Solid state forms of (4as,6r,8as)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6h-benzofuro[3a,3,2-ef][2]benzazepin-6-benzoate gluconate

Abstract

The present invention relates to a solid state forms of (4aS,6R,8aS)-4a,5,9,10,11,12- hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-benzoate gluconate, which is referred to as Benzgalantamine gluconate and represented by the following structural formula-1. The present invention also relates to a process for the preparation of solid state forms of Benzgalantamine gluconate.

Description

[0001] Solid state forms of (4aS,6R,8aS)-4a,5,9,10,ll,12-hexahvdro-3-methoxy-ll-methyl-6H- benzofuro[3a.,3.,2-ef| [21benzazepin-6-benzoate gluconate

[0002] Related Application:

[0003] This application claims the benefit of priority of our Indian patent application number 202541025642 filed on 20thMarch 2025 which are incorporated herein by reference.

[0004] Field of the Invention:

[0005] The present invention relates to a solid state forms of (4aS,6R,8aS)-4a,5,9,10,ll,12-hexahydro-3 -methoxy- 11 -methyl-6H-benzofuro[3a,3,2-ef] [2]benzazepin-6-benzoate gluconate, which is referred to as Benzgalantamine gluconate and represented by the following structural formula- 1 ,

[0006]

[0007] Formula- 1

[0008] The present invention also relates to a process for the preparation of solid state forms of Benzgalantamine gluconate.

[0009] Background of the Invention:

[0010] Benzgalantamine is a prodrug of an approved acetylcholinesterase inhibitor (AChEI), galantamine. It has been uniquely designed to significantly reduce the side-effects observed with the other AChEIs. Benzgalantamine is absorbed in the small intestine as an inert drug. Binding with AChE in the gastrointestinal nervous system is blocked by the addition of a benzoyl ester to galantamine. This reduces overstimulation of local neurons, reduces GI sideeffects, and increases bioavailability. Once absorbed, Benzgalantamine is metabolized in the liver to the active drug and galantamine and is carried to the brain in the circulatory system.US20090253654 discloses Benzgalantamine or a pharmaceutically acceptable salt. This patent also discloses a process for the preparation of Benzgalantamine.

[0011]

[0012] Galantamine .HBr Benzgalantamine

[0013] US 11077119B2 discloses Benzgalantamine gluconate and process for its preparation. US’ 119 also discloses crystalline form of Benzgalantamine gluconate and process for its preparation.

[0014] Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and / or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

[0015] Polymorphic forms (or) solid state forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.Brief description of the Invention:

[0016] The present invention relates to solid state forms of Benzgalantamine gluconate and process for its preparation.

[0017] Brief description of the Drawings:

[0018] Figure- 1A: Illustrates the PXRD pattern of Benzgalantamine gluconate prepared according to the example- 1.5 of US 11077119 B2.

[0019] Figure-1: Illustrates the PXRD pattern of solid dispersion of Benzgalantamine gluconate with povidone-K30.

[0020] Figure-2: Illustrates the PXRD pattern of solid dispersion of Benzgalantamine gluconate with HPMC-E5.

[0021] Figure-3: Illustrates the PXRD pattern of solid dispersion of Benzgalantamine gluconate with HPMC-AS.

[0022] Figure-4: Illustrates the PXRD pattern of Crystalline Form-M of Benzgalantamine.

[0023] Figure-5: Illustrates the PXRD pattern of solid dispersion of Benzgalantamine gluconate with HPMC -Phthalate.

[0024] Figure-6: Illustrates the PXRD pattern of Benzgalantamine (after treating with Hydrochloric acid) as per example-7.

[0025] Detailed description of the Invention:

[0026] As used herein the term “solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and thelike; “polar-aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, acetyl acetone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene glycol-400, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water and or mixtures thereof.

[0027] The term “pure” in relation to compound of formula- 1 of Benzgalantamine Gluconate prepared by the process of the present invention is substantially free from the impurities. The said compound of formula- 1 of Benzgalantamine Gluconate obtained according to the present invention is substantially pure having a purity of >99%, preferably >99.5% by HPLC.

[0028] 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 defined by the number ±10% of its value, preferably a range defined by the number ±5%, more preferably a range defined by the number ±2%, still more preferably a range defined by the number ±1%. 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, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

[0029] As used herein, the term “solid dispersion” refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two or more components (polymer and API) form a homogeneous one -phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.As used herein, the term “excipient” refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.

