DESC:

FIELD OF THE INVENTION
The present invention relates to a crystalline form of centanafadine free base and process for preparation thereof. The present invention also relates to eutectic mixture of centanafadine hydrochloride, compound of Formula I with one or more co-former and process for preparation thereof. The present invention also relates to a pharmaceutical composition comprising a crystalline form of centanafadine free base or eutectic mixture of centanafadine hydrochloride, compound of Formula I and co-former with one or more additional pharmaceutically acceptable excipients and process for preparation thereof.

BACKGROUND OF THE INVENTION
Centanafadine hydrochloride (EB 1020) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI), chemically known as (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo [3.1.0] hexane hydrochloride, compound of Formula I.

International (PCT) Publication No. WO 2007/016155 discloses azabicyclo derivatives including centanafadine or pharmaceutically acceptable salt thereof and process for preparation thereof.
International (PCT) Publication No. WO 2016/205762 discloses crystalline Forms A, B, C and amorphous form of centanafadine hydrochloride and process for preparation thereof. It also discloses crystalline Form D of centanafadine citrate, Form E and F of crystalline centanafadine phosphate and process for preparation thereof.
International (PCT) Publication No. WO 2019/114394 discloses crystalline Form CS1 of centanafadine hydrochloride and preparation thereof.
International (PCT) Publication No. WO 2018/119291 and WO 2021/075494 and disclose processes for preparation of crystalline Form A of centanafadine hydrochloride.
International (PCT) Publication No. WO 2022/256215 discloses crystalline form CN1 of centanafadine hydrochloride and preparation thereof.
None of the above prior art teaches about polymorphism of centanafadine free base and eutectic mixture of centanafadine hydrochloride with one or more co-former.

There is always a scope to provide a novel solid form of pharmaceutically active substance with improves pharmacologically beneficial properties. The present invention provides a stable crystalline form of centanafadine free base and eutectic mixture of centanafadine hydrochloride, compound of Formula I with suitable co-former and process for preparation thereof. The present invention also provides a pharmaceutical composition comprising a crystalline form of centanafadine free base or eutectic mixture of centanafadine hydrochloride, compound of Formula I with co-former with one or more additional pharmaceutically acceptable excipients and process for preparation thereof.

SUMMARY OF THE INVENTION
In one general aspect, the present invention provides a multicomponent mixture of centanafadine hydrochloride, compound of Formula I with one or more co-formers.

In one general aspect, there is provided a stable eutectic mixture of centanafadine hydrochloride, compound of Formula I with one or more co-formers.


In another general aspect, there is provided a process for the preparation of stable eutectic mixture of centanafadine hydrochloride with one or more co-formers.
In another general aspect, there is provided a process for the preparation of a eutectic mixture of centanafadine hydrochloride with one or more co-formers, the process comprising:
(a) providing a physical blend of centanafadine hydrochloride with one or more co-formers;
(b) optionally, preparing a slurry of the physical blend in one or more solvents; and
(c) obtaining the eutectic mixture of centanafadine hydrochloride with co-former by the removal of the solvent.

In another general aspect, there is provided a process for the preparation of eutectic mixture of centanafadine hydrochloride and a co-former, the process comprising:
(a) providing a solution or suspension of centanafadine hydrochloride with a co-former in the presence of one or more solvents; and
(b) obtaining the eutectic mixture of centanafadine hydrochloride with the co-former by removal of the solvent.
In another general aspect, there is provided a crystalline form of centanafadine free base.
In another general aspect, there is provided a stable crystalline form of centanafadine free base.
In another general aspect, there is provided a process for the preparation of a crystalline form of centanafadine free base, the process comprising:
(a) providing a solution or suspension of centanafadine hydrochloride in one or more solvents;
(b) adding a base into the solution or suspension of step (a); and
(c) obtaining the crystalline form of centanafadine free base by the removal of the solvents.
In another general aspect, there is provided a process for the preparation of a crystalline form of centanafadine free base, the process comprising:
(a) providing a solution or suspension of centanafadine free base in one or more solvents; and
(b) obtaining the crystalline form of centanafadine free base by removal of the solvents.
In another general aspect, there is provided a process for the preparation of crystalline centanafadine free base, the process comprising:
(a) reacting (1S,2R)-2-aminomethyl-2-naphthylene-2-ylcyclopropylmethanol tosylate with thionyl chloride in one or more solvents to obtain a reaction mixture;
(b) removing the solvent and treating the reaction mixture with an aqueous solution of a base;
(c) adding one or more solvent and separating organic layer;
(d) optionally, treating the organic layer with activated carbon; and
(e) obtaining the crystalline centanafadine free base by the removal of the solvent.

