DESC:FIELD OF THE INVENTION:
The present invention relates to an amorphous solid dispersion of Tegoprazan of Formula-I with pharmaceutically acceptable excipients.
The present invention also relates to an efficient and industrially advantageous process for preparation of amorphous solid dispersion of Tegoprazan of Formula-I with pharmaceutically acceptable excipients such as colloidal silica and Neusilin.

BACKGROUND OF THE INVENTION:
Tegoprazan is chemically known as (-)-4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide, having the structure of Formula-I.

[Formula-I]
Tegoprazan has been developed by RaQualia Pharma Inc. and in the partnership with CJ HealthCare Corporation launched in South Korea. Tegoprazan was approved by Korean Food and Drug Administration (KFDA) on July 05th, 2018 under the proprietary name K-CAP®. Tegoprazan is a pharmaceutical ingredient for preventing and treating diseases mediated by an acid pump antagonistic activity, including gastrointestinal diseases, for example, a gastroesophageal disease, a gastroesophageal reflux disease (GERD), a peptic ulcer, a gastric ulcer and a duodenal ulcer, an ulcer induced by NSAID, a gastritis, a Helicobacter pylori infection, a dyspepsia and a functional dyspepsia, a Zollinger-Ellison syndrome, a nonerosive reflux disease (NERD), a visceral pain, a purosis, a nausea, an esophagitis, a dysphagia, a salivation, an airway lesion and an asthma.
U.S. patent number US7723321 first discloses Tegoprazan. However, this patent does not disclose crystalline nature of Tegoprazan.
U.S. patent number US9908870 discloses crystalline Tegoprazan, which is advantageous for preparing a formulation because of being stable under a long-term and stress storage condition, having no crystal transition observed due to a change with the passage of time, having an excellent photostability, and having a low hygroscopicity and a low induction of static electricity.
The above-mentioned compound has a limitation to selection of salts because the compound has a very low water solubility (0.02 mg/ml, pH 6.8), has a solubility increased (0.7 mg/ml, pH 3.0) under an acidic condition, but without a great effect, and has a degradation product increased under an acidic condition, such that the compound does not have a good stability. Also, in case of using a solubilizing agent, such as a surfactant, to improve solubility, excessive amounts of excipients are needed, thus causing a difficulty.
U.S. patent number US11535610 (hereinafter US ‘610) specifically discloses several acid addition salts of Tegoprazan, wherein acid is selected from succinic acid, fumaric acid, oxalic acid, citric acid, L-pyroglutamic acid, 1,5-naphinalene disulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, L-malic acid, nicotinic acid, 2,5-dihydroxybenzoic acid and L-tartaric acid. US ‘610 also discloses process for preparation of amorphous form of Tegoprazan comprising dissolving Tegoprazan in methanol at 25°C to form a solution and then resulting solution was concentrated at 50° C followed by stirring until a solid was precipitated. To a resulting concentrate co-solvent of acetone and ethyl acetate (1:4) was added at 25°C and resulting solution was stirred agitatedly for 30 minutes. The solid was filtered out under decompression, washed with ethyl acetate, and dried under vacuum at 40° C for 16 hours to obtain white powder of Tegoprazan amorphous.
The major problem associated with amorphous Tegoprazan is, it is unstable at room temperature as it gets converted into crystalline form. Further, most of the aforesaid salts are hygroscopic and unstable as it gets degraded at accelerated conditions.
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. 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). For some therapeutic indications, one bioavailability pattern may be favoured over another.
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 form development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have stable amorphous form of drugs with high purity to meet the needs of regulatory agencies and highly reproducible processes for their preparation.
Most of the prior art salts or amorphous Tegoprazan have their own disadvantages like unstable or gets degraded. Thus, there is an urgent need to stabilize the amorphous form of Tegoprazan.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an amorphous solid dispersion of Tegoprazan of Formula-I with pharmaceutically acceptable excipients.
Another object of the present invention is to provide a process for preparation of amorphous solid dispersion of Tegoprazan of Formula-I with colloidal silica as a pharmaceutically acceptable excipient.
Another one object of the present invention is to provide a process for preparation of amorphous solid dispersion of Tegoprazan of Formula-I with Neusilin as a pharmaceutically acceptable excipient.
One more object of the present invention is to provide a pharmaceutical composition of amorphous solid dispersion of Tegoprazan of Formula-I with pharmaceutically acceptable excipients.
SUMMARY OF INVENTION:
First aspect of the present invention is to provide an amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with at least one pharmaceutically acceptable excipient.
Second aspect of the present invention is to provides a process for the preparation of amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with at least one pharmaceutically acceptable excipient, comprising the steps of:
a) providing a mixture of Tegoprazan of Formula-I and at least one pharmaceutically acceptable excipient in solvent;
b) removing the solvent from the mixture obtained in step a); and
c) isolating amorphous solid dispersion of Tegoprazan of Formula-I.
Third aspect of the present invention is to provide an amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with colloidal silica as a pharmaceutically acceptable excipient.
Fourth aspect of the present invention is to provide a process for the preparation of amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with colloidal silica as a pharmaceutically acceptable excipient, comprising the steps of:
a) providing a mixture of Tegoprazan of Formula-I and colloidal silica as a pharmaceutically acceptable excipient in solvent;
b) removing the solvent from the mixture obtained in step a); and
c) isolating amorphous solid dispersion of Tegoprazan of Formula-I.
Fifth aspect of the present invention is to provide an amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with Neusilin as a pharmaceutically acceptable excipient.
Sixth aspect of the present invention is to provide a process for the preparation of amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with Neusilin as a pharmaceutically acceptable excipient, comprising the steps of:
a) providing a mixture of Tegoprazan of Formula-I and Neusilin as a pharmaceutically acceptable excipient in solvent;
b) removing the solvent from the mixture obtained in step a); and
c) isolating amorphous solid dispersion of Tegoprazan of Formula-I.
Seventh aspect of the present invention is to provide a pharmaceutical composition comprising:
amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
and pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 01: Illustrates the X-ray powder diffractogram (XRPD) of amorphous solid dispersion of Tegoprazan of Formula-I with colloidal silica obtained according to example-01.
Figure 02: Illustrates the X-ray powder diffractogram (XRPD) of amorphous solid dispersion of Tegoprazan of Formula-I with Neusilin obtained according to example-02.
DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
According to first embodiment, present invention is to provide an amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with at least one pharmaceutically acceptable excipient.
In the first embodiment, pharmaceutically acceptable excipients can 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), Neusilin®, polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), 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 acetatepolyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; 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, and guanidine or its derivatives, sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silica or mixtures thereof.