[0030] In the present application, solid dispersion and premix are used interchangeably to describe solid states disclosed herein.

[0031] In the first embodiment, the present invention provides a solid dispersion of Benzgalantamine gluconate with one or more pharmaceutically acceptable excipients.

[0032] In the first embodiment, the suitable pharmaceutically acceptable excipient is selected from but not limited to syloid, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), co-povidone, crospolyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodex trins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate,propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

[0033] In the second embodiment, the present invention provides a process for the preparation of solid dispersion of Benzgalantamine gluconate with one or more pharmaceutically acceptable excipients, which comprises:

[0034] a) providing a solution comprising Benzgalantamine gluconate and at least one pharmaceutically acceptable excipient in a solvent or a mixture of solvents; and b) isolating the solid dispersion of Benzgalantamine gluconate.

[0035] In the process of the second embodiment, providing a solution of Benzgalantamine gluconate in step-a) comprises dissolving Benzgalantamine gluconate in a suitable solvent at a suitable temperature of about 25 °C to the reflux temperature of the solvent. Optionally, the solution can be filtered to make it particle free.

[0036] In the process of the second embodiment, further adding at least one pharmaceutically acceptable excipient to the obtained solution at a suitable temperature of about 25°C and above.

[0037] In the process of second embodiment, the suitable pharmaceutically acceptable excipient used in step-a) is same as defined in the first embodiment.

[0038] In the first aspect of the second embodiment, the present invention provides a process for the preparation of solid dispersion of Benzgalantamine gluconate with povidone-K30, which comprises:

[0039] a) providing a solution comprising Benzgalantamine gluconate and povidone-K30; and b) isolating the solid dispersion of Benzgalantamine gluconate with povidone-K30. In the process of the first aspect of second embodiment, providing a solution of Benzgalantamine gluconate in step-a) comprises dissolving Benzgalantamine gluconate in an alcohol solvent at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0040] In the process of the first aspect of second embodiment, further adding povidone-K30 to the obtained solution or adding the obtained solution to povidone-K30 at a suitabletemperature of about 25°C and above.

[0041] In the second aspect of the second embodiment, the present invention provides a process for the preparation of solid dispersion of Benzgalantamine gluconate with HPMC-E5, which comprises:

[0042] a) providing a solution comprising Benzgalantamine gluconate and HPMC-E5; and b) isolating the solid dispersion of Benzgalantamine gluconate with HPMC-E5.

[0043] In the process of the second aspect of second embodiment, providing a solution of Benzgalantamine gluconate in step-a) comprises dissolving Benzgalantamine gluconate in an alcohol solvent at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0044] In the process of the second aspect of second embodiment, further adding HPMC-E5 to the obtained solution or adding the obtained solution to HPMC-E5 at a suitable temperature of about 25 °C and above.

[0045] In the third aspect of the second embodiment, the present invention provides a process for the preparation of solid dispersion of Benzgalantamine gluconate with HPMC-AS, which comprises:

[0046] a) providing a solution comprising Benzgalantamine gluconate and HPMC-AS; and b) isolating the solid dispersion of Benzgalantamine gluconate with HPMC-AS.

[0047] In the process of the third aspect of second embodiment, providing a solution of Benzgalantamine gluconate in step-a) comprises dissolving Benzgalantamine gluconate in an alcohol solvent at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0048] In the process of the third aspect of second embodiment, further adding HPMC-AS to the obtained solution or adding the obtained solution to HPMC-AS at a suitable temperature of about 25 °C and above.

[0049] In the fourth aspect of the second embodiment, the present invention provides a process for the preparation of solid dispersion of Benzgalantamine gluconate with HPMC Phthalate, which comprises:a) providing a solution comprising Benzgalantamine gluconate and HPMC- Phthalate; and

[0050] b) isolating the solid dispersion of Benzgalantamine gluconate with HPMC- Phthalate. In the process of the fourth aspect of second embodiment, providing a solution of Benzgalantamine gluconate in step-a) comprises dissolving Benzgalantamine gluconate in an alcohol solvent at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0051] In the process of the fourth aspect of second embodiment, further adding HPMC-Phthalate to the obtained solution or adding the obtained solution to HPMC- Phthalate at a suitable temperature of about 25 °C and above.

