DE202011000756U1 - Ebastins, non-micronised ebastine particles and pharmaceutical compositions comprising ebastines - Google Patents

Abstract

Ebastin, obtained by a process involving the reaction of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one (Compound II) and diphenylmethanol in the presence a dehydrating agent in an organic solvent system to obtain ebacterium fumarate salt (Compound IV) in organic solvent.

Description

FIELD OF THE INVENTION

The invention relates to ebastine and the use thereof in a formulation without its micronization. The invention thus relates to 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one (Compound II), an intermediate or a preparation of ebastine and the use same in the production of ebastin.

BACKGROUND OF THE INVENTION

1- [4- (1,1-dimethylethyl) phenyl] -4- [4-diphenylmethoxy) -1-piperidinyl] -1-butanone, commonly known as ebastine. Ebastin was discovered and developed by Fordonal. The structure of ebastin is given below:

Commercially available ebastin dosage forms include tablets and mouth-melting tablets. The inadequate bioavailability of ebastine due to its poor water solubility has been a problem in the formulation of ebastin into solid dosage forms.

Ebastin is generally prepared from 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one and diphenylmethylbromide. Several methods for the production of ebastine and its compositions are known in the literature.

The U.S. Patent No. 4,550,116 discloses the synthesis of ebastine according to the following schemes. The first scheme is as follows:

During the preparation of ebacterium fumarate (IV) in the above scheme, 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one (II) was treated with diphenylmethylbromide (II). III) in the presence of sodium carbonate and methyl isobutyl ketone for 36 hours under reflux.

The above disclosed scheme has several disadvantages as follows:
The compound (II) is purified in the form of fumarate salt and further reacts with the compound (III). The compound (III) is extremely unstable and sensitive to moisture. In addition, the compound (III) is expensive. Further, the process requires reflux of the reaction mixture for more than 36 hours with addition of compound (III) at 12 hour intervals.

The U.S. Patent No. 4,550,116 also discloses a second scheme which is as follows:

In the second scheme, a process for producing ebacterium fumarate (IV) was carried out by refluxing a mixture of 4-diphenylmethoxypiperidine with 1- (4-butylphenyl) -4-chlorobutan-1-one in the presence of sodium carbonate and methyl isobutyl ketone as a solvent.

In the above scheme, the preparation of 1-ethoxycarbonyl-4-diphenylmethoxypiperidine is extremely expensive and economically unacceptable due to its low yields.

The EP 614 362 B1 discloses a solid pharmaceutical composition having improved dissolution properties which comprises a compound corresponding to the formula (including ebastine) and its salts; characterized in that the compound of the formula is micronized.

The EP 1 898 882 A2 discloses a stable nanoparticulate ebastine or salt thereof, the composition comprising: (a) particles of ebastine or a salt thereof having an effective average particle size of less than about 2000 nm; and (b) at least one surface stabilizer.

The EP 1 716 848 B1 discloses a solid pharmaceutical composition comprising at least a first and a second excipient reactive with a crystalline active ingredient of the formula (including ebastine) or a pharmaceutically acceptable salt of the active ingredient in particles having a maximum particle size of less than about 500 is mixed, characterized in that the first adjuvant is a non-ionic, surface-active substance.

Thus, there is a need for a simple, inexpensive, and less time consuming process for producing ebastin that can be used without micronization to develop a bioequivalent formulation.

OBJECT OF THE INVENTION

An object of the present invention is to provide a low cost or viable method of producing ebastin.

Another object of the present invention is to provide ebastin, which takes less time to produce.

Another object of the present invention is to provide ebastin with as few process steps as possible.

Another object of the present invention is to provide an ebastin using compound II.

Another object of the present invention is to provide pure ebastine having a D _{[V, 0.9]} particle size in a range of 250 μm to 1000 μm and a maximum particle size of more than 1000 μm.