In another general aspect, there is provided a pharmaceutical composition comprising a crystalline centanafadine free base with one or more additional pharmaceutically acceptable excipients, diluents or carriers.
In another general aspect, there is provided a pharmaceutical composition comprising a eutectic mixture of centanafadine hydrochloride and a co-former, with one or more of pharmaceutically acceptable excipients, diluents, or carriers.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: X-ray powder diffraction (XRPD) pattern of crystalline form of centanafadine freebase.
Figure 2: Differential Scanning Calorimetry (DSC) of crystalline form of centanafadine freebase
Figure 3: Differential Scanning Calorimetry (DSC) of eutectic mixture of centanafadine hydrochloride and succinic acid (1:1 Mole equivalent).
Figure 4: Differential Scanning Calorimetry (DSC) of eutectic mixture of centanafadine hydrochloride and salicylic acid (1:1 Mole equivalent).
Figure 5: Differential Scanning Calorimetry (DSC) of eutectic mixture of centanafadine hydrochloride and fumaric acid (1:1 Mole equivalent).
Figure 6: Differential Scanning Calorimetry (DSC) of eutectic mixture of centanafadine hydrochloride and maleic acid (1:1 Mole equivalent).
Figure 7: Differential Scanning Calorimetry (DSC) of eutectic mixture of centanafadine hydrochloride and tartaric acid (1:1 Mole equivalent).
Figure 8: X-ray powder diffraction (XRPD) pattern of eutectic mixture of centanafadine hydrochloride and tartaric acid (1:1 Mole equivalent).

DETAILED DESCRIPTION OF THE INVENTION
The aforementioned objectives of the present invention are fulfilled by one or more of the aspects/process described herein.
All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “from”, and “to” are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The term “solution” does not limit to a clear solution only and includes a hazy solution or slurry which is a heterogeneous mixture.
The term “pharmaceutical compositions” herein includes pharmaceutical formulations like tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The term “composition” used herein means a physical mixture of two or more components.
The term “substantially free” herein means crystalline centanafadine free base or eutectic mixture of centanafadine hydrochloride, compound of Formula I with suitable co-former having each single individual impurity, about 0.15% or less, by area percentage of HPLC. In particular, about 0.10% or less, by area percentage of HPLC. More particular, about 0.07% or less, by area percentage of HPLC. Most particularly, the said impurities are present in the range of not detected to 0.15% by area percentage of HPLC, relative to centanafadine hydrochloride, compound of Formula I.
The terms “obtaining” means isolating the crystalline centanafadine free base or eutectic mixture of centanafadine hydrochloride, compound of Formula I with suitable co-former by way of filtration, filtration under vacuum, centrifugation, decantation, extraction, evaporation, precipitation, spray dry and freeze dry (lyophilization). The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a spray drier, tray drier, dried under vacuum and/or in a fluid bed drier.
The term “blend” indicates a mixture of two or more molecular species without chemical bonding between them and can be induced by mechanical blending, physical means such as coprecipitation, or by chemical means.
The term “stable” herein means crystalline centanafadine free base or eutectic mixture of centanafadine hydrochloride, compound of Formula I with suitable co-former that after exposure to 40 °C/75% RH or 25 °C/60% RH, for a period of at least 6 months contains less than about 0.5% (wt/wt) total impurities and doesn't change to any other solid forms.
The term “eutectic system” is a mixture of two or more components which melts at a single temperature which is generally lower than the melting point of the components presents in it. Eutectic mixtures have potential to enhance stability and bioavailability of the drugs.
In one general aspect, there is provided a multicomponent mixture of centanafadine hydrochloride, compound of Formula I with one or more co-formers.

