DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

STABLE AMORPHOUS FORM OF POTASSIUM –COMPETITIVE ACID BLOCKER AND PROCESS FOR THE PREPARATION THEREOF

We, LEE PHARMA LIMITED,
a company incorporated under the companies act, 1956 having address at Sy.No: 257 & 258/1; Door No: 11-6/56-C; Opp: IDPL Factory; Moosapet; Balanagar (Post); Hyderabad, Telangana; 500037- India.

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a stable amorphous Tegoprazan of the formula (I).

The present invention relates to stable amorphous Tegoprazan free from other solid state forms and stable over shelf life and does not convert into any other solid state forms.

The present invention also relates to a process for the preparation of stable amorphous Tegoprazan of the formula (I).

The present invention also relates to pharmaceutical compositions comprising the stable amorphous form of Tegoprazan.

BACKGROUND OF THE INVENTION
Tegoprazan, a reversible H+/K+-ATPase inhibitor, is chemically described as (S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo(d)imidazole-6-carboxamide. Its molecular formula is C20H19F2N3O3, molecular weight is 387.38 g/mol and has the following structure:

Tegoprazan, is the world’s first potassium-competitive acid blocker (P-CAB), has a mechanism similar to that of an acid pump antagonist (APA), and blocks gastric acid secretion by competing with potassium ions for binding to the enzyme H+/K+– ATPase (proton pump) that secretes H+ ions, which are a component of gastric acid, from the gastric parietal cells into the gastric lumen. Since tegoprazan is not a prodrug such as a proton pump inhibitor (PPI), it does not require an activation process, and thus acts not only on an active proton pump but also on an inactive proton pump. Thus, Tegoprazan has the advantages of exhibiting its effect rapidly and reaching the maximum effect within one hour.

Polymorphism has been observed for Tegoprazan. US 9,908,870 B2 claims Form A of Tegoprazan with specific XRD data. This patent also discloses non-crystalline Tegoprazan which was prepared according to the method disclosed in Example 2 of Japanese Patent No. 4481344. This patent discloses evaporation of solvent which was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 °C resulting in non-crystalline material. Another method disclosed is purification by column chromatography on amino gel (ethyl acetate : methanol gradient elution from 50 : 1 to 20 : 1 ) to afford the compound as a white solid.

US 9,908,870 B2 also provides the stability of non-crystalline form and Form A as shown below :

Crystal form Non-crystalline form Crystalline form A
Period initial stage after 4 weeks initial stage after 4 weeks
Appearance white powder Yellow powder White powder White powder
Content of optical isomers 0.04% 0.47% N.D. N.D.
Content of impurities 0.16% 0.49% 0.10 0.10

However, neither JP ‘344 nor US ‘870 provide the physicochemical characteristics of the non-crystalline material nor the polymorphic purity and stability over shelf life.

It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007).

An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may have resulted in the difference in their in-vivo bioavailability. Therefore, it is desirable to have stable amorphous Tegoprazan with high purity and good stability.

Surprisingly, the inventors of the present invention found that stable amorphous Tegoprazan prepared as per the present invention has high chemical purity, chiral purity polymorphic purity and stability.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide stable amorphous Tegoprazan of the formula (I).

Another objective of the present invention is to provide stable amorphous Tegoprazan free from other solid state forms and stable over shelf life and does not convert into any other solid state forms.

Yet another objective of the present invention is to provide a process for the preparation of stable amorphous Tegoprazan of the formula (I).

Still another objective of the present invention is to provide pharmaceutical compositions comprising the stable amorphous form of Tegoprazan.

SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a stable amorphous Tegoprazan of the formula (I).
Formula (I)

The present invention also relates to a process for the preparation of stable amorphous Tegoprazan which comprises the steps:
i) providing a solution of Tegoprazan in a suitable solvent,
ii) optionally treating the solution obtained in step (i) with charcoal, and
iii) spray drying the resulting solution to obtain stable amorphous Tegoprazan.

In another aspect, the present invention relates to a process for the preparation of stable amorphous Tegoprazan which comprises the steps:
i) preparing Tegoprazan by deprotection of compound of formula (II)
Formula (II)
wherein Pg amino protecting group using a base in a solvent,
ii) dissolving the obtained Tegoprazan in a suitable solvent,
ii) optionally treating the solution obtained in step (ii) with charcoal, and
iii) spray drying the resulting solution to obtain stable amorphous Tegoprazan.

In another aspect, the present invention relates to a process for the preparation of stable amorphous Tegoprazan which comprises the steps:
i) preparing Tegoprazan by detosylation of (-)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1-[(4-methylphenyl)-sulfonyl]-1H-benzimidazole-6-carboxamide of formula (IIa)
Formula (IIa)

with sodium hydroxide in mixture of DMF and Methanol,
ii) dissolving the obtained Tegoprazan in a suitable solvent,
ii) optionally treating the solution obtained in step (ii) with charcoal, and
iii) spray drying the resulting solution to obtain stable amorphous Tegoprazan.