In another aspect, there is provided a pharmaceutical composition comprising ebastin in non-micronized form, wherein the D _{[V, 0.9]} particle size of an active ingredient ranges from 250 μm to 1000 μm, and the maximum particle size of the active Ingredient more than 1000 microns.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided a pure ebastin prepared by reacting 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one, Compound (II), and diphenylmethanol is prepared in the presence of a dehydrating agent in an organic solvent system to obtain ebacterium fumarate salt (Compound IV).

According to another aspect of the present invention, there is provided 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one, compound (II), which is further incorporated by reference the preparation of ebastine is obtained, wherein the compound (II) is obtained by a method comprising a coupling reaction between compound (I) and 4-hydroxypiperidine in the presence of a base in an organic solvent system, distilling the solvent under vacuum, dissolving the resulting residue in ethyl acetate and water, washing the aqueous in acidic pH with an organic solvent to obtain compound II from a mixture of ethyl acetate and n-hexane directly without any further purification.

According to another aspect of the present invention, the pure ebastine prepared by the method described above is used for the pharmaceutical composition without micronizing the same.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising ebastin in non-micronized form prepared by the method described above, wherein the D _{[V, 0.9]} value of the active ingredient particle size is in the range from 250 μm to 1000 μm, and the maximum particle size of the active ingredient is more than 1000 μm.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an efficient and inexpensive pure ebastin obtained by a synthesis process which involves the preparation of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butane. 1-one by reacting 1- (4-tert-butylphenyl) -4-chlorobutan-1-one and 4-hydroxypiperidine in an organic solvent system under basic conditions and further refluxing the thus obtained 1- [4- (1,1-) Dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one with diphenylmethanol in the presence of a dehydrating agent by removing the generated water as an azeotrope to obtain the ebastine, which is then converted to fumarate salt. The ebastin fumarate salt is then treated with a base, and pure ebastine is crystallized from alcohol.

According to one embodiment, the present invention provides an ebastin obtained by a process having the following synthetic scheme:

According to the present invention, the coupling reaction between compound (I) and 4-hydroxypiperidine is carried out in the presence of a base in an organic solvent system, the organic solvent being selected from a water-soluble solvent such as acetonitrile, dioxane, N, N-dimethylformamide, acetone, etc ., And a water-immiscible solvent such as toluene, methyl isobutyl ketone, dichloromethane, xylene, chloroform, cyclohexane and mixtures thereof. Preferably, the reaction is carried out in the presence of toluene. The organic base may be selected from organic and inorganic bases. The organic base may be selected from alkali metal carbonate or bicarbonate, such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, and metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The organic base may be selected from triethylamine, diisopropylethylamine or pyridine. The preferred base is sodium bicarbonate.

The reaction can be carried out from ambient temperature to the reflux temperature of the solvent and generally takes 6-12 hours to complete. In general, the reaction is carried out at the reflux temperature of the solvent for about 6 to 8 hours. After the reaction proceeds to a desired stage, as judged by HPLC analysis, the solvent is distilled off under vacuum and the resulting residue is dissolved in ethyl acetate and water. The pH of the organic layer is adjusted to acid with mineral acids such as hydrochloric acid, sulfuric acid or acetic acid. The preferred pH is 2-3, and a preferred acid is HCl. At an acidic pH, the aqueous layer is washed with organic solvent to remove impurities, the desired product is obtained directly without any further purification from a mixture of ethyl acetate and n-hexane.