In another general aspect, there is provided a multicomponent mixture of centanafadine hydrochloride, compound of Formula I with one or more co-formers comprises solid dispersion, premix, co-crystal, eutectic mixture, physical mixture, and co-amorphous solids.
In another general aspect, there is provided a multicomponent mixture of centanafadine hydrochloride, compound of Formula I with one or more co-formers comprises co-crystal or eutectic mixture.
In another general aspect, there is provided a stable eutectic mixture of centanafadine hydrochloride with one or more co-formers.
In another general aspect, there is provided a eutectic mixture of centanafadine hydrochloride and co-former, wherein the eutectic mixture comprises centanafadine hydrochloride and co-former in the ratio from 1:10 to 10:1 mole/mole.
In another general aspect, the ratio of centanafadine hydrochloride to the co-former in eutectic mixture is 1:5 to 5:1 mole/mole, preferably 1:3 to 3:1 mole/mole, more preferably 1:2 to 2:1, most preferably 1:1 mole/mole.
In another general aspect, the co-former can be selected from citric acid, ascorbic acid, succinic acid, tartaric acid, D (-)-tartaric acid, L (+)-tartaric acid, salicylic acid, maleic acid, fumaric acid, lactic acid, sorbic acid and glutaric acid or mixtures thereof.
In another general aspect, there are provided crystalline eutectic mixtures of centanafadine hydrochloride with co-former, the eutectic mixtures comprising:
(a) crystalline eutectic mixture of centanafadine hydrochloride with succinic acid (1:1 mole/mole);
(b) crystalline eutectic mixture of centanafadine hydrochloride with tartaric acid (1:1 mole/mole);
(c) crystalline eutectic mixture of centanafadine hydrochloride with salicylic acid (1:1 mole/mole);
(d) crystalline eutectic mixture of centanafadine hydrochloride with fumaric acid (1:1 mole/mole); and
(e) crystalline eutectic mixture of centanafadine hydrochloride with maleic acid (1:1 mole/mole).
In another general aspect, there is provided a eutectic mixture of centanafadine hydrochloride and D-(-)-tartaric acid, characterized by one or more of the following:
(a) X-ray powder diffraction (XRPD) pattern having peaks expressed in degrees 2? at 5.0°, 18.5°, 19.4°, 20.6°, 25.4°, 27.3° and 32.7°±0.2°; or
(b) d-spacing (Å) at 17.35, 4.78, 4.57, 4.29, 3.50, 3.26, 2.73; or
(c) Differential Scanning Calorimetry (DSC) having endothermic peak at 157°±3 °C.
In another general aspect, there is provided a eutectic mixture of centanafadine hydrochloride with D-(-)-tartaric acid, characterized by one or more of the following:
(a) X-ray powder diffraction (XRPD) pattern having peaks expressed in degrees 2? at 5.0°, 17.8°, 18.5°, 19.4°, 20.6°, 21.9°, 22.9°, 23.2°, 23.5°, 27.3° and 32.7° or similar to pattern as same as depicted in Figure 8; or
(b) Differential Scanning Calorimetry (DSC) having onset at 154.8 °C±3 °C and peak at 158.59 °C±3 °C or similar to that of Figure 7.
In another general aspect, there is provided a eutectic mixture of centanafadine hydrochloride with D-(-)-tartaric acid, characterized by Powder X-Rays Diffractogram (PXRD) pattern having peaks expressed in degrees 2? at 5.0°±0.2° with d-spacing (Å) value at about 17.35 in combination of one or more of the following:
(a) X-ray powder diffraction (XRPD) pattern having peaks expressed in degrees 2? at 17.8°, 18.5°, 19.4°, 20.6°, 21.9°, 22.9°, 23.2°, 23.5°, 27.3° and 32.7°±0.2°;
(b) one or more d-spacing values (Å) at 4.97, 4.78, 4.57, 4.29, 4.05, 3.87, 3.84, 3.77, 3.26, 2.73;
(c) Differential Scanning Calorimetry (DSC) endothermic peak at 157±3 °C
In another general aspect, there are provided crystalline eutectic mixtures of centanafadine hydrochloride with co-former, wherein the eutectic mixtures comprising:
(a) crystalline eutectic mixture of centanafadine hydrochloride with succinic acid (1:1 mole/mole), characterized by DSC onset at 144.83 °C and endotherm peak at 147.58 °C or substantially similar as of Figure 3;
(b) crystalline eutectic mixture of centanafadine hydrochloride with tartaric acid (1:1 mole/mole) obtained from example 2, characterized by DSC onset at 151.45 °C and endotherm peak at 154.67 °C;
(c) crystalline eutectic mixture of centanafadine hydrochloride with salicylic acid (1:1 mole/mole), characterized by DSC onset at 113.42 °C and endotherm peak at 115.77 °C or similar as of Figure 4;
(d) crystalline eutectic mixture of centanafadine hydrochloride with fumaric acid (1:1 mole/mole), characterized by DSC onset at 181.70 °C and endotherm peak at 185.21 °C or similar as of Figure 5;
(e) crystalline eutectic mixture of centanafadine hydrochloride with maleic acid (1:1 mole/mole), characterized by DSC onset at 99.27 °C and endotherm peak at 102.70 °C or similar as of Figure 6;
(f) crystalline eutectic mixture of centanafadine hydrochloride with tartaric acid (1:1 mole/mole) obtained from example 3, characterized by DSC onset at 154.89 °C and endotherm peak at 158.59 °C or similar as of Figure 7;
(g) crystalline eutectic mixture of centanafadine hydrochloride with tartaric acid (1:1 mole/mole) obtained from example 3, characterized by powder X-rays Diffractogram similar pattern as depicted in Figure 8.
In another general aspect, there is provided a eutectic mixture of centanafadine hydrochloride, compound of Formula I with one or more co-former substantially free from impurities.
In another general aspect, there is provided a process for the preparation of eutectic mixture of centanafadine hydrochloride, compound of Formula I with one or more co-former.
In another general aspect, there is provided a process for the preparation of eutectic mixture of centanafadine hydrochloride, with one or more of co-former, the process comprising:
(a) providing a physical blend of centanafadine hydrochloride with one or more co-formers;
(b) optionally, preparing a slurry of the physical blend in one or more solvents; and
(c) obtaining the eutectic mixture of centanafadine hydrochloride with co-former by the removal of the solvent.
In general, the co-former can be selected from one or more of citric acid, ascorbic acid, succinic acid, tartaric acid, D (-)-tartaric acid, L (+)-tartaric acid, salicylic acid, maleic acid, fumaric acid, lactic acid, sorbic acid and glutaric acid or mixtures thereof.
In general, one or more solvents can be selected from polar or non-polar solvents not limited to water, C1-4 alcohols, nitriles, C2-6 esters, C3-5 ketones, C2-5 aldehydes, C2-5 carboxylic acids, C2-5 amides, ethers, cyclic ethers, hydrocarbons, halogenated hydrocarbons and sulfoxides or mixture thereof.
In general, the solvent at step (b) is selected from one or more of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, n-heptane, cycloheptane, octane, benzene, toluene, xylene, methylene dichloride, ethylene dichloride, carbon tetrachloride, chlorobenzene, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof. Preferably isopropyl acetate, ethyl acetate may be used.
In another general aspect, there is provided a process for the preparation of eutectic mixture of centanafadine hydrochloride and a co-former, the process comprising:
(a) providing a physical blend of centanafadine hydrochloride with one or more co-formers; and
(b) obtaining the eutectic mixture of centanafadine hydrochloride with co-formers.
In another general aspect, there is provided a eutectic mixture of centanafadine hydrochloride and a co-former, the process comprising:
(a) providing a solution or suspension of centanafadine hydrochloride with a co-former in one or more solvents; and
(b) obtaining the eutectic mixture of centanafadine hydrochloride with the co-former by the removal of the solvent.
In general, the co-former can be selected from citric acid, ascorbic acid, succinic acid, tartaric acid, D (-)-tartaric acid, L (+)-tartaric acid, salicylic acid, maleic acid, fumaric acid, lactic acid, sorbic acid and glutaric acid or mixtures thereof.
In general, the solvent at step (a) is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, benzene, toluene, methylene dichloride, ethylene dichloride, dimethylformamide, dimethylsulfoxide, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof. Preferably, isopropyl acetate, ethyl acetate may be used.

