KR20090005271A - Crystalline hydrate of bepotastine metal salt, method for preparing same and pharmaceutical composition comprising same - Google Patents

Abstract

A crystalline bepotastine metal salt hydrate, a method for preparing the crystalline bepotastine metal salt hydrate, and a pharmaceutical composition containing the bepotastine metal salt hydrate are provided to improve optical stability and to enhance anti-histamine and anti-allergy activity. A crystalline bepotastine metal salt hydrate is represented by the formula 1, wherein M is calcium or strontium. The crystalline bepotastine metal salt hydrate is prepared by reacting bepotastine with calcium hydroxide or strontium hydroxide in a mixture solvent comprising water and at least one organic solvent selected from methanol, ethanol, 2-propanol, acetonitrile and acetone.

Description

Crystalline bepotastine metal salt hydrate, a manufacturing method thereof and a pharmaceutical composition comprising the same {CRYSTALLINE HYDRATE OF BEPOTASTINE METAL SALT, METHOD FOR PREPARING SAME AND PHARMACEUTICAL COMPOSITION COMPRISING SAME}

The present invention relates to a crystalline form of bepotastine metal salt hydrate, a method for preparing the same, and a pharmaceutical composition for antihistamine or anti-allergy including the same.

The chemical stability of pharmacologically active ingredients is very important in the pharmaceutical field where high quality and long term retention are required. In particular, optical stability should also be ensured and maintained when the pharmacologically active ingredient consists of one of the optical isomers. The chemical and optical stability of these active ingredients should be maintained throughout the shelf life of the medicinal product, which is largely dependent on the solidity of the ingredients themselves, and generally non-hygroscopic crystalline forms are very desirable.

Bepotastine represented by the following Chemical Formula 2 (chemical name: ( S ) -4- [4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidin-1-yl] butanoic acid) was orally administered. It is a selective antihistaminic agent that exhibits fast effects, has low drug interactions, and has no side effects such as drowsiness and arrhythmia, and was first disclosed as a racemate compound in Japanese Patent Application Laid-Open No. 2-25465.

<Formula 2>

On the other hand, Japanese Patent Application Laid-open No. Hei 10-237070 discloses that bepotastine of the S-configuration as in Formula 2 is far superior in pharmacological activity than the isomer of the corresponding R-configuration. However, bepotastine of the general formula (2) is very poor in crystallinity and is usually obtained as a syrup, so it is difficult to secure and maintain high quality, and thus there is a limitation in using it directly as a medicine. For example, Japanese Patent Application Laid-Open No. 2001-261553 discloses that when bepotastine is formulated with additives such as conventional excipients and binders, the bepotastine of the S-configuration is dependent on the corresponding R-configuration by the moisture in the additive. Since racemization occurs with isomers, it is stated that it is necessary to secure bepotastine with high optical purity, and that an agent that does not cause racemization is required.

Therefore, in order to obtain a stable crystalline bepotastine, bepotastine is a salt of acid addition salt using pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, tartaric acid and malic acid. It is manufactured in the form. However, the majority of existing bepotastine acid addition salts have been obtained in oil, syrup, or hygroscopic crystalline form. Bepotastine salts known as relatively stable and non-hygroscopic crystalline forms include benzenesulfonates and benzoates disclosed in Japanese Patent Application Laid-open No. Hei 10-237070. Other Leone ^TM (Talion ^TM), which are commercially available from Tanabe (Tanabe) of Japan is that the anti-histamine drugs chopping Porta sustaining benzene sulfonic acid salt as an active ingredient.

However, even bepotastine benzenesulfonate appeared to be not stable enough. For example, exposure of bepotastine benzenesulfonate to conventional accelerated test conditions (40 ° C. temperature, 75% relative humidity) yields isomers and degradation products of the R-configuration.

Therefore, a bepotastine form is required to provide a raw material with high optical purity, and to maintain optical purity even under various conditions such as high temperature and high humidity during storage and distribution, and furthermore, solubility, dissolution rate, elution amount and absorption amount are required. New forms of discovery that can be improved will expand the formulation area for the development of new release systems or compositions in the pharmaceutical field.

Accordingly, the present inventors have studied a novel crystalline form of bepotastine, and as a result, developed a specific crystalline bepotastine metal salt hydrate that has not been known so far, and the developed material is non-hygroscopic and excellent in chemical and optical stability, thus providing a pharmaceutical composition. The present invention has been found to be useful in the present invention.