[0052] Solid dispersions of Benzgalantamine Gluconate are found to be stable under various conditions.

[0053] Presented below is an exemplary tabular summary demonstrating the stability of a solid dispersion of Benzgalantamine Gluconate with Povidone K-30 according to the present invention under different conditions.

[0054]

[0055] In an embodiment, Benzgalantamine gluconate and pharmaceutically acceptable excipients present in weight ratio ranging from about 1:0.05 to about 1:5. Preferably, the ratio is about 1:1.

[0056] In an embodiment, Benzgalantamine gluconate and pharmaceutically acceptable excipients present in weight ratio ranging from about 0.5: 99.5 to about 99.5: 0.5. Preferably, the ratio is about 50: 50.In an aspect of the present invention, the weight ratio of the Benzgalantamine gluconate to the excipient(s) in the solid dispersion can be selected from about 1 : 0.05, about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1.0, about 1:1.5, about 1:2.0, about 1:2.5, about 1:3.0, about 1:3.5, about 1:4.0, about 1:4.5 or about 1 :5 or any other suitable weight ratio falling between thereof.

[0057] In the third embodiment, the present invention provides a crystalline Form-M of Benzgalantamine.

[0058] The first aspect of the third embodiment provides crystalline Form-M of Benzgalantamine, which is characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 8.1, 13.0 and 17.7 ± 0.2 degrees 2-theta.

[0059] The second aspect of the third embodiment provides crystalline Form-M of Benzgalantamine characterized by its powder X-Ray diffraction (XRD) pattern as illustrated in figure-4.

[0060] In the fourth embodiment, the present invention provides a process for the preparation of crystalline Form-M of Benzgalantamine, comprising:

[0061] a) providing a solution of Benzgalantamine in a solvent,

[0062] b) isolating crystalline Form-M of Benzgalantamine.

[0063] In step-a) of the fourth embodiment, the solvent is selected from alcohol solvent, ester solvent, chloro solvent, ether solvent, ketone solvent, nitrile solvent, polar-aprotic solvent, water or mixtures thereof.

[0064] In the fifth embodiment, the present invention provides a process for the preparation of pure Benzgalantamine Gluconate of formula-1, comprising of the following steps:

[0065] a) reacting Galantamine or its pharmaceutically acceptable salts of formula-3 with benzoyl chloride in presence of a suitable base and a nitrile solvent to provide Benzgalantamine of formula-2,

[0066]

[0067] b) optionally treating the obtained Benzgalantamine with an acid followed by treatment with a base;

[0068] c) treating Benzgalantamine of formula-2 with D-(+)-Glucono-l,5-lactone in isopropanol to obtain Benzgalantamine gluconate of formula- 1; and

[0069] d) optionally purifying the Benzgalantamine Gluconate in a solvent or mixture of solvents to obtain pure Benzgalantamine Gluconate.

[0070] Wherein, the suitable base used in step-a) or b) is selected from organic base or inorganic base; the acid is selected from inorganic acid or organic acid; the suitable solvent used in step-d) is selected from alcohol solvent, ester solvent, chloro solvent, ether solvent, ketone solvent, nitrile solvent, polar-aprotic solvent, water or mixtures thereof; the suitable nitrile solvent used in step-a) is selected from acetonitrile, propionitrile, isobutyronitrile and the like

[0071] The starting material of compound of formula-3 used in the present invention, can be prepared by any of the processes known in the art.

[0072] In an aspect of the fifth embodiment, the present invention provides a pure Benzgalantamine Gluconate of formula- 1 having a purity greater than about 99.5% by weight. Which is substantially free from one or more impurities selected from ‘Dihydrogalantamine benzoate impurity’, ‘Enti-galantamine benzoate impurity’ and ‘N-oxide impurity’ as measured by HPLC (High performance liquid chromatography) method.

[0073]

[0074] Dihydrogalantamine Enti-galantamine N-oxide impurity benzoate impurity benzoate impurity

[0075] As used herein, 'substantially free' refers to pure Benzgalantamine Gluconate containing one or more impurities selected from ‘Dihydrogalantamine benzoate impurity’, ‘Enti-galantamine benzoate impurity’ and ‘N-oxide impurity’ in amount less than about 0.5% or less than about 0.1% or less than about 0.05% as measured by the High-Performance Liquid Chromatography (HPLC) method.