In yet another aspect, the present invention relates to a process for the preparation of stable amorphous Tegoprazan which comprises the steps:
i) preparing Tegoprazan by debenzylation of (S)-1-benzyl-4-((5,7-difluoro chroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[D] imidazole-6-carboxamide of formula (IIb)
Formula (IIb)

using a catalyst in a solvent,
ii) dissolving the obtained Tegoprazan in a suitable solvent,
ii) optionally treating the solution obtained in step (ii) with charcoal, and
iii) spray drying the resulting solution to obtain stable amorphous Tegoprazan.

BRIEF DESCRIPTION OF DRAWINGS
Fig.1: Represents X-ray powder diffraction pattern of stable amorphous Tegoprazan of the present invention.
Fig.2: Represents DSC pattern of stable amorphous Tegoprazan of the present invention.
Fig.3: Represents TGA of stable amorphous Tegoprazan of the present invention.
Fig.4: Represents X-ray powder diffraction pattern of stable amorphous Tegoprazan obtained by spray drying process after 1 month stability.
Fig.5: Represents X-ray powder diffraction pattern of stable amorphous Tegoprazan obtained by spray drying process after 3 month stability.
Fig.6: Represents X-ray powder diffraction pattern of amorphous Tegoprazan obtained by rotavapor process after 3 month stability.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to stable amorphous Tegoprazan.

In one aspect, the present invention provides stable amorphous Tegoprazan characterized by XRD as shown in figure 1.

In one aspect, the present invention provides stable amorphous Tegoprazan characterized by DSC as shown in figure 2. The stable amorphous Tegoprazan melt with decomposition between 40 to 120 ºC and does not show any sharp melting point.

In one aspect, the present invention provides stable amorphous Tegoprazan characterized by TGA as shown in figure 3. The stable amorphous Tegoprazan of the present invention has water content below 3.0%. The product specifically has water content as measured by thermogravimetry is 2.48 and by KF is 2.7 to 2.9 which remained same over the shelf life.

In yet another embodiment, the starting material Tegoprazan used in the present invention can be prepared by any procedures disclosed in the prior-art.

Pg amino protecting group as used herein is benzyl, tosyl, t-Butyloxycarbonyl and carboxybenzyl.

The catalyst used herein for the removal of protecting group by hydrogenolysis using a transition metal catalyst selected from Pd/C in the presence or absence of ammonium formate.

Base as used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or organic bases such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4- methylimidazole and the like.

Solvent as defined in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tertbutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2- pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine, acids such as formic acid, acetic acid, propionic acid and/or mixtures thereof.

The amorphous Tegoprazan of the present invention is stable over the shelf life under different stability conditions, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling. The stable amorphous Tegoprazan of the present invention is also suitable for formulating into different dosage forms.

The stability data of the amorphous Tegoprazan of the present invention is compared with the product obtained by using Rotary evaporator. The water content is increasing after 3 months and the crystalline peaks are observed in XRD showing conversion of amorphous into crystalline form as shown below.

Test Product obtained by Rotary Evaporator Product obtained by Spray Drying
Time Initial 3 months Initial 3 months
Water content by KFR 1.44 3.32 2.78 2.92
XRD absence of crystalline Crystallinity observed absence of crystalline absence of crystalline

The above data clearly shows the non-crystalline material obtained by the process of prior-art specifically by using Rotary evaporator does not have polymorphic stability. The water content has changed from the initial time to 3 months shelf life. Similarly, the amorphous nature is not retained over the shelf life. This can be visualized from the XRD given in Figure 6. The given XRD pattern show clear visible peaks relating to crystalline form. On the contrary, the XRD pattern of stable amorphous Tegoprazan obtained by spray drying process does not show any crystallinity after 1 month or 3 months. The XRD data of stable amorphous Tegoprazan obtained by spray drying process after 1 month and 3 months is given Figures 4 and 5 respectively.

In pharmaceutical products both thermal stability and polymorphic stability is very important. Otherwise one solid state form converts into other solid state form. Further there is no control on the conversion rate at different time intervals and in different storage conditions. This means at different time points during shelf life the product might have mixture of two different solid states in different ratios. It is clearly reported in the literature that this has impact on the solubility and bioavailability of the product. This has direct impact on the efficacy of the product. Hence, it is very important to have polymorphic stability.

The stable amorphous Tegoprazan prepared by the process of the present invention is thermally stable when compared to the non-crystalline form obtained by the prior-art process. The impurity profile data of the both products is given below:

Crystal form Product obtained by Rotary Evaporator stable amorphous Tegoprazan
Period initial stage after 4 weeks initial stage after 4 weeks
Appearance white powder Yellow powder Off White powder Off White powder
Content of optical isomers 0.04% 0.47% ND / BDL ND / BDL
Content of impurities 0.16% 0.49% 0.09 % 0.16 %
ND – Not Detected ; BDL – Below Detection Limits

In a preferred embodiment, the present invention provides a pharmaceutical composition of stable amorphous Tegoprazan along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, lubricants and or anti-adherents.

The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions comprising stable amorphous Tegoprazan may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using procedures such as direct blending, dry granulation, wet granulation, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. 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.

EXAMPLES

Example 1 - Process for the preparation of stable amorphous Tegoprazan

To a stirred solution of (S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide (Tegoprazan Stage-1) (30.0 g, 55 mmoles), in 270 ml of Isopropyl alcohol was added Sodium hydroxide solution (12g, 300 mmoles dissolved in 150 ml of Water) at 25-30°C and the resulting solution was stirred for 4.0-5.0 hrs at 25-30°C, reaction progress was monitored by TLC (mobile phase: Chloroform: Methanol 9.2:0.8 ratio). Reaction mass was diluted with 300 ml of Ethylacetate and separated, aqueous layer was extracted with 75 ml of Ethylacetate. Combined organic layer was washed with 3x300 ml of DM Water. Resulting organic layer was diluted with 150 ml of DM Water, pH was adjusted to 2.0-3.0 with Aqueous HCl at 10-15°C, maintained for 10-20 min at 10-15°Cand readjusted the reaction mass pH to 7.0-8.0 with Ammonia solution, organic layer was separated followed by washed with DM Water and dried over Sodium sulfate finally distilled under vacuum at below 55°C to obtain crude material, which was isolated in 60 ml of Methyl ethyl ketone at 0-5°C and finally, this material was purified in 45 ml of Isopropyl alcohol to obtain wet material. This wet material was dissolved in Methanol, treated with activated carbon and feeded into spray drier as per below mentioned conditions to obtain wet material.

1. Feeding rate: 15-20 ml/min
2. Inlet temperature: 45-50°C.
3. Outlet temperature: 25-30°C.
4. Atomizer pressure: 1±0.5Kg/cm2.
5. Oxygen% :NMT 5.0%

Above obtained wet material was dried for 12-14hrs under vacuum at 55-60°C to obtain (S)-7-((5,7-Difluorochroman-4-yl)-oxy)-N,N,2-trimethyl-1H-benzo-[d]imidazole-5-carboxamide Amorphous form (Tegoprazan Amorphous) (66% molar yield with above 99.5% purity).

Example 2 - Process for the preparation of stable amorphous Tegoprazan

The process involves de-benzylation of 100 g of (S)-1-benzyl-4-((5,7-difluoro chroman-4-yl) oxy)-N,N,2-trimethyl-1H-benzo[D] imidazole-6-carboxamide with 15 g of Pd/C in 10V of Methanol. Reaction mass filter and completely distilled out the solvent medium after TLC complies. To the reaction mass add 2.5V of MTBE and heat to 70-75ºC for 1 hr. Cool the reaction mass and filter the solid. The solid was further crystallized in IPA to obtain wet (3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a] pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. Obtained wet material dissolved in Methanol (10 Vols) followed by charcoal treatment and obtained clear solution upon spray drying results Tegoprazan Amorphous form (65% molar yield with above 99.5% purity).

Example 3 - Process for the preparation of stable amorphous Tegoprazan

The process involves de-benzylation of 100 g of (S)-1-benzyl-4-((5,7-difluoro chroman-4-yl) oxy)-N,N,2-trimethyl-1H-benzo[D] imidazole-6-carboxamide with 15 g of Pd/C in 10V of Methanol. Reaction mass filter and completely distilled out the solvent medium after TLC complies. To the reaction mass add 2.5V of MTBE and heat to 70-75ºC for 1 hr. Cool the reaction mass and filter the solid. The solid was further crystallized in IPA to obtain wet (3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a] pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. Obtained wet material dissolved in ethanol (20 vols) followed by charcoal treatment and obtained clear solution upon spray drying results Tegoprazan Amorphous form (60% molar yield with above 99.5% purity).