It is an object of the present invention to provide a crystalline form of bepotastine metal salt hydrate that is excellent in stability and non-hygroscopic.

It is another object of the present invention to provide a method for preparing the crystalline bepotastine metal salt hydrate.

Still another object of the present invention is to provide an antihistamine or anti-allergic pharmaceutical composition comprising the crystalline form of bepotastine metal salt hydrate as an active ingredient.

In accordance with the above object, the present invention provides a bepotastine metal salt hydrate of the crystalline form represented by the following formula (1).

<Formula 1>

Wherein M is calcium or strontium.

Hereinafter, the present invention will be described in detail.

The bepotastine metal salt hydrate of the crystalline form according to the present invention is characterized by being nonhygroscopic and excellent in stability, especially in optical stability.

The bepotastine metal salt of the formula (1) according to the present invention is a hydrate crystal in which two molecules of water are bound by crystalline water to a bepotastine metal salt formed from divalent calcium or strontium and two molecules of bepotastine, and its crystal form is CuK. Characterized by the characteristic 2theta (2θ) diffraction angle peaks shown in the XRPD spectrum irradiated with the _α light source, the relative peak intensity according to each diffraction angle, and the distance between crystal planes. In addition, whether or not the water molecule of the bepotastine metal salt according to the present invention can be confirmed by the presence or absence of a dehydration point in the differential scanning calorimetry, thermogravity analysis at the dehydration point (Karl-Fisher) Moisture can be used to determine the number of water molecules contained.

Specifically, the bepotastine calcium salt dihydrate of the crystalline form according to one embodiment of the present invention has a relative strength of at least 15% in XRPD (I / I _o ; I is the intensity of each peak; I _o is the intensity of the largest peak) Peaks with) are characteristic at diffraction angles (2 θ ± 0.2) of 12.3, 14.2, 14.7, 15.1, 16.5, 17.0, 18.7, 19.1, 20.6, 22.8, 23.8, 24.2, 25.5, 28.6, and 31.8 (See FIG. 1). In addition, the bepotastine calcium salt dihydrate has an endothermic peak corresponding to a dehydration point at about 115.9 ° C. in a differential scanning calorimetry, and a thermogravimetric decrease of about 4.5% is shown at the dehydration point (see FIG. 2). On the other hand, the water content measured by Karl-Fischer moisture measurement method is about 4.3%, this value corresponds to the amount of water contained in the bepotastine calcium salt dihydrate (theoretical value 4.23%). The bepotastine calcium salt dihydrate is represented by the following formula (3).

<Formula 3>

According to another embodiment of the present invention, the crystalline bepotastine strontium salt dihydrate has a peak having a relative intensity (I / I _o ) of at least 15% in XRPD of 4.8, 6.2, 7.3, 8.4, 9.5, 10.6, 12.2 Characteristically at diffraction angles (2 θ ± 0.2) of 12.5, 13.3, 14.1, 14.3, 14.6, 16.5, 16.9, 18.7, 19.1, 20.2, 21.3, 22.2, 23.0, 23.9, 25.0, 25.5, 27.5, 29.7, and 31.8 It has a crystal structure that appears (see FIG. 3). In addition, the bepotastine strontium salt dihydrate has an endothermic peak corresponding to a dehydration point at a differential scanning calorimetry at about 122.4 ° C., and a thermogravimetric loss of about 4.2% is shown at the dehydration point (see FIG. 4). On the other hand, the moisture content measured by Karl-Fischer moisture measurement method is about 4.3%, which corresponds to the amount of water (theoretical value 4.01%) contained in the bepotastine strontium salt dihydrate. The bepotastine strontium salt dihydrate is represented by the following formula (4).

<Formula 4>

The bepotastine metal salt hydrate of the present invention has improved optical stability compared to bepotastine benzenesulfonate salt, which has been used as an active ingredient in conventional pharmaceutical compositions for antihistamines, and therefore, for long-term storage of the pharmaceutical composition including bepotastine. Is advantageous.