[0076] The inventors of the present invention have developed a cost-effective and industrially feasible process for the preparation of Benzgalantamine using a suitable nitrile solvent. The obtained Benzgalantamine is further treated with an acid, followed by treatment with a base, to obtain Benzgalantamine with high purity and yield. Subsequently, Benzgalantamine is converted to its gluconate salt in isopropanol. The use of isopropanol is advantageous for improving yield. The process of the present invention is significantly more efficient in achieving enhanced purity and yield compared to existing synthetic approaches

[0077] In the process of present invention, isolating involves removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, 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 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.

[0078] In the process of the present invention, drying involves by 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 pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

[0079] Benzgalantamine or solid state forms of Benzgalantamine gluconate prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.

[0080] In the present invention, the starting material of Benzgalantamine gluconate can be used in the form of amorphous or crystalline or any other physical form with the process prepared from any of the processes known in the art.

[0081] In the present invention, pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.

[0082] In the process of the present invention the resulting, solid dispersion of Benzgalantamine gluconate can be amorphous, crystalline or a mixture thereof.

[0083] In an embodiment, pharmaceutical composition comprising solid dispersion of Benzgalantamine gluconate and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

[0084] In an embodiment, the present invention provides a method of treating a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a solid dispersion comprising Benzgalantamine gluconate and one or more pharmaceutically acceptable excipients.

[0085] As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.P-XRD Method of Analysis:

[0086] PXRD analysis of compound of formula- 1 was carried out by using BRUKER / D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03° / min.

[0087] The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

[0088] Examples:

[0089] Reference Example-1: Preparation of Benzgalantamine gluconate as per the Example-1.5 of US11077119B2.

[0090] Benzgalantamine (9.4 g) in 96% ethanol (28 ml) was added to the mixture of D-glucono-delta lactone (6.416 g) in 96% ethanol (10 ml) at 25-30°C. Heated the mixture to 55-60°C and stirred for 30 minutes. Mixture kept at 25-30° for 2 days. Filtered the precipitated solid and washed with ethanol (2 X 20 ml) and isopropanol (60 ml). Dried the mixture at 40 mbar at 25-30° for 20 hours. Yield: 11.7 g;

[0091] The PXRD pattern of the obtained compound is illustrated in figure- 1 A.

[0092] Example-1: Preparation of solid dispersion of Benzgalantamine gluconate with povidone-K30.

[0093] Povidone-K30 (150 mg) was added to the mixture of Benzgalantamine gluconate (150 mg) and Methanol (15 ml) at 25-30°C. Heated the mixture to 45-50°C and stirred for 30 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the mixture to get the title compound. Yield: 265 mg;

[0094] The PXRD pattern of the obtained compound is illustrated in figure- 1.

[0095] Example-2: Preparation of solid dispersion of Benzgalantamine gluconate with HPMC-E5.

[0096] HPMC-E5 (150 mg) was added to the mixture of Benzgalantamine gluconate (150 mg) and Methanol (15 ml) at 25-30°C. Heated the mixture to 45-50°C and stirred for 30 minutes.Filtered the mixture to make it particle free. Distilled off the solvent completely from the mixture to get the title compound. Yield: 250 mg;

[0097] The PXRD pattern of the obtained compound is illustrated in figure-2.

[0098] Example-3: Preparation of solid dispersion of Benzgalantamine gluconate with HPMC-AS.

[0099] HPMC-AS (150 mg) was added to the mixture of Benzgalantamine gluconate (150 mg) and Methanol (15 ml) at 25-30°C. Heated the mixture to 45-50°C and stirred for 30 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the mixture to get the title compound. Yield: 260 mg;

[0100] The PXRD pattern of the obtained compound is illustrated in figure-3.

[0101] Example-4: Preparation of Benzgalantamine.

[0102] Triethylamine (151 ml) and 4-Dimethylamino pyridine (3.3 g) were slowly added to the pre-cooled mixture of Galantamine Hydrobromide (100 g) in Dichloromethane (500 ml) at 10-15°C. Mixture further cooled to 0-5°C and slowly added benzoyl chloride (38 ml). Stirred the mixture for 2 hours at 0-5°C. Water (500 ml) was added to the mixture at 0-5°C and stirred for 10 minutes. Mixture allowed to heat at 25-30°C and stirred for 10 minutes. Separated the organic layer from aqueous layer. Organic layer washed with aqueous hydrochloric acid solution and water. Organic layer treated with activated carbon at 25-30°C. Distilled-off the organic layer and further co-distilled in ethylacetate to obtain titled product.