It is well known that the process for producing a substance has an influence on the structure of the substance, particularly the crystal structure of the solid substrate. According to the literature of the prior art, ebastine can be prepared by refluxing compound (II) with diphenylmethyl bromide or chloride in the presence of sodium carbonate. According to the present invention, the compound (II) and diphenylmethanol are reacted in the presence of a dehydrating agent in an organic solvent system, which organic solvent may be selected from a high boiling organic solvent such as toluene, xylene, methyl isobutyl ketone or dichloroethane. The preferred solvent is toluene. The dehydrating agent may be selected from p-toluenesulfonic acid monohydrate (PISA), sulfuric acid, methanesulfonic acid, phosphorus pentoxide, titanium tetrachloride or dicyclohexylcarbodiimide (DCC), etc. The preferred dehydrating agent is p-toluenesulfonic acid monohydrate. The reaction may be conducted for 6 to 16 hours, preferably for 6 to 8 hours, at a reflux temperature of the solvent to remove water as an azeotrope. After the reaction has proceeded to a desired stage, as judged by HPLC analysis, the desired compound (IV) is isolated in the form of a fumarate salt in organic solvent. The organic solvent can be selected from alcohols, such as methanol, ethanol or isopropanol; Nitriles, such as acetonitrile or propionitrile; Esters, such as ethyl acetate, propyl acetate or butyl acetate; Toluene, methyl isobutyl ketone and mixtures thereof. The preferred solvent is ethyl acetate.

In another embodiment of the invention, pure ebastine is obtained from ebacterium fumarate salt (IV) using a base. The base is selected from alkali metal hydroxides, carbonates and bicarbonates, ammonia, tertiary amines and mixtures thereof. The preferred base is sodium hydroxide.

In another embodiment of the invention, pure ebastine is crystallized from the resulting residue obtained from ebacterium fumarate salt (IV) in the presence of an organic solvent at -5 to + 25 ° C. The organic solvent is selected from C ₁ to C ₆ alcohols such as methanol, ethanol and propanol; Hexane, cyclohexane; Diisopropyl ether and mixtures thereof. The preferred solvent is methanol. The purity of the ebastin thus obtained is more than 96.6% by HPLC.

The method described above is used to directly produce non-micronized ebastine compositions. The pharmaceutical compositions are administered orally. The pharmaceutical composition may be a solid dosage form. The solid dosage form can be one or more of: tablets, capsules, powders, platelets, coated tablets, beads, pellets, encapsulated beads, minitablets, capsulated minitablets, encapsulated pellets, sachets, and the like.

The pharmaceutical composition may be a tablet, which may be a multi-layered tablet. The tablet may be one that melts in the mouth.

The pharmaceutical composition contains ebastine as an active ingredient, which is prepared by the above-mentioned method. The pharmaceutical composition may contain between 1 and 25% by weight of the active ingredient ebastine. The active ingredient may be in the form of powder, pellets, pellets, beads, microtablets, minitablets and crystals.

Ebastin is used herein in non-micronized form. The D _{[V, 0.9]} value of the particle size of ebastin is in the range of 250 μm to 1000 μm. The maximum particle size of ebastine is more than 1000 μm. The pharmaceutical composition comprises one or more pharmaceutically acceptable inert adjuvants. The pharmaceutically acceptable inert adjuvants may be one or more of diluents, binders, surfactants, disintegrants, lubricants, flow agents, solvents, sweeteners and flavorings, and the like.

Suitable diluents may be one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like.

Suitable binders may be one or more of povidone, starch, stearic acid, gums, hydroxypropyl cellulose and the like.

Suitable surfactants may include one or more of benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, TPGS (d-alpha tocopheryl polyethylene glycol succinate), dioctyl sodium sulfosuccinate, poloxamers, polyoxyethylene glycracycane / caprin mono- and diglycerides, polyoxyethylene castor oil, hydrogenated castor oil, polyoxyethylene cetostearyl ether; polyoxyethylene; Polysorbate-20 and polysorbate-80, propylene glycol laurate, sodium lauryl sulfate, oleic acid, sodium oleate, triethanolamine oleate, glyceryl monostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, lecithin, stearyl triethanolamine, laurylaminopropionic acid and the like. The surfactant is used in a concentration of about 1 to 30% by weight of the pharmaceutical composition.

A suitable disintegrating agent may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and the like.

A suitable lubricant may be one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.

A suitable flow agent may be one or more of colloidal silica, talc or cornstarch, and the like.

Suitable solvents may be one or more of isopropyl alcohol, methylene chloride, water or the like.