In addition, the crystalline bepotastine metal salt hydrate of the general formula (1) according to the present invention is non-hygroscopic, even if the moisture content increase rate is low even if left under high humidity conditions. In contrast, alkali metal salts such as lithium, sodium, potassium, magnesium, or barium of bepotastine, transition metal salts such as zinc, aluminum, bismuth, or iron, ammonium salts, ethylamine, dimethylamine, tri, and the like, as shown in Table 1 below. Organic amine salts such as ethylamine or N-methylglucamine, and amino acid salts such as arginine, lysine or histidine, etc., are mostly hygroscopic even if they are not obtained as crystals or obtained as crystals or partial crystals. For example, chopping Porta sustaining sodium salt XRPD at 6.2, 6.8 and 31.6 2 θ diffraction angle peak and 15.0 to 25.0 large areas of moderate 2 θ is the high partial crystallization of hygroscopic showing a diffraction angle peak of the (see FIG. 5 Bepotastine potassium salt has a crystal structure characteristic of 2 θ diffraction angle peaks of 6.3, 9.4, 9.6, 15.7, 18.0, 18.8, 19.3, 20.7, 27.4 and 28.3 in XRPD (see FIG. 6). Hygroscopicity is also very large.

Crystalline bepotastine metal salt hydrate of Formula 1 having the above characteristics is water or a mixed solvent of water and at least one organic solvent selected from the group consisting of methanol, ethanol, 2-propanol, acetonitrile and acetone, a A) reacting bepotastine with calcium or strontium hydroxide, or b) bepotastine with a base selected from sodium hydroxide, potassium hydroxide, ammonia, and an organic amine to give sodium, potassium, ammonium or organic salts of bepotastine. The amine salt may be prepared by reacting it with a reactive salt of calcium or strontium and then recovering the precipitated crystals.

The amount of the solvent used in the present invention is preferably 3 to 30 ml, preferably 5 to 15 ml, based on 1 g of bepotastine. In this case, when a mixed solvent of water and an organic solvent is used, the amount of the organic solvent may not exceed 30% by volume.

In addition, the reaction is carried out at a boiling point temperature of the solvent to 0, preferably 10 to 50 ℃, the step of precipitating salt crystals after the reaction may be carried out at -20 to 50 ℃, preferably 0 ℃ to room temperature. .

In the case of the a) method, calcium hydroxide or strontium hydroxide is preferably used in 0.5 to 0.75 molar equivalents with respect to 1 molar equivalent of bepotastine, but is not limited thereto.

In the case of b), a base such as sodium hydroxide, potassium hydroxide, ammonia or an organic amine is preferably used in an amount of 1.0 to 1.4 molar equivalents based on 1 molar equivalent of bepotastine, and a reactive salt of calcium or strontium is used as the base. It is preferable to use 0.5-0.75 molar equivalent with respect to 1 molar equivalent.

The organic amine means lower organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, and the like. The reactive salts of calcium or strontium are halogenated salts of calcium or strontium, nitrates, sulfates, and the like. , Acetate, oxalate, citrate and the like.

As an example of the method according to the present invention, one of the methods for preparing bepotastine calcium salt hydrate is described in detail. After dissolving bepotastine in water, sodium hydroxide at room temperature is added to the bepotastine sodium salt. After preparing and slowly adding and stirring the calcium chloride solution, the precipitated crystals can be obtained by filtration.

Bepotastins of S-arrays used in the preparation of the bepotastine metal salt hydrates of the present invention can be prepared according to the methods described in US Pat. No. 6,307,052 or similar or new methods of preparation.

The bepotastine metal salt hydrate of Formula 1 thus obtained is a non-hygroscopic crystal having high optical purity of 99.5% or more, and has superior optical stability as compared to conventional bepotastine benzenesulfonate, and the pharmaceutical composition comprising the same has a high temperature. High optical purity can be maintained even under various conditions such as high humidity and high humidity, which is advantageous for distribution and storage, thereby maintaining high purity for a long time.

Accordingly, the present invention further provides a pharmaceutical composition for antihistamine or anti-allergic, comprising as an active ingredient crystalline bepotastine metal salt hydrate of Formula 1 and a pharmaceutically acceptable carrier.

The pharmaceutical composition for antihistamine or antiallergic of the present invention can be usefully used for the prevention or treatment of allergic rhinitis, urticaria, pruritus and nasal obstruction, dermatitis and eczema. .

The pharmaceutical composition according to the present invention can be administered in various forms such as oral, rectal, injectable and other forms, and the most preferred form is for oral administration. Specific examples include tablets, capsules, granules, and the like. Can be.