According to second embodiment, present invention is to provides a process for the preparation of amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with at least one pharmaceutically acceptable excipient, comprising the steps of:
a) providing a mixture of Tegoprazan of Formula-I and at least one pharmaceutically acceptable excipient in solvent;
b) removing the solvent from the mixture obtained in step a); and
c) isolating amorphous solid dispersion of Tegoprazan of Formula-I.
In the second embodiment of step a), Tegoprazan of Formula-I can be prepared by process known in the prior-art.
In the second embodiment of step a), pharmaceutically acceptable excipients can 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), Neusilin®, polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), 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 acetatepolyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; 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, and guanidine or its derivatives, sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silica or mixtures thereof.
In the second embodiment of step a), solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the second embodiment of step a), solvent can be used in 2.0 volume to 15.0 volume with respect to Tegoprazan of Formula-I.
In the second embodiment of step a), pharmaceutically acceptable excipients can be added in the percentage of 1 to 5 with respect to Tegoprazan of Formula-I.
In the second embodiment of step a), mixture of Tegoprazan of Formula-I and at least one pharmaceutically acceptable excipient in solvent can be obtain at temperature 20°C to reflux temperature of the solvent used.
In the second embodiment of step a), mixture of Tegoprazan of Formula-I and at least one pharmaceutically acceptable excipient in solvent can be obtain by dissolving Tegoprazan of Formula-I and at least one pharmaceutically acceptable excipient in a solvent simultaneously or by dissolving components in solvent separately to form individual mixture and combining those mixture later.
In the second embodiment of step b), solvent can be removed by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to solvent evaporation under atmospheric pressure or reduced pressure or vacuum or spray drying or freeze drying or agitated thin film drying and the like.
According to third embodiment, present invention is to provide an amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with colloidal silica as a pharmaceutically acceptable excipient.
According to fourth embodiment, present invention is to provide a process for the preparation of amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with colloidal silica as a pharmaceutically acceptable excipient, comprising the steps of:
a) providing a mixture of Tegoprazan of Formula-I and colloidal silica as a pharmaceutically acceptable excipient in solvent;
b) removing the solvent from the mixture obtained in step a); and
c) isolating amorphous solid dispersion of Tegoprazan of Formula-I.
In the fourth embodiment of step a), solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the fourth embodiment of step a), solvent can be used in 2.0 volume to 15.0 volume with respect to Tegoprazan of Formula-I.
In the fourth embodiment of step a), colloidal silica as a pharmaceutically acceptable excipient can be added in the percentage of 1 to 5 with respect to Tegoprazan of Formula-I.
In the fourth embodiment of step a), mixture of Tegoprazan of Formula-I and colloidal silica as a pharmaceutically acceptable excipient in solvent can be obtain at temperature 20°C to reflux temperature of the solvent used.
In the fourth embodiment of step a), mixture of Tegoprazan of Formula-I and colloidal silica as a pharmaceutically acceptable excipient in solvent can be obtain by dissolving Tegoprazan of Formula-I and colloidal silica as a pharmaceutically acceptable excipient in a solvent simultaneously or by dissolving components in solvent separately to form individual mixture and combining those mixture later.
In the fourth embodiment of step b), solvent can be removed by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to solvent evaporation under atmospheric pressure or reduced pressure or vacuum or spray drying or freeze drying or agitated thin film drying and the like.
In the fourth embodiment, present invention provides an amorphous solid dispersion of Tegoprazan of Formula-I with colloidal silica as a pharmaceutically acceptable excipient, characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-01.
According to fifth embodiment, present invention is to provide an amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with Neusilin as a pharmaceutically acceptable excipient.
According to sixth embodiment, present invention is to provide a process for the preparation of amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with Neusilin as a pharmaceutically acceptable excipient, comprising the steps of:
a) providing a mixture of Tegoprazan of Formula-I and Neusilin as a pharmaceutically acceptable excipient in solvent;
b) removing the solvent from the mixture obtained in step a); and
c) isolating amorphous solid dispersion of Tegoprazan of Formula-I.
In the sixth embodiment of step a), solvent can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the sixth embodiment of step a), solvent can be used in 2.0 volume to 15.0 volume with respect to Tegoprazan of Formula-I.
In the sixth embodiment of step a), Neusilin as a pharmaceutically acceptable excipient can be added in the percentage of 1 to 5 with respect to Tegoprazan of Formula-I.
In the sixth embodiment of step a), mixture of Tegoprazan of Formula-I and Neusilin as a pharmaceutically acceptable excipient in solvent can be obtain at temperature 20°C to reflux temperature of the solvent used.
In the sixth embodiment of step a), mixture of Tegoprazan of Formula-I and Neusilin as a pharmaceutically acceptable excipient in solvent can be obtain by dissolving Tegoprazan of Formula-I and Neusilin as a pharmaceutically acceptable excipient in solvent simultaneously or by dissolving components in solvent separately to form individual mixture and combining those mixture later.
In the sixth embodiment of step b), solvent can be removed by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to solvent evaporation under atmospheric pressure or reduced pressure or vacuum or spray drying or freeze drying or agitated thin film drying and the like.
In the sixth embodiment, present invention provides an amorphous solid dispersion of Tegoprazan of Formula-I with Neusilin as a pharmaceutically acceptable excipient, characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-02.
According to seventh embodiment, present invention is to provide a pharmaceutical composition comprising:
amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
and pharmaceutically acceptable excipients.
In the seventh embodiment, pharmaceutically acceptable excipients can 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), Neusilin® polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), 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 acetatepolyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; 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, and guanidine or its derivatives, sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silica or mixtures thereof.
EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example-01: Preparation of solid dispersion of amorphous Tegoprazan Formula-I with colloidal silica
To a stirred solution of Tegoprazan (1 g) and methanol (5 mL), colloidal silica (aerosil 200) (20 mg) was added at 40°C to 50°C. Resulting mixture was stirred and solvent was distilled at 50°C to 55°C under reduced pressure. The resulting solid was dried at the same temperature under reduced pressure to obtain the title compound.
Yield: 90%.
Example-02: Preparation of solid dispersion of amorphous Tegoprazan Formula-I with Neusilin
To a stirred solution of Tegoprazan (1 g) and methanol (5 mL), Neusilin (20 mg) was added at 40°C to 50°C. Resulting mixture was stirred and solvent was distilled at 50°C to 55°C under reduced pressure. The resulting solid was dried at the same temperature under reduced pressure to obtain the title compound.
Yield: 90%.