[0103] Example-5: Preparation of Crystalline Form-M of Benzgalantamine.

[0104] Ethyl acetate (25 ml) and cyclohexane (500 ml) were added to the mixture obtained in example-4. Heated the mixture to 40-45 °C and stirred for 30 minutes. Allowed to cool the mixture to 25-30°C and stirred for 30 minutes. Mixture cooled to 0-5°C and stirred for 2 hours. Filtered the mixture and dried to get the titled product.

[0105] Yield: 76.5 g;

[0106] The PXRD pattern of the obtained compound is illustrated in figure-4.

[0107] Example-6: Preparation of solid dispersion of Benzgalantamine gluconate with HPMC-Phthalate.

[0108] HPMC-Phthalate (100 mg) was added to the mixture of Benzgalantamine gluconate (100 mg) in Methanol (15 ml) and Dichloromethane (15 ml) at 25-30°C. Stirred for 30 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the mixture to get the title compound. Yield: 130 mg;

[0109] The PXRD pattern of the obtained compound is illustrated in figure-5.

[0110] Example-7 : Preparation of Benzgalantamine.

[0111] Triethylamine (151 ml) and 4-Dimethylamino pyridine (6.6 g) were slowly added to the pre-cooled mixture of Galantamine Hydrobromide (100 g) in acetonitrile (300 ml) at 0-5°C. Slowly added benzoyl chloride (38 ml) to the mixture at 0-5°C. Raised the mixture temperature to 25-30°C and stirred for 18 hours. Cooled the mixture to 0-5°C. Acetonitrile (100 ml), water (200 ml) and Ethyl-acetate (500 ml) were added to the mixture at 0-5°C. Acidified the mixture pH by using aq. Hydrochloric acid at 0-5°C and stirred for 8 hours. Filtered the mixture. To the filtered mixture acetonitrile (300 ml) and ethyl-acetate (500 ml) were added at 25-30°C. Cooled the mixture to 0-5°C and stirred for 2 hours. Filtered the mixture. Yield: 146 g;

[0112] The PXRD pattern of the obtained compound is illustrated in figure-6

[0113] Water (300 ml) was added to the obtained solid at 25-30°C. Basified the mixture pH by using aq. sodium bicarbonate solution at 25-30°C. Methyl tert-butyl ether (1500 ml) was added to the mixture at 25-30°C and stirred for 30 minutes. Separated the organic layer from the mixture and treated with carbon powder. Distilled-off the organic layer. Cyclohexane (200 ml) was added to the mixture at 25-30°C and stirred for 1 hour. Filtered the mixture and dried to obtain title product. Yield: 81.6 g; Purity by HPLC: 99.86%

[0114] The PXRD pattern of the obtained compound is illustrated in figure-4.

[0115] Example-8: Preparation of Benzgalantamine Gluconate.

[0116] D-(+)-Glucono-l,5-lactone (30 g) was added to the mixture of Benzgalantamine (60 g) in isopropanol (180 ml) and water (30 ml) at 25-30°C. Heated the mixture to 70-75°C and stirred for 1 hour. Filtered the mixture to get particle free solution. Cooled the mixture to SO-55 °C and seeded the mixture with Benzgalantamine gluconate (600 mg). Allowed to cool themixture to 25-30°C and stirred for 30 minutes. Isopropanol (1200 ml) was slowly added to the mixture at 25-30°C and stirred for 10 hours. Cooled the mixture to 0-5°C and stirred for 3 hours. Filtered the mixture and dried to get title compound. Yield: 77 g; Purity by HPLC: 99.97% Enti-galantamine benzoate impurity: Not detected; N-oxide impurity: 0.01%;

[0117] The PXRD pattern of the obtained compound is illustrated as Figure- 1 A.

Claims

We Claim:

1. A solid dispersion of Benzgalantamine Gluconate and one or more pharmaceutically acceptable excipients.Formula-12. The solid dispersion according to claim 1 is storage stable at 25°C to 30°C temperature condition.