Such oral composition may be prepared by mixing the bepotastine metal salt crystalline hydrate of the present invention with a pharmaceutically acceptable carrier, diluent or excipient, and the like, and examples of suitable carriers, diluents or excipients used herein include starch, sugar Excipients such as, and mannitol; Fillers and extenders such as calcium phosphate and silicic acid derivatives; Binders such as cellulose derivatives such as carboxymethyl cellulose or hydroxypropyl cellulose, gelatin, alginate, and polyvinyl pyrrolidone; Lubricants such as talc, calcium stearate or magnesium, hydrogenated castor oil, and solid polyethylene glycols; Disintegrants such as povidone, sodium croscarmellose, and crospovidone; Surfactants such as polysorbate, cetyl alcohol, glycerol monostearate and the like. In addition, various pharmaceutical compositions comprising a specific amount of the active ingredient, together with or without additives such as carriers, diluents or excipients, can be prepared according to known conventional methods ( Remington 's Pharmaceutical Sciences , Mack Publishing). Company, Easton, PA, 19 ^th Edition, 1995).

The pharmaceutical composition for oral administration of the present invention may contain, as an active ingredient, the crystalline bepotastine metal salt hydrate of Formula 1 in an amount of 0.1 to 95% by weight, preferably 1 to 70% by weight, based on the total weight of the composition. .

Bepotastine metal salt crystalline hydrate of formula (I) as an active ingredient is at least once a day in an amount of 0.5 to 500 mg / kg body weight, preferably 1 to 100 mg / kg body weight per day for mammals including humans, It can be administered at one time or in divided doses.

The bepotastine metal salt hydrate of the crystalline form according to the method of the present invention is not only excellent in optical stability but also a non-hygroscopic salt, and can be stored for a long time without a decrease in pharmacological activity due to the decrease in optical purity. It can be usefully used as an effective ingredient of.

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Examples, which are intended to assist in understanding the present invention, but the scope of the present invention is not limited thereto.

In the following Reference Examples, Examples and Test Examples, the optical purity is a value calculated by the following Equation 1 after separating the enantiomers by chiral HPLC under the following analytical conditions.

<Analysis Condition>

Detector: ultraviolet absorption photometer (detection wavelength: 225 nm)

Column: YMC Chiral β-CDs (4.6 x 250 mm, 5 μm)

Mobile phase: Methanol / ammonium acetate buffer solution = 45/55 (v / v,%)

Flow rate: 0.8 ml / min

Optical Purity (%) = P _S / (P _S + P _R ) x 100

Where

P _S is the peak area of S-array bepotastine obtained on a chromatograph,

P _R is the peak area of the R-isomers obtained on the chromatograph.

Reference Example 1 Preparation of Bepotastine Benzenesulfonate

First, by the method described in US Pat. No. 6,307,052, 5.0 g of bepotastine was dissolved in 250 ml of ethyl acetate, and then 2.0 g of benzenesulfonic acid monohydrate was added and concentrated under reduced pressure. 250 ml of ethyl acetate was added to the residue, which was left in the refrigerator for about 1 week, and a small amount of crystals were scraped with a spatula and left for two days. Precipitated crystals were obtained by filtration, which was recrystallized with 50 ml of acetonitrile to give 4.2 g of the title compound as an off-white crystalline powder.

Subsequently, bepotastine (45.0 g, 0.12 mol) was dissolved in 450 ml of acetonitrile, benzene sulfonic acid monohydrate (16.1 g, 0.10 mol) was added, and 0.1 g of the benzene sulfonate obtained above was inoculated. The mixture was stirred at room temperature for 12 hours and the precipitate was filtered to give 33 g of the title compound as an off-white crystalline powder.

Melting Point: 161 ~ 163 ℃ (Literature Value 161.5 ℃)

Moisture: 0.4% (Karl-Fischer Moisture Measurement)

Optical purity: 99.9%

The obtained crystalline powder was identified through XRPD having a peak having a relative intensity of 15% or more (I / I _o ; I is the intensity of each peak; I _o is the intensity of the largest peak). Got it.

Example 1 Preparation of Bepotastine Calcium Salt Dihydrate

40.0 g of bepotastine was dissolved in 300 ml of water, and 4.5 g of sodium hydroxide was added thereto, followed by stirring at room temperature for 30 minutes. A solution of 7.3 g of calcium chloride dissolved in 100 ml of water was slowly added thereto, stirred for 12 hours, and then the precipitate was filtered to give 35 g (yield 83%) of the title compound as a white crystalline powder.

Moisture: 4.3% (Karl-Fischer Moisture Determination, 4.23% of Dihydrate)

Optical purity: 99.9%

Melting Point: 236 ~ 240 ℃ (Decomposition)

¹ H-NMR (DMSO-d ⁶ , ppm): δ 8.4 (d, 1H), 7.8 (t, 1H), 7.5 (d, 1H), 7.4 (m, 4H), 7.2 (t, 2H), 5.6 (s, 1H), 3.5 (m, 1H), 2.6 (m, 2H), 2.2 (t, 2H), 1.9 (m, 4H), 1.8 (m, 2H), 1.6 (m, 4H).

