvorexant comprises: (i) dissolving Salcaprozate sodium in a suitable alcoholic solvent; (ii) adding Suvorexant to the obtained solution; (iii) stirring the obtained suspension for sufficient period of time; preferably for 15-30 mins at room temperature; and (iv) isolating the solid dispersion by spray drying.

[0087] In another preferred embodiment, a process for the preparation of solid dispersion of Salcaprozate sodium using Risdiplam, comprises (i) dissolving Salcaprozate sodium in a suitable alcoholic solvent; (ii) adding Risdiplam to the obtained solution; (iii) stirring the obtained suspension for a sufficient period of time, preferably for 15-30 mins at roomtemperature; and (iv) isolating the solid dispersion of Salcaprozate sodium with Risdiplam by spray drying.

[0088] In another preferred embodiment, a process for the preparation of solid dispersion of Salcaprozate sodium using Asciminib hydrochloride comprises (i) dissolving Salcaprozate sodium in a suitable alcoholic solvent; (ii) adding Asciminib hydrochloride to the obtained solution; (iii) stirring the obtained suspension for sufficient period of time, preferably for 15- 30 mins at room temperature; and (iv) isolating the solid dispersion of Salcaprozate sodium using Asciminib hydrochloride by spray drying.

[0089] In another preferred embodiment, a process for the preparation of solid dispersion of Salcaprozate sodium with Asciminib hydrochloride comprises (i) dissolving Salcaprozate sodium in a suitable alcoholic solvent; (ii) adding Asciminib hydrochloride to the obtained solution; (iii) stirring the obtained suspension for sufficient period of time, preferably for 15- 30 mins at room temperature; and (iv) isolating the solid dispersion of Salcaprozate sodium using Asciminib hydrochloride by filtration.

[0090] In a preferred embodiment, a process for the preparation of solid dispersion of Salcaprozate sodium with Asciminib hydrochloride comprises (i) dissolving Salcaprozate sodium in a mixture of DMSO and water; (ii) adding Asciminib hydrochloride to the obtained solution; (iii) stirring the obtained suspension for sufficient period of time, preferably for 15- 30 mins at room temperature; and (iv) isolating the solid dispersion of Asciminib- Salcaprozate sodium solid dispersion by freeze drying.In another embodiment, the present invention disclosure shows solubility analysis of active pharmaceutical ingredient and its Salcaprozate solid dispersion. The solubility study shown enhancement of drug substance solubility in presence of Salcaprozate sodium. Suvorexant, Asciminib hydrochloride, Selexipag have low solubility and high permeability. A solid dispersion of these APIs with Salcaprozate sodium can increase the compound solubility / dissolution, thereby improving their bioavailability.The following examples illustrate the present invention but should not be construed as limiting the scope of the invention.EXAMPLES

[0091] Example 1: Purification of Salcaprozate sodium.Salcaprozate sodium (50g) was dissolved in ethanol (1000 mL) and heated to 55-70°C. Activated charcoal (3gm) was added to the reaction mass and stirred. The reaction mass was passed through resin column. The filtrate obtained was dried and then cooled to 25-30°C. The solid formed was dried under vacuum to yield pure Salcaprozate sodium.Yield: 85% (w / w);HPLC Purity: 99.9% (w / w). (total impurities less than 0.1%(w / w); sodium content: 6.8 to 8.36PXRD: Fig. 1.DSC: Fig. 2;Scanning Electron Microscopy (SEM): Fig. 3

[0092] Example 2: Preparation of solid dispersion of Suvorexant with Salcaprozate sodium.Suvorexant (15 g) and Salcaprozate sodium (15 g) were dissolved in methanol (600 mL) at 25- 30°C and stirred for 5-10 mins. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:Inlet Temperature : 60°CAspirator : 1600Feed Rate : 20ml / minThe solid so obtained was unloaded and dried under vacuum for 12-15 hour at below 50°C to yield solid dispersion of suvorexant (1) with Salcaprozate sodium. Yield: 65%(w / w).

[0093] Example 3: Preparation of solid dispersion of Suvorexant with Salcaprozate sodium.Suvorexant (1 g) and Salcaprozate sodium (3 g) were dissolved in methanol (10 v) at 25-30°C and stirred for 5-10 mins. The total reaction mixture was evaporated by Buchi distillation to yield solid dispersion of Suvorexant (1) with Salcaprozate sodium. Yield: 90 (w / w).PXRD: Fig. 4

[0094] Example 4: Preparation of solid dispersion of Risdiplam with Salcaprozate sodium.Risdiplam (5.0g) and Salcaprozate sodium (25.0 g) were dissolved in methanol (85 volumes) at 25-30°C and stirred for 5 min. The reaction mass temperature was heated to 60-65°C and stirred. The total reaction mixture was then transferred to a beaker and spray dried with the below settings:Inlet Temperature : 70°COutlet Temperature : 30°CN2 pressure : 2KgAspirator : 1600Feed pump : 40 RPMThe solid obtained was unloaded and dried under vacuum to yield solid dispersion of Risdiplam with Salcaprozate sodium.