3. A process for the preparation of a solid dispersion of Benzgalantamine Gluconate comprising:a) providing a solution or suspension of Benzgalantamine Gluconate and one or more pharmaceutically acceptable excipients in a solvent or a mixture of solvents; and b) isolating the solid dispersion comprising Benzgalantamine Gluconate and the excipient.

4. The solid dispersion according to claim 1 or 3, wherein the pharmaceutically acceptable excipient is selected from syloid, eudragit, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), co-povidone, crospolyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose K-100, hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates.

5. The solid dispersion according to claim 1 or 3, wherein the pharmaceutically acceptable excipient is povidone-K30, hydroxy propyl methylcellulose E5, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl Methylcellulose phthalate.

6. The solid dispersion according to claim 1 or 3 , wherein the weight ratio of Benzgalantamine Gluconate to the excipient ranges from about 1:0.05 to about 1:5.

7. The process according to claim 3, wherein step (a) is carried out at a temperature ranging from about 25 °C to the reflux temperature of the solvent.

8. A process for the preparation of a solid dispersion of Benzgalantamine Gluconate with povidone-K30 comprising:a) providing a solution or suspension of Benzgalantamine Gluconate and povidone-K30 in an alcohol solvent; andb) isolating the solid dispersion.

9. A process for the preparation of a solid dispersion of Benzgalantamine Gluconate with Hydroxypropyl methylcellulose E5 comprising;a) providing a solution or suspension of Benzgalantamine Gluconate and Hydroxy propyl methylcellulose E5 in an alcohol solvent; andb) isolating the solid dispersion.

10. A process for the preparation of a solid dispersion of Benzgalantamine Gluconate with Hydroxypropyl methylcellulose acetate succinate comprising;a) providing a solution or suspension of Benzgalantamine Gluconate and hydroxypropyl methylcellulose acetate succinate in an alcohol solvent; andb) isolating the solid dispersion.

11. A process for the preparation of a solid dispersion of Benzgalantamine Gluconate with Hydroxypropyl methylcellulose phthalate comprising;a) providing a solution or suspension of Benzgalantamine Gluconate and Hydroxypropyl methylcellulose phthalate in an alcohol solvent or chloro solvent or mixture thereof; andb) isolating the solid dispersion.

12. The process according to any one of the preceding claims, wherein the isolation techniques which includes decantation, 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 buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, filtration, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture.

13. A pharmaceutical composition comprising a solid dispersion of Benzgalantamine Gluconate and at least one pharmaceutically acceptable excipient.

14. A process for the preparation of Benzgalantamine gluconate of formula- 1, comprising; a) reacting Galantamine or a pharmaceutically acceptable salt thereof of formula-3 with benzoyl chloride in presence of a base and a nitrile solvent to provide Benzgalantamine of formula-2,b) optionally treating the obtained Benzgalantamine with an acid followed by treatment with a base;c) treating the Benzgalantamine of formula-2 with D-(+)-Glucono-l,5-lactone in isopropanol to obtain Benzgalantamine gluconate of formula- 1; andd) optionally purifying the Benzgalantamine Gluconate in a solvent or mixture of solvents to obtain pure Benzgalantamine Gluconate.

15. The process according to claim 14, wherein the nitrile solvent used in step-a) is selected from acetonitrile, propionitrile, isobutyronitrile, and mixture thereof.

16. The process according to claim 14, wherein the step-b) provides crystalline Form-M of Benzgalantamine.

17. Crystalline Form-M of Benzgalantamine characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 8.1, 13.0 and 17.7 ± 0.2 degrees of 2-theta.

18. The crystalline Form-M of Benzgalantamine according to claim 17, further characterized by an X-ray diffraction (XRD) pattern as illustrated in figure-4.

19. Pure Benzgalantamine gluconate having one or more impurities selected from ‘Dihydrogalantamine benzoate impurity’, ‘Enti-galantamine benzoate impurity’ and ‘N- oxide impurity’ present in an amount lower than about 0.5% or lower than about 0.2% or lower than about 0.15% or lower than about 0.1% or lower than about 0.05% as measured by High-Performance Liquid Chromatography (HPLC).

20. The pure Benzgalantamine gluconate according to claim 19, having a purity greater than about 99.5% or greater than about 99.7% or greater than about 99.9% as measured by HPLC.

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