CLAIMS:I / We Claim:

1. An amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with at least one pharmaceutically acceptable excipient.
2. The amorphous solid dispersion of Tegoprazan as claimed in claim-1, wherein pharmaceutically acceptable excipients is 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), Neusilin®, polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), 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 acetatepolyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; 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, and guanidine or its derivatives, sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silica or mixtures thereof.
3. A process for the preparation of amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
with at least one pharmaceutically acceptable excipient, comprising the steps of:
a) providing a mixture of Tegoprazan of Formula-I and at least one pharmaceutically acceptable excipient in solvent;
b) removing the solvent from the mixture obtained in step a); and
c) isolating amorphous solid dispersion of Tegoprazan of Formula-I.
4. The process as claimed in claim-3, wherein pharmaceutically acceptable excipients is 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), Neusilin®, polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), 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 acetatepolyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; 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, and guanidine or its derivatives, sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silica or mixtures thereof.
5. The process as claimed in claim-3, wherein solvent is selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
6. A pharmaceutical composition comprising amorphous solid dispersion of Tegoprazan of Formula-I,

[Formula-I]
and pharmaceutically acceptable excipients.
7. The pharmaceutical composition as claimed in claim-6, wherein pharmaceutically acceptable excipients is 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), Neusilin®, polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), 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 acetatepolyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; 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, and guanidine or its derivatives, sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silica or mixtures thereof.

Dated this 18th day of August 2024

Dr. Virendra Thakrar,
Sr. Vice- President R&D,
Ami Lifesciences Pvt. Ltd.