In another general aspect, there is provided a process for the preparation of a eutectic mixture of centanafadine hydrochloride with suitable co-former in one or more solvents.
In another general aspect, there is provided a crystalline form of centanafadine free base.
In another general aspect, there is provided a stable crystalline form of centanafadine free base.
In another general aspect, there is provided a process for the preparation of crystalline form of centanafadine free base, the process comprising:
(a) providing a solution or suspension of centanafadine hydrochloride in the presence of one or more solvents;
(b) adding a base into the solution or suspension of step (a); and
(c) obtaining the crystalline form of centanafadine free base by the removal of the solvents.
One or more solvents for the reaction can be selected from polar or non-polar solvents not limited to water, C1-4 alcohols, nitriles, C2-6 esters, C3-5 ketones, C2-5 aldehydes, C2-5 carboxylic acids, C2-5 amides, ethers, cyclic ethers, hydrocarbons, halogenated hydrocarbons and sulfoxides or mixture thereof.
In general, the solvent at step (a) is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate isopropyl acetate, t-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, benzene, toluene, xylene, methylene dichloride, ethylene dichloride, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, diethyl ether, diisopropyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof. Preferably, water, tetrahydrofuran, toluene, and/or 2-methyl tetrahydrofuran may be used.
In general, the base at step (b) can be selected from but not limited to, alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, alkali and alkaline earth metal bicarbonates, alkali metal alkoxides, alkali and alkaline earth metal hydride, and organic bases selected from trimethyl amine, triethyl amine, diisopropyl ethyl amine, pyridine, dimethyl amino pyridine, diisopropyl amine, an ammonia. Preferably, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethyl amine, and pyridine can be used.
In another general aspect, the present invention provides a process for the preparation of crystalline form of centanafadine free base, the process comprising:
(a) providing a solution or suspension of centanafadine free base in one or more solvents; and
(b) obtaining the crystalline form of centanafadine free base by the removal of the solvents.
In general, the solvents for the reaction can be selected from polar or non-polar solvents not limited to water, C1-4 alcohols, nitriles, C2-6 esters, C3-5 ketones, C2-5 aldehydes, C2-5 carboxylic acids, C2-5 amides, ethers, cyclic ethers, hydrocarbons, halogenated hydrocarbons and sulfoxides or mixture thereof.
In general, the solvent at step (a) is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate isopropyl acetate, t-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, benzene, toluene, xylene, methylene dichloride, ethylene dichloride, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof. Preferably, water, tetrahydrofuran, toluene, or 2-methyl tetrahydrofuran may be used.
In another general aspect, there is provided a crystalline centanafadine free base, characterized by one or more of the following:
(a) X-ray powder diffraction (XRPD) pattern having peaks expressed in degrees 2? at 6.9°, 13.5°, 16.3°, 18.1°, 18.8°, 19.1° and 23.3°±0.2°; or
(b) a differential scanning calorimetry (DSC) having onset at 93.50 °C±3 °C and endothermic peak at 97.87 °C±3 °C.
In another general aspect, there is provided a crystalline centanafadine free base, characterized by Powder X-Ray Diffractogram (PXRD) having peaks expressed in degrees 2? at 18.8°±0.2° with combination of one or more of:
(a) peaks express in degrees 2? at 6.9°, 13.5°, 16.3°, 18.1°, 19.1°, and 23.3°±0.2°; or
(b) one or more d-spacing values (Å) at 12.8, 6.5, 5.4, 4.9, 4.6, and 3.8; or
(c) Differential Scanning calorimetry (DSC) having endothermic peak at 99°± 3 °C.
In another general aspect, there is provided a crystalline centanafadine free base, characterized by powder X-Rays diffractogram (PXRD) having peak expressed in degrees 2? at 18.8°±0.2° with 100% relative intensity with combination of one or more of:
(a) peaks expressed in degrees 2? at 6.9°, 13.5°, 16.3°, 18.1°, 19.1°, and 23.3°±0.2°; or
(b) one or more d-spacing values (Å) at 12.8, 6.5, 5.4, 4.9, 4.6, 3.8; or
(c) Differential Scanning calorimetry (DSC) having endothermic peak at 99°± 3 °C.
In another general aspect, there is provided a process for the preparation of crystalline centanafadine free base, the process comprising:
(a) reacting (1S,2R)-2-aminomethyl-2-naphthylene-2-ylcyclopropylmethanol tosylate with thionyl chloride in one or more solvents to obtain a reaction mixture;
(b) removing the solvent and treating the reaction mixture with an aqueous solution of a base;
(c) adding one or more solvent and separating organic layer;
(d) optionally, treating the organic layer with activated carbon; and
(e) obtaining the crystalline centanafadine free base by the removal of the solvent.
In general, the solvent the solvent at step (a) and (c) is selected from one or more of water, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, n-hexane, cyclohexane, benzene, toluene, methylene dichloride, ethylene dichloride, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or mixture thereof.
In general, the wherein the base at step (b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
In another general aspect, there is provided a crystalline form of centanafadine free base is substantially free from impurities or any other solid forms.
In another general aspect, there is provided a pharmaceutical composition comprising a crystalline centanafadine free base with one or more additional pharmaceutically acceptable excipients, diluents or carriers.
In another general aspect, there is provided a pharmaceutical composition comprising a eutectic mixture of centanafadine hydrochloride and a co-former, with one or more of pharmaceutically acceptable excipients, diluents or carriers.
The co-former in the pharmaceutical composition is selected from citric acid, ascorbic acid, succinic acid, tartaric acid, D (-)-tartaric acid, L (+)-tartaric acid salicylic acid, maleic acid, fumaric acid, lactic acid, sorbic acid and glutaric acid or mixtures thereof.
In another general aspect, the pharmaceutically acceptable excipients comprise of amino acids, antioxidants, preservatives, diluents or fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants or mixture thereof known in the prior art.