Suitable sweeteners may be one or more of aspartame, acesulfame potassium, cyclamate, glycyrrhizin, sucralose, saccharin, neohesperidin dihydrochalone, and the like.

Suitable flavoring agents may be one or more of mint flavor, orange flavor, lemon flavor, banana flavor, vanilla flavor, grapefruit flavor cherry flavor, strawberry flavor, chocolate flavor, coffee flavor, and the like.

The solid dosage form may optionally be film-coated. The solid dosage form may include film formers, solvents, plasticizers, and the like.

Suitable film formers may be one or more of hydroxypropylmethylcellulose, methylhydroxyethylcellulose, ethylcellulose, hydroxypropylcellulose, povidone, sodium carboxymethylcellulose, polyethylene glycol, acrylates, and the like.

Suitable solvents may be one or more of water, ethanol, methanol, isopropanol, chloroform, acetone, methyl ethyl ketone, methylene chloride and the like.

Suitable plasticizers may be one or more of propylene glycol, castor oil, glycerol, polyethylene glycol, polysorbates, and the like.

The pharmaceutical composition may be prepared by methods known to those of ordinary skill in the art including, but not limited to, dry granulation, wet granulation, and direct compression. The wet granulation may be aqueous or non-aqueous granulation.

• i. Lösen von Ebastin in einem geeigneten Lösungsmittel, optional mit pharmazeutisch annehmbaren, inerten Hilfsstoffen, um eine Lösung zu bilden,
• ii. Hinzufügen von pharmazeutisch annehmbaren, inerten Hilfsstoffen, um eine Mischung zu bilden,
• iii. Granulieren der Mischung von Schritt (ii) mit einer in Schritt (i) gebildeten Lösung, um ein Granulat zu bilden,
• iv. Komprimieren des in Schritt (iii) gebildeten Granulats unter Verwendung geeigneter Werkzeuge.

When wet granulation is used to prepare the tablet composition, the process comprises the following steps:

• i. Dissolving ebastine in a suitable solvent, optionally with pharmaceutically acceptable inert adjuvants to form a solution,
• ii. Adding pharmaceutically acceptable inert adjuvants to form a mixture
• iii. Granulating the mixture of step (ii) with a solution formed in step (i) to form granules,
• iv. Compressing the granules formed in step (iii) using suitable tools.

The particle size data of 3 batches are in the 1 to 3 shown.

The present invention may be illustrated in one of its embodiments by the following non-limiting examples.

EXAMPLE 1:

Preparation of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one:

A mixture of 4-hydroxypiperidine (50 g), 1- (4-tert-butylphenyl) -4-chlorobutan-1-one (119 g) and sodium bicarbonate (84 g) in toluene (500 ml) was allowed to stand for 6 to 8 hours Reflux cooked. The progress of the reaction was monitored by HPLC. The solvent was completely distilled off under vacuum; the resulting residue was dissolved in ethyl acetate and water. An ethyl acetate layer was separated and washed with water, the pH of the ethyl acetate layer was adjusted to 2 to 3 with 3N HCl solution, the aqueous layer was washed with ethyl acetate, and the aqueous solution was made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was completely removed under vacuum. The title compound was isolated from a 1: 5 mixture of ethyl acetate and n-hexane.
Yield: 105 g, melting point: 63-65 ° C.

EXAMPLE 2

Preparation of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydraxypiperidin-1-yl) butan-1-one:

A mixture of 4-hydroxypiperidine (10g), 1- (4-tert-butylphenyl) -4-chlorobutan-1-one (24g) and triethylamine (20g) in methyl isobutyl ketone (100ml) became 6 to 8 hours cooked under reflux. The progress of the reaction was monitored by HPLC. The reaction mass was cooled to room temperature and washed with water. The pH of the organic layer was adjusted to 2 to 3 with 3N HCl solution; the aqueous layer was washed with methyl isobutyl ketone, and the aqueous solution was made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was completely removed under vacuum. The title compound was isolated from a 1: 5 mixture of ethyl acetate and n-hexane.
Yield: 18 g, melting point: 63-65 ° C.

EXAMPLE 3

Preparation of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydraxypiperidin-1-yl) butan-1-one:

A mixture of 4-hydroxypiperidine (14 g), 1- (4-tert-butylphenyl) -4-chlorobutan-1-one (33 g) and sodium carbonate (30 g) in acetonitrile (100 ml) was allowed to stand for 10 to 14 hours Reflux cooked. The progress of the reaction was monitored by HPLC. The solvent was completely distilled off under vacuum, and the resulting residue was dissolved in ethyl acetate (100 g) and water (100 ml). The ethyl acetate layer was separated and washed with water. The pH of the ethyl acetate layer was adjusted to 2 to 3 with 3N HCl solution; and the aqueous solution was made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and the solvent was completely removed under vacuum. The title compound was isolated from a 1: 5 mixture of ethyl acetate and n-hexane.
Yield: 14 g, melting point: 61-64 ° C.

EXAMPLE 4

Production of Ebastin:

A mixture of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one (150 g) and p-toluenesulfonic acid monohydrate (105 g) in toluene (500 ml) was boiled at 100 to 110 ° C. A solution of diphenylmethanol (60 g) in toluene (80 ml) was added over 1 hour at reflux temperature with continuous removal of water as an azeotrope. Another solution of diphenylmethanol (60 g) in toluene (80 mL) was added over 1 h at reflux with continuous removal of water as an azeotrope, and the mixture was refluxed for 1.5 h. Another solution of diphenylmethanol of the same amount was added under similar conditions. The reaction mixture was refluxed for 4 to 5 hours. The progress of the reaction was monitored by HPLC. The solvent was completely distilled off under vacuum, and the resulting residue was dissolved in ethyl acetate (750 ml) and 10% sodium hydroxide solution (600 ml) at 45 to 50 ° C. The organic layer was separated and washed with water and 3N HCl solution and with 10% sodium bicarbonate solution. The ethyl acetate layer was then dried with sodium sulfate and refluxed with fumaric acid (85 g, 0.73 mol). The resulting ebacterium fumarate was filtered, washed with ethyl acetate and dried at 80-85 ° C.

The ebacterium fumarate salt (240 g) was suspended in ethyl acetate (900 ml) and 10% sodium hydroxide solution (800 ml), stirred for 0.5 hours at room temperature to give a clear solution. The organic layer was separated and washed with water until its pH was neutral. The solvent was completely distilled off under vacuum and crystallized. The resulting residue was crystallized from methanol. The resulting pure Ebastin solid was filtered and dried at 60-65 ° C.
Yield: 150 g, melting point: about 86 ° C. Purity by HPLC: 99.9%.

EXAMPLE 5

Production of Ebastin:

A mixture of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one (150 g), p-toluenesulfonic acid monohydrate (105 g) and diphenylmethanol (180 g) in toluene (600 ml) was refluxed for 12 to 15 hours with continuous removal of water as an azeotrope. The progress of the reaction was monitored by HPLC. Solvent was completely distilled off under vacuum, and the resulting residue was dissolved in ethyl acetate (750 ml) and 10% sodium hydroxide solution (600 ml) at 45 to 50 ° C. The organic layer was separated and washed with water and 3N HCl solution and with 10% sodium bicarbonate solution. The ethyl acetate layer was dried with sodium sulfate and refluxed with fumaric acid (85 g, 0.73 mol). The resulting ebacterium fumarate was filtered, washed with ethyl acetate and dried at 80-85 ° C.

The ebacterium fumarate salt (200 g) was then suspended in ethyl acetate (800 ml) and 10% sodium hydroxide solution (700 ml), stirred for 0.5 hours at room temperature to give a clear solution. The organic layer was separated and washed with water. Solvent was completely distilled off under vacuum and the resulting residue was crystallized from methanol. The resulting pure Ebastin solid was filtered and dried at 60-65 ° C.
Yield: 118 g (51%), m.p .: about 86 ° C. Purity by HPLC: 99.85%.

EXAMPLE 6

Production of Ebastin:

A mixture of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one (25 g, 0.08 mol), sulfuric acid (24.2 g , 0.25 mol) and diphenylmethanol (30 g, 0.16 mol) in toluene (100 ml) was refluxed for 8 to 10 hours with continuous removal of water as an azeotrope. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried with sodium sulfate and solvent was completely removed under vacuum. The resulting residue was refluxed with ethyl acetate and fumaric acid (14.3 g). The resulting ebacterium fumarate salt was filtered, washed with ethyl acetate and dried at 80-85 ° C.

The ebastinfurmate salt (25 g) was suspended in ethyl acetate (150 ml) and 10% sodium hydroxide solution (100 ml), stirred at room temperature for 0.5 hours to obtain a clear solution. The organic layer was separated and washed with water , The solvent was completely distilled off under vacuum and the resulting residue was crystallized from methanol. The resulting pure Ebastin solid was filtered and dried at 60-65 ° C.
Yield: 12 g, melting point: about 86 ° C. Purity by HPLC: 99.7%.

EXAMPLE 7

Production of Ebastin:

A mixture of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one (100 g) and p-toluenesulfonic acid monohydrate (69.0 g). in methyl isobutyl ketone (500) was boiled at 100-110 ° C. Diphenylmethanol (120 g) was added to the reaction mixture over 3 hours at reflux temperature with continuous removal of water as an azeotrope. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 50-55 ° C, 10% sodium hydroxide solution (500 ml) and stirred for 30 minutes at the same temperature. The organic layer was separated and washed with water, 3N HCl solution and 10% sodium bicarbonate solution. The ethyl acetate layer was dried with sodium sulfate and refluxed with fumaric acid (56 g). The resulting ebacterium fumarate was filtered, washed with ethyl acetate and dried at 80-85 ° C.

The ebacterium fumarate salt (140 g) was suspended in ethyl acetate (500 ml) and 10% sodium hydroxide solution (350 ml) and stirred for 0.5 hours at room temperature to obtain a clear solution. The organic layer was separated and washed with water until its pH was also neutral. The solvent was completely distilled off under vacuum and the resulting residue was crystallized from methanol. The resulting pure Ebastin solid was filtered and dried at 60-65 ° C.
Yield: 75 g, melting point: about 86 ° C. Purity by HPLC: 99.9%.

EXAMPLE 8

Table 1: Pharmaceutical composition SN ingredients Quantity (mg) intragranular 1. ebastine 10,000 Second sodium lauryl sulfate 1,500 Third isopropyl alcohol qs 4th methylene chloride qs 5th mannitol 124.500 6th crospovidone 20,000 extragranular 7th aspartame 1,000 8th. Peppermint Premium powder 2,000 9th crospovidone 30,000 10th Colloidal silica 5,000 lubritic 11th sodium stearyl 6,000

The manufacturing process is briefly summarized below:
Ebastin API, prepared by the method described above, was dissolved in a mixture of isopropyl alcohol and methylene chloride to form a solution. Sodium lauryl sulfate was dispersed in solution to form a dispersion. Mannitol and crospovidone were sieved to form a mixture. The resulting mixture was granulated with the dispersion that was formed to form a wet mass. The resulting wet mass was dried and classified to form beads. Aspartame, premium peppermint powder, crospovidone and colloidal silica were sieved and mixed with beads to form a batch.