IR (KBr, cm ⁻¹ ): 3338, 2945, 2825, 1589, 1562, 1490, 1471, 1432, 1412.9, 1308, 1116, 1092, 1061, 1014, 994, 808, 776, 750.

The obtained crystalline powder was identified by XRPD having a peak having a relative intensity of 15% or more (I / I _o ; I is the intensity of each peak; I _o is the intensity of the largest peak). Got it.

Example 2: Preparation of Bepotastine Calcium Salt Dihydrate

Bepotastine was dissolved in a mixed solvent of 60 ml of water and 15 ml of acetone, and 0.96 g of sodium hydroxide was added thereto, followed by stirring at room temperature for 30 minutes. To this was added a solution of 1.6 g of calcium chloride dissolved in 25 ml of water slowly, and the resulting suspension was stirred at room temperature for 12 hours. The precipitate was filtered to give 7.9 g (yield 89%) of the title compound as a white crystalline powder.

Moisture: 4.6% (Karl-Fischer Moisture Measurement)

Optical purity: 99.9%

Melting Point: 235 ~ 239 ℃ (Decomposition)

Example 3: Preparation of Bepotastine Calcium Salt Dihydrate

After dissolving 5.0 g of bepotastine in a mixed solvent of 35 ml of water and 2.5 ml of methanol, 0.56 g of sodium hydroxide was added thereto, followed by stirring at room temperature for 30 minutes. To this was slowly added a solution in which 0.93 g of calcium chloride was dissolved in 12.5 ml of water, and the resulting suspension was stirred at room temperature for 12 hours. The precipitate was filtered to give 4.1 g (yield 78%) of the title compound as a white crystalline powder.

Moisture: 4.5% (Karl-Fischer Moisture Measurement)

Optical purity: 99.9%

Melting Point: 235 ~ 239 ℃ (Decomposition)

Example 4 Preparation of Bepotastine Calcium Salt Dihydrate

After dissolving 5.0 g of bepotastine in a mixed solvent of 35 ml of water and 2.5 ml of methanol, 0.58 g of calcium hydroxide was added thereto and stirred at room temperature for 12 hours. The precipitate was filtered to give 4.1 g (yield 78%) of the title compound as a white crystalline powder.

Moisture: 4.5% (Karl-Fischer Moisture Determination, 4.23% of Dihydrate)

Optical purity: 99.9%

Melting Point: 235 ~ 239 ℃ (Decomposition)

Example 5 Preparation of Bepotastine Strontium Salt Dihydrate

After dissolving 15.0 g of bepotastine in 100 ml of water, 1.7 g of sodium hydroxide was added and stirred at room temperature for 30 minutes. Here, a solution in which 6.72 g of strontium chloride (6H ₂ O) was dissolved in 50 ml of water was slowly added, and the resulting suspension was stirred at room temperature for 12 hours. The precipitate was filtered to give 15 g (90% yield) of the title compound as a white crystalline powder.

Moisture: 4.3% (Kar-Fischer Moisture Determination, Dihydrate Theoretical 4.01%)

Optical purity: 99.9%

Melting Point: 240 ~ 245 ℃

¹ H-NMR (DMSO-d ⁶ , ppm): δ 8.4 (d, 1H), 7.8 (t, 1H), 7.5 (d, 1H), 7.4 (m, 4H), 7.2 (t, 2H), 5.6 (s, 1H), 3.3 (brs, 1H), 2.6 (m, 2H), 2.1 (t, 2H), 1.9 (m, 4H), 1.8 (m, 2H), 1.5 (m, 4H)

IR (KBr, cm ⁻¹ ): 3332, 2946, 2825, 1589, 1559, 1490, 1471, 1412, 1308, 1114, 1091, 1014, 994, 807, 775, 751.

The obtained crystalline powder was identified by X-ray powder diffraction spectroscopy (XRPD) to identify peaks having a relative intensity of at least 15% (I / I _o ; I is the intensity of each peak; I _o is the intensity of the largest peak). As a result, the same result as in Table 4 was obtained.

Example 6 Preparation of Bepotastine Strontium Salt Dihydrate

After dissolving 5.0 g of bepotastine in 25