In another general aspect, the pharmaceutically acceptable excipient comprises, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble carrier is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolate, and cross-linked styrene divinyl benzene.
In another general aspect, pharmaceutically acceptable excipient may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), HPMC 3CPS, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxy methyl ethyl cellulose, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, and lactitol, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, and propylene glycol derivatives, organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, amino acid but not limited to, citric acid, ascorbic acid, the amino acid selected from L-lysine, L-valine, L-tryptophan (or 5-hydroxytryptophan), L-phenylalanine, L-methionine, L-leucine, L-threonine, L-isoleucine, L-arginine, L-histidine, L-tyrosine, L-carnitine, L-serine, L-glutamine, aspartic acid, L-proline, L-glycine, taurine, L-cysteine, Gamma-aminobutyric acid (GABA), L-alanine, and L-glutamic acid or mixture thereof, antioxidant such as butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), carotenoids, glutathione, sodium metabisulfite, sodium ethylenediaminetetraacetate, cysteine, methionine, sesamol and guanidine or its derivatives.
The use of mixtures of one or more pharmaceutical excipient to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.
In another general aspect, there is provided a process for the preparation of a crystalline centanafadine freebase or eutectic mixture of centanafadine hydrochloride, compound of Formula I with suitable co-former, wherein the obtained crystalline form of centanafadine free base or eutectic mixture of centanafadine hydrochloride is stable for atleast 6 months at 40 °C and 75% RH and can be formulated easily for administering to patients.
In another general aspect, the stable crystalline centanafadine free base or stable eutectic mixture of centanafadine hydrochloride, compound of Formula I with co-former is having residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example, but not limited to less than 0.5%, particularly less than 0.3% or more particularly less than 0.2%.
In another general aspect, the solution or suspension of crystalline form of centanafadine free base preparation can be obtained by known methods that includes, but not limited to:
(I) direct use of a reaction mixture containing centanafadine free base or pharmaceutically acceptable salt thereof that is obtained in the course of its synthesis; or
(II) dissolving centanafadine free base or pharmaceutically acceptable salt thereof in one or more of solvents or mixture thereof.
In another general aspect, one or more solvents in the present invention can be selected from polar or non-polar solvents not limited to water, C1-4 alcohols, nitriles, C2-6 esters, C3-5 ketones, C2-5 aldehydes, C2-5 carboxylic acids, C2-5 amides, ethers, cyclic ethers, hydrocarbons, halogenated hydrocarbons and sulfoxides or mixture thereof.
In another general aspect, examples of the solvent that may be used in the present methods include, but are not limited to C1-4 alcohol selected from methanol, ethanol, n-propanol, isopropanol and n-butanol; C2-6 ester selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; ketone selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; hydrocarbon selected from n-hexane, cyclohexane, n-heptane, cycloheptane, octane, benzene, toluene, xylene, halogenated hydrocarbon selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene, polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidone, ether solvent selected from dimethyl ether, diethyl ether, diisopropyl ether and cyclic ether solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof.
In another general aspect, centanafadine hydrochloride, compound of Formula I in any physical form may be utilized for providing the physical blend of centanafadine hydrochloride, compound of Formula I with suitable co-former.
In another general aspect, the present invention provides a crystalline centanafadine free base or eutectic mixture of centanafadine hydrochloride, compound of Formula I is having a purity of about 98% or more, particularly, about 99% or more, most particularly, about 99.9% or more, by area percentage of HPLC.
In another general aspect, a crystalline centanafadine free base or eutectic mixture of centanafadine hydrochloride, compound of Formula I, obtained by the process of the present invention is characterized by mean particle size distribution of 300 µm or less, particularly of about 200 µm or less, and most particularly, about 100 µm or less.
In another general aspect, a stable crystalline centanafadine free base or eutectic mixture of centanafadine hydrochloride, compound of Formula I of the present invention is having a water content of up to about 5% wt/wt, particularly of about 3% wt/wt or less, more particularly of about 1% wt/wt or less and most particularly of about 0.5% wt/wt or less.
The stable eutectic mixture of centanafadine hydrochloride, compound of Formula I or crystalline form of centanafadine free base of the present invention may be characterized by Powder X-ray diffraction patterns obtained by following method:

Characterization by X-Ray Powder Diffraction
The X-ray powder diffraction spectrum was measured under the following experimental conditions:
Instrument: X-Ray Diffractometer, Empyrean,
Make: Malvern PANalytical.
X-Ray : Cu K alpha radiation
Tension : 45KV
Current : 40mA
Divergence slit : Automatic
Incident beam side
Off set : 0.000
Anti-scatter slit : ½°
Receiving slit : None
Detector : PIXcel1D-Medipix3
Mode : Scanning line detector (1D)
Method parameter
Start position : 2°2?
End position : 40°2?
Step size : 0.02° rad
Time per step : 67.575s
Scan mode : Continuous

The present invention is further illustrated by following examples which are provided merely to exemplify the invention and do not limit the scope of it.
The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in various publications.

EXAMPLES
Example-1 (Physical Blending): Preparation of eutectic mixture of centanafadine hydrochloride, compound of Formula I and succinic acid (1:1 mole equivalent)
Centanafadine hydrochloride, compound of Formula I (6g, 0.0244 mole) and succinic acid (2.88g, 0.0244 mole) were taken together and physically blended by using mortar and pestle. After proper blending at 25-30 °C, the material was unloaded to obtain a eutectic mixture of centanafadine hydrochloride and succinic acid (8.83 g; yield 99.43%). Purity > 99.5% by HPLC.

Example-2 (Physical Blending): Preparation of crystalline eutectic mixture of centanafadine hydrochloride, compound of Formula I and tartaric acid (1:1 mole equivalent)
Centanafadine hydrochloride, compound of Formula I (6g, 0.0244 mole) and D (-)-tartaric acid (3.66g, 0.0244 mole) were taken together and physically blended by using mortar and pestle. After proper blending at 25-30 °C, the material was unloaded to obtain a eutectic mixture of centanafadine hydrochloride and D (-)-tartaric acid (9.61 g; yield 99.48%). Purity > 99.5% by HPLC.

Example-3 (Slurry Preparation): Preparation of crystalline eutectic mixture of centanafadine hydrochloride, compound of Formula I and tartaric acid (1:1 mole equivalent)
A slurry of physical blend of centanafadine hydrochloride and D (-)-tartaric acid (3 g) (in example 2) was prepared in isopropyl acetate and heated at 85-90 °C for 30 min. The slurry was cooled to room temperature and filtered and washed with isopropyl acetate (2 x 3 mL) and dried at 55-60 °C for 4 hours to obtain eutectic mixture of centanafadine hydrochloride and D (-)-tartaric acid (3 g; yield 100%). Purity > 99.74% by HPLC.

Example-4 (Physical Blending): Preparation of crystalline eutectic mixture of centanafadine hydrochloride, compound of Formula I and fumaric acid (1:1 mole equivalent)
Centanafadine hydrochloride, compound of Formula I (6g, 0.0244 mole) and fumaric acid (2.83g, 0.0244mole) were taken together and physically blended by using mortar and pestle. After proper blending at 25-30 °C, the material was unloaded to obtain crystalline eutectic mixture of centanafadine hydrochloride and fumaric acid (8.77 g; yield 99.32%). Purity > 99.5% by HPLC.