The resulting mixture was pressed using suitable tools with sodium stearyl fumarate as a lubricant.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 4550116 [0005, 0008]
• EP 614362 B1 [0011]
• EP 1898882 A2 [0012]
• EP 1716848 B1 [0013]

Claims (24)

Ebastin, obtained by a process involving the reaction of 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-one (Compound II) and diphenylmethanol in the presence a dehydrating agent in an organic solvent system to obtain ebacterium fumarate salt (Compound IV) in organic solvent. Ebastin according to claim 1, wherein the organic solvent is selected from high boiling solvents such as toluene, xylene, methyl isobutyl ketone and dichloroethane, preferably toluene. Ebastin according to claim 1 or 2, wherein the dehydrating agent is selected from p-toluenesulfonic acid monohydrate (PTSA), sulfuric acid, methanesulfonic acid, phosphorus pentoxide, titanium tetrachloride and dicyclohexylcarbodiimide (DCC), preferably p-toluenesulfonic acid monohydrate. Ebastin according to any one of claims 1 to 3, wherein the reaction is carried out at a reflux temperature of the solvent to remove water as an azeotrope. Ebastin according to claim 4, wherein the reaction is carried out for 6 to 8 hours. Ebastin according to any one of claims 1 to 5, wherein the organic solvent for obtaining Ebastinfumaratsalz (compound IV) is selected from alcohols, nitriles, esters, hydrocarbons, ketonic solvents and mixtures thereof. Ebastin according to claim 6, wherein the alcohol is selected from methanol, ethanol and isopropanol. Ebastin according to claim 6, wherein the nitrile is selected from acetonitrile or propionitrile. Ebastin according to claim 6, wherein the ester is selected from ethyl acetate, propyl acetate, butyl acetate, preferably ethyl acetate. Ebastin according to any one of claims 1 to 9, further comprising preparing pure ebastine from ebastin fumarate salt (IV) using a base in organic solvent. Ebastin according to claim 10, wherein the base is selected from alkali metal hydroxides, carbonates, bicarbonates, ammonia, tertiary amines and mixtures thereof, preferably sodium hydroxide. Ebastin according to claim 10, wherein the organic solvent is selected from C ₁ to C ₆ alcohols, hexane, cyclohexane, diisopropyl ether and mixtures thereof. Ebastin according to claim 12, wherein the C ₁ to C ₆ alcohols are selected from methanol, ethanol and propanol, preferably from methanol. Ebastin according to any one of claims 1 to 13, wherein the preparation of the 1- [4- (1,1-dimethylethyl) phenyl] -4- (4-hydroxypiperidin-1-yl) butan-1-ans, compound (II), a coupling reaction between compound (I) and 4-hydroxypiperidine in the presence of a base in an organic solvent system and direct obtaining of compound (II) from a mixture of ethyl acetate and n-hexane, without further purification. Ebastin according to any one of claims 1 to 14, wherein the obtained ebastine particles have a maximum particle size of more than 1000 μm. Ebastin according to any one of claims 1 to 15, wherein the obtained ebastine has a D90 particle size between 250 μm to 1000 μm. Non-micronised ebastine particles with a D _{[V, 0.9]} particle size in the range of 250 μm to 1000 μm. Non-micronised ebastine particles with a maximum particle size greater than 1000 μm. A pharmaceutical composition comprising non-micronized ebastine particles having a D _{[V, 0.9]} particle size in the range of 250 μm to 1000 μm. A pharmaceutical composition according to claim 19, wherein the composition is in the form of a solid dosage form. A pharmaceutical composition according to claim 20, wherein the composition is in the form of tablets. The pharmaceutical composition of claim 21, further comprising pharmaceutically acceptable inert adjuvants. The pharmaceutical composition of claim 22, wherein the pharmaceutically acceptable inert adjuvants are selected from one or more of diluents, binders, surfactants, disintegrants, lubricants, flow agents, solvents, sweeteners and flavoring agents. A tablet comprising a pharmaceutical composition according to any one of claims 19 to 23, wherein the tablet is prepared by the following steps: i. Dissolving non-micronised ebastine in a suitable solvent, optionally with pharmaceutically acceptable inert adjuvants to form a solution, ii. Adding pharmaceutically acceptable inert adjuvants to form a mixture iii. Granulating the mixture in step (ii) with a solution formed in step (i) to form granules, iv. Pressing the granules formed in step (iii) using suitable tools, The table of claim 24, wherein the suitable solvent is one or more of isopropyl alcohol, methylene chloride and water.

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