Example 4 - Process for the preparation of stable amorphous Tegoprazan

The process involves de-benzylation of 100 g of (S)-1-benzyl-4-((5,7-difluoro chroman-4-yl) oxy)-N,N,2-trimethyl-1H-benzo[D] imidazole-6-carboxamide with 15 g of Pd/C in 10V of Methanol. Reaction mass filter and completely distilled out the solvent medium after TLC complies. To the reaction mass add 2.5V of MTBE and heat to 70-75ºC for 1 hr. Cool the reaction mass and filter the solid. The solid was further crystallized in IPA to obtain wet (3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a] pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. Obtained wet material dissolved in IPA (50 vols) followed by charcoal treatment and obtained clear solution upon spray drying results Tegoprazan Amorphous form (70% molar yield with above 99.5% purity).

Example 5 - Process for the preparation of stable amorphous Tegoprazan

The process involves de-benzylation of 100 g of (S)-1-benzyl-4-((5,7-difluoro chroman-4-yl) oxy)-N,N,2-trimethyl-1H-benzo[D] imidazole-6-carboxamide with 15 g of Pd/C in 10V of Methanol. Reaction mass filter and completely distilled out the solvent medium after TLC complies. To the reaction mass add 2.5V of MTBE and heat to 70-75ºC for 1 hr. Cool the reaction mass and filter the solid. The solid was further crystallized in IPA to obtain wet (3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a] pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. Obtained wet material dissolved in n-Butanol (20 vols) followed by charcoal treatment and obtained clear solution upon spray drying results Tegoprazan Amorphous form (64% molar yield with above 99.5% purity).

Example 6 - Process for the preparation of stable amorphous Tegoprazan

The process involves de-benzylation of 100 g of (S)-1-benzyl-4-((5,7-difluoro chroman-4-yl) oxy)-N,N,2-trimethyl-1H-benzo[D] imidazole-6-carboxamide with 15 g of Pd/C in 10V of Methanol. Reaction mass filter and completely distilled out the solvent medium after TLC complies. To the reaction mass add 2.5V of MTBE and heat to 70-75ºC for 1 hr. Cool the reaction mass and filter the solid. The solid was further crystallized in IPA to obtain wet (3R,4S)-3-ethyl-4-(3H-imidazo[1,2-a] pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. Obtained wet material dissolved in DCM (10 vols) followed by charcoal treatment and obtained clear solution upon spray drying results Tegoprazan Amorphous form (67% molar yield with above 99.5% purity).

Comparative Example - Process for the preparation of Tegoprazan by Rotary evaporator

Wet material obtained in Example 1 or 2 was dissolved in Methanol followed by charcoal treatment and obtained clear solution undergo Rota vapor Flask and distill off methanol completely under vacuum (650±50 mm/Hg) at below 55ºC. Degas for 30-40min under vacuum (650±50 mm/Hg) at below 55ºC and scratch the material to make it powder and continue de-gas for 2.0-3.0hrs under vacuum (650±50 mm/Hg) at below 55oC. Dry the material for 12.0-14.0hrs at 55-60ºC under vacuum results Tegoprazan Amorphous form (60% molar yield with above 99.5% purity). ,CLAIMS:We Claim:

1. A stable amorphous Tegoprazan of the formula (I).

2. The stable amorphous Tegoprazan as claimed in claim 1, characterized by XRD as shown in figure 1, DSC as shown in figure 2 and melt with decomposition between 40 to 120 ºC.

3. The stable amorphous Tegoprazan as claimed in claim 1, having water content below 3.0%.

4. The process for the preparation of stable amorphous Tegoprazan, as claimed in claim 1 which comprises the steps:
i) providing a solution of Tegoprazan in a suitable solvent,
ii) optionally treating the solution obtained in step (i) with charcoal, and
iii) spray drying the resulting solution to obtain stable amorphous Tegoprazan.

5. The process for the preparation of stable amorphous Tegoprazan, as claimed in claim 1 which comprises the steps:
i) preparing Tegoprazan by deprotection of compound of formula (II)
Formula (II)
wherein Pg amino protecting group using a base in a solvent,
ii) dissolving the obtained Tegoprazan in a suitable solvent,
ii) optionally treating the solution obtained in step (ii) with charcoal, and
iii) spray drying the resulting solution to obtain stable amorphous Tegoprazan.

6. The process as claimed in claim 5, wherein Pg is benzyl, tosyl, t-Butyloxycarbonyl and carboxybenzyl.

7. The process as claimed in claim 5, wherein Pg is deprotected by hydrogenolysis using a transition metal catalyst selected from Pd/C in the presence or absence of ammonium formate

8. The process as claimed in claim 5, wherein the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4- methylimidazole.

9. The process as claimed in claim 5, wherein the solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, acetonitrile, propionitrile, butyronitrile and isobutyronitrile di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tertbutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, dichloromethane, 1,2-dichloroethane, chloroform, diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine, formic acid, acetic acid, propionic acid and/or mixtures thereof.

Dated this Seventeenth (17th) day of February, 2024
_______________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883