Example-5 (Physical Blending): Preparation of crystalline eutectic mixture of centanafadine hydrochloride, compound of Formula I and maleic acid (1:1 mole equivalent)
Centanafadine hydrochloride, compound of Formula I (6g, 0.0244 mole) and maleic acid (2.83g, 0.0244mole) were taken together and physically blended by using mortar and pestle. After proper blending at 25-30 °C, the material was unloaded to obtain crystalline eutectic mixture of centanafadine hydrochloride and maleic acid (8.77 g; yield 99.32%). Purity > 99.5% by HPLC.

Example-6 (Physical Blending): Preparation of crystalline eutectic mixture of centanafadine hydrochloride, compound of Formula I and salicylic acid (1:1 mole equivalent)
Centanafadine hydrochloride, compound of Formula I (6g, 0.0244mole) and salicylic acid (3.37g, 0.0244mole) were taken and physically blended by using mortar and pestle. After proper blending at 25-30 °C the material was unloaded to obtain crystalline eutectic mixture of centanafadine hydrochloride and salicylic acid (9.03 g; yield 96.37%). Purity > 99.5% by HPLC.

Example-7 (Solution or Suspension preparation): Preparation of crystalline eutectic mixture of centanafadine hydrochloride, compound of Formula I and tartaric acid (1:1 mole equivalent)
A suspension of centanafadine hydrochloride and D (-)-tartaric acid (1:1 mole equivalent) was prepared in isopropyl acetate (15 mL) and heated at 85-90 °C for 30 min to 40 min. The suspension was cooled to room temperature and filtered under vacuum and washed with isopropyl acetate and dried at 55-60 °C for 4-5 hours to obtain eutectic mixture of centanafadine hydrochloride and D (-)-tartaric acid (2.8 g). Purity > 99.7% by HPLC.

Example-8: Crystallization of centanafadine free base
In 100 mL RBF, centanafadine free base (5g) was dissolved in 2-methyl tetrahydrofuran (30 ml) under stirring at 25-35 °C and then heated at 45-55 °C. The reaction mixture was then cooled to room temperature and activated charcoal (0.5g) was added into the reaction mass and stirred at 25-35 °C for 30 to 45 minutes. The reaction mixture was filtered through hyflow bed and washed with 2-methyl tetrahydrofuran and concentrated under vacuum below 60 °C and then degassed at 60-65 °C to obtain crystalline centanafadine free base (4.8g; Yield: 96%). Purity > 92.5% by HPLC.

Example-9: Crystallization of centanafadine free base
In 100mL RBF, centanafadine free base (5g) was dissolved in toluene (30 mL) under stirring at 25-35 °C and then heated at 45-55 °C. The reaction mixture was cooled to room temperature and activated charcoal (0.5g) was added and stirred at 25-35 °C for 30 to 45 minutes. The reaction mixture was filtered through hyflow bed and washed with toluene and then concentrated under vacuum below 60 °C and then degassed at 70-80 °C to obtain crystalline centanafadine free base (4.9g; Yield: 98%).

Example-10: Preparation of centanafadine free base
In 100 mL RBF, centanafadine hydrochloride (5 g) was dissolved in 2-methyl tetrahydrofuran (30 ml) and water (30 mL) under stirring at 25-35 °C. Aqueous solution of sodium hydroxide was added into the reaction mass and the organic layer was separated and then concentrated under vacuum below 60 °C and then degassed at below 60 °C to obtain crystalline centanafadine free base (4g; Yield: 93.89%). Purity > 99.7% by HPLC.

Example 11: Preparation of centanafadine free base
To the 3 L round bottom flask (RBF), 2-methyl tetrahydrofuran (125 mL) and (1S,2R)-2-aminomethyl-2-naphthylene-2-ylcyclopropylmethanol tosylate (30g) were added under nitrogen atmosphere at room temperature. The reaction mixture was cooled to 0-10 °C and thionyl chloride (6.56 mL) was added into the reaction mixture under nitrogen atmosphere at 0-10 °C. After completion of addition, temperature was increased to room temperature and the reaction mixture was stirred for 1.5-2.5 hours and then the solvent was distilled under vacuum. The reaction mixture was cooled to 0-10 °C and water (4 mL) and sodium hydroxide solution (5 mL) were added into the reaction mixture and stirred for 1 hour at room temperature. Toluene (90mL) and water (75mL) were added into the reaction mixture, salted and the organic layer was separated. Activated carbon was mixed in the organic layer and filtered. The organic layer was concentrated under vacuum below 60 °C and degassed at 70-80 °C to obtain centanafadine free base. Yield: 97.8%.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

,CLAIMS:We claim:
1. A process for the preparation of a eutectic mixture of centanafadine hydrochloride with one or more co-formers, the process comprising:
(a) providing a physical blend of centanafadine hydrochloride with one or more co-formers;
(b) optionally, preparing a slurry of the physical blend in one or more solvents; and
(c) obtaining the eutectic mixture of centanafadine hydrochloride with co-former by the removal of the solvent.

2. The process as claimed in claim 1, wherein the co-former can be selected from one or more of citric acid, ascorbic acid, succinic acid, tartaric acid, D (-)-tartaric acid, L (+)-tartaric acid, salicylic acid, maleic acid, fumaric acid, lactic acid, sorbic acid and glutaric acid or mixtures thereof.