[0095] Example 5: Preparation of solid dispersion of Risdiplam with Salcaprozate sodium.Risdiplam (1 g) and Salcaprozate sodium (2 g) were dissolved in methanol (10 v) at 25-30°C and stirred for 5-10 mins. The solution was transferred into a Buchi flask and heated to 45-55 °C. Distilled off the solvent completely from the reaction mixture under vacuum and dried the material provide the title compound. Yield: 90 % (w / w).PXRD: Fig. 5

[0096] Example 6: Preparation of amorphous solid dispersion of Asciminib hydrochloride with Salcaprozate sodium.A mixture of Asciminib hydrochloride (100 mg) and Salcaprozate sodium (250 mg) was dissolved in methanol (25 ml) at 25 30°C. The solution was transferred into a Buchi flask and heated to 45-55 °C. Distilled off the solvent completely from the reaction mixture under vacuum and dried the material provide the title compound. Yield: 91.5%. PXRD: Fig. 6.

[0097] Example 7: Preparation of amorphous solid dispersion of Asciminib hydrochloride with Salcaprozate sodium.Asciminib hydrochloride (3 gram) was dissolved in methanol (400 mL) at room temperature. To this, Salcaprozate sodium (7.5 g) was added and stirred for 15 to 30 minutes at the same temperature. The reaction mixture was spray dried to obtain amorphous solid dispersion ofAsciminib hydrochloride (1) with Salcaprozate sodium:Operation parameters:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 49.5%

[0098] Example 8: Preparation of solid dispersion of Asciminib hydrochloride with Salcaprozate sodium.A mixture of DMSO (60 ml) and water (2.50 ml) was added to Asciminib hydrochloride (1) (1 gram) and Salcaprozate sodium (2.5 gram) at room temperature and stirred for 15 to 30 minutes at the same temperature. The reaction mass was freeze dried (lyophilization) at -10 to -40°C and dried the material to obtain amorphous solid dispersion of Asciminib hydrochloride (1) with Salcaprozate sodium.Yield: 85.7%.

[0099] Example 9: Process for the preparation of amorphous solid dispersion ofSelexipag with Salcaprozate sodiumSelexipag (1 g) and Salcaprozate sodium (2 g) were dissolved in methanol (10 v) at 25-30°C and stirred for 5-10 mins. The solution was transferred into a Buchi flask and heated to 45-55 °C. Distilled off the solvent completely from the reaction mixture under vacuum and dried the material provide the title compound. Yield: 90 % (w / w). PXRD: Fig. 7

[0100] Example 10: Preparation of amorphous solid dispersion of Selexipag with Salcaprozate sodium.Dissolved Selexipag (1 g) in methanol (10 v) at room temperature. To this Salcaprozate sodium(2 g) was added and stirred for 15 to 30 minutes at the same temperature. The reaction mixture was spray dried to obtain amorphous solid dispersion of Selexipag with Salcaprozate sodium:Operation parameters:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 60%

[0101] Example 11: Process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride (1) with Salcaprozate sodiumPitolisant hydrochloride (1 g) and Salcaprozate sodium (3 g) were dissolved in methanol (10 v) at 25-30°C and stirred for 5-10 mins. The solution was transferred into a Buchi flask and heated to 45-55 °C. Distilled off the solvent completely from the reaction mixture under vacuum and dried the material provide the title compound. Yield: 90 % (w / w). PXRD: Fig. 8

[0102] Example 12: Preparation of amorphous solid dispersion of Olaparib with Salcaprozate sodium.Pitolisant hydrochloride (1 g) was dissolved in methanol (10 v) at room temperature. To this Salcaprozate sodium (3 g) was added and stirred for 15 to 30 minutes at the same temperature.The reaction mixture was spray dried to obtain amorphous solid dispersion of Pitolisant hydrochloride (1) with Salcaprozate sodium:Operation parameters:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 60%

[0103] Example 13: Process for the preparation of amorphous solid dispersion ofOlaparib (1) with Salcaprozate sodiumOlaparib (1 g) and Salcaprozate sodium (2 g) were dissolved in methanol (10 v) at 25-30°C and stirred for 5-10 mins. The solution was transferred into a Buchi flask and heated to 45-55 °C. Distilled off the solvent completely from the reaction mixture under vacuum and dried the material provide the title compound. Yield: 90 % (w / w). PXRD: Fig. 9.Example 14: Preparation of amorphous solid dispersion of Olaparib with Salcaprozate sodium.Olaparib (1 g) was dissolved in methanol (10 v) at room temperature. To this Salcaprozate sodium (2 g) was added and stirred for 15 to 30 minutes at the same temperature. The reaction mixture was spray dried to obtain amorphous solid dispersion of Olaparib (1) with Salcaprozate sodium:Operation parameters:Inlet Temperature : 50°COutlet Temperature : 30°CAspirator : 70%Feeding rate : 20 mL / minN2 Pressure : 2.0 kg / cm2Yield: 60%

Claims

We claim:

1. A solid dispersion comprising of Salcaprozate sodium with one or more active pharmaceutical ingredients.

2. The solid dispersion of claim 1, wherein the active pharmaceutical ingredient is selected from the group consisting of: Suvorexant, Risdiplam, Asciminib Hydrochloride, Mitapivat, Relugolix, Bempedoic acid, Cariprazine hydrochloride, Selexipag, Pimavanserin, Tavaborole, Crisaborole, Cannabidiol, Viloxazine hydrochloride, Tafamidis, Pitolisant hydrochloride, Ribociclib, Rucaparib, Eluxadoline, Abemaciclib, Venetoclax, Roxadustat, Apalutamide, Betrixaban, or combinations thereof.

3. The solid dispersion of claim 1, wherein the active pharmaceutical ingredient is a therapeutically active peptide.

4. The solid dispersion of claim 1, wherein the solid dispersion has improved stability, improved solubility, or improved membrane permeability.

5. A process for the preparation of a solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients, said process comprises:(a) dissolving Salcaprozate sodium with one or more active pharmaceutical ingredients in one or more solvents, and(b) isolating solid dispersion of Salcaprozate sodium with one or more active pharmaceutical ingredients.

6. A process for the preparation of a solid dispersion of Salcaprozate sodium with Suvorexant, which comprises:(a) dissolving Salcaprozate sodium and Suvorexant in one or more solvents; and(b) isolating solid dispersion of Salcaprozate sodium with Suvorexant. wherein, the characteristic XRPD pattern as depicted in Figure 47. A process for the preparation of a solid dispersion of Salcaprozate sodium with Risdiplam, said process comprises:(a) dissolving Salcaprozate sodium and Risdiplam in one or more solvents, and(b) isolating solid dispersion of Salcaprozate sodium with Risdiplam. wherein, the characteristic XRPD pattern as depicted in Figure 58. A process for the preparation of a solid dispersion of Salcaprozate sodium with Asciminib hydrochloride, said process comprises:(a) dissolving Salcaprozate sodium and Asciminib hydrochloride in one or more solvents, and(b) isolating solid dispersion of Salcaprozate sodium with Asciminib hydrochloride.wherein, the characteristic XRPD pattern as depicted in Figure 69. A process for the preparation of a solid dispersion of Salcaprozate sodium with Selexipag, said process comprises:(a) dissolving Salcaprozate sodium and Selexipag in one or more solvents, and(b) isolating solid dispersion of Salcaprozate sodium with Selexipag. wherein, the characteristic XRPD pattern as depicted in Figure 710. A process for the preparation of a solid dispersion of Salcaprozate sodium with Pitolisant hydrochloride, said process comprises:(a) dissolving Salcaprozate sodium and Pitolisant hydrochloride in one or more solvents, and(b) isolating solid dispersion of Salcaprozate sodium with Pitolisant hydrochloride wherein, the characteristic XRPD pattern as depicted in Figure 811. A process for the preparation of a solid dispersion of Salcaprozate sodium with Olaparib, said process comprises:(a) dissolving Salcaprozate sodium and Olaparib in one or more solvents; and(b) isolating solid dispersion of Salcaprozate sodium with Olaparib wherein, the characteristic XRPD pattern as depicted in Figure 912. The process as claimed in any of the proceeding claims wherein, the ratio of Salcaprozate sodium with active pharmaceutical ingredient ranges from about 0.4 to 1 and 20:

113. The process as claimed in any of the proceeding claims, wherein the solvent is selected from a group consisting of N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, l-methyl-2-pyrrolidone, l-methyl-2-piperidone, l,3-dimethyl-2- imidazolidinone, acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, methanol, ethanol, isopropanol, water, and any combination thereof.

14. The process as claimed in any of the proceeding claims, wherein isolating involves removal of solvent from the reaction is carried out by at least one of evaporation, spray drying, and freeze drying.

15. The solid dispersion of claim 1, wherein the dispersion is a stable amorphous solid dispersion comprising Salcaprozate sodium with one or more active pharmaceutical ingredients.

16. A pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion of claim 1.

17. A composition comprising: Salcaprozate sodiumwherein Salcaprozate sodium comprises one or more impurity is present in an amount that is greater than zero and equal to or less than 1 weight percent of the composition and metal impurities less than lOppm18. A composition comprising: Salcaprozate sodium wherein Salcaprozate sodium is having specific surface area less than (SSA) 25 m2 / gm19. A process for the preparation of pure Salcaprozate sodium, comprising the steps of: a) providing Salcaprozate sodium (1) in a suitable solvent; b) treating the reaction mixture with activated charcoal. c) passing the reaction mixture through resin column; and d) isolating pure Salcaprozate sodium (1) wherein Salcaprozate sodium contains less than lOppm of colour impurities and characterized by X-Ray powder diffraction pattern as shown in figure 1, and DSC as shown in figure 220. The process as claimed in claim 19, wherein the solvent is selected from methanol, ethanol, isopropyl alcohol, n-propanol, butanol and / or mixture thereof.

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