3. The process as claimed in claim 1, wherein the solvent at step (b) is selected from one or more of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, n-heptane, cycloheptane, octane, benzene, toluene, xylene, methylene dichloride, ethylene dichloride, carbon tetrachloride, chlorobenzene, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof.

4. A process for the preparation of a eutectic mixture of centanafadine hydrochloride and a co-former, the process comprising:
(a) providing a solution or suspension of centanafadine hydrochloride with a co-former in one or more solvents; and
(b) obtaining the eutectic mixture of centanafadine hydrochloride with the co-former by the removal of the solvent.

5. The process as claimed in claim 4, wherein the co-former can be selected from citric acid, ascorbic acid, succinic acid, tartaric acid, D (-)-tartaric acid, L (+)-tartaric acid, salicylic acid, maleic acid, fumaric acid, lactic acid, sorbic acid and glutaric acid or mixtures thereof.

6. The process as claimed in claim 4, wherein the solvent at step (a) is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, benzene, toluene, methylene dichloride, ethylene dichloride, dimethylformamide, dimethylsulfoxide, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof.

7. The process as claimed in claim 1 or claim 4, wherein the eutectic mixture comprises centanafadine hydrochloride and co-former in the ratio from 1:10 to 10:1 mole/mole.

8. A process as claimed in claim 1 or 4, wherein the eutectic mixture is a eutectic mixture of centanafadine hydrochloride and D-(-)-tartaric acid, characterized by one or more of the following:
(a) X-ray powder diffraction (XRPD) pattern having peaks expressed in degrees 2? at 5.0°, 18.5°, 19.4°, 20.6°, 25.4°, 27.3° and 32.7°±0.2°; or
(b) d-spacing (Å) at 17.35, 4.78, 4.57, 4.29, 3.50, 3.26, 2.73; or
(c) Differential Scanning Calorimetry (DSC) having endothermic peak at 157°±3 °C.

9. A process for the preparation of a crystalline form of centanafadine free base, the process comprising:
(a) providing a solution or suspension of centanafadine hydrochloride in one or more solvents;
(b) adding a base into the solution or suspension of step (a); and
(c) obtaining the crystalline form of centanafadine free base by the removal of the solvents.

10. The process as claimed in claim 9, wherein the solvent at step (a) is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate isopropyl acetate, t-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, benzene, toluene, xylene, methylene dichloride, ethylene dichloride, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, diethyl ether, diisopropyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof.

11. The process as claimed in claim 9, wherein the base at step (b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethyl amine, and pyridine.

12. A process for the preparation of a crystalline form of centanafadine free base, the process comprising:
(a) providing a solution or suspension of centanafadine free base in one or more solvents; and
(b) obtaining the crystalline form of centanafadine free base by removal of the solvents.

13. The process as claimed in claim 12, wherein the solvent at step (a) is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, cyclohexane, benzene, toluene, xylene, methylene dichloride, ethylene dichloride, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or mixture thereof.

14. The process as claimed in claim 9 or claim 12, wherein the crystalline centanafadine free base, is characterized by one or more of the following:
(a) X-ray powder diffraction (XRPD) pattern having peaks expressed in degrees 2? at 6.9°, 13.5°, 16.3°, 18.1°, 18.8°, 19.1° and 23.3°±0.2°; or
(b) a differential scanning calorimetry (DSC) having onset at 93.50 °C±3 °C and endothermic peak at 97.87 °C±3 °C.

15. A pharmaceutical composition comprising a crystalline centanafadine free base with one or more additional pharmaceutically acceptable excipients, diluents or carriers.

16. A pharmaceutical composition comprising a eutectic mixture of centanafadine hydrochloride and a co-former, with one or more of pharmaceutically acceptable excipients, diluents or carriers.

17. The pharmaceutical composition as claimed in claim 16, wherein the co-former is selected from citric acid, ascorbic acid, succinic acid, tartaric acid, D (-)-tartaric acid, L (+)-tartaric acid salicylic acid, maleic acid, fumaric acid, lactic acid, sorbic acid and glutaric acid or mixtures thereof.

18. A process for the preparation of crystalline centanafadine free base, the process comprising:
(a) reacting (1S,2R)-2-aminomethyl-2-naphthylene-2-ylcyclopropylmethanol tosylate with thionyl chloride in one or more solvents to obtain a reaction mixture;
(b) removing the solvent and treating the reaction mixture with an aqueous solution of a base;
(c) adding one or more solvent and separating organic layer;
(d) optionally, treating the organic layer with activated carbon; and
(e) obtaining the crystalline centanafadine free base by the removal of the solvent.

19. The process as claimed in claim 18, wherein the solvent at step (a) and (c) is selected from one or more of water, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, n-hexane, cyclohexane, benzene, toluene, methylene dichloride, ethylene dichloride, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or mixture thereof.

20. The process as claimed in claim 18, wherein the base at step (b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

Dated this 11th day of July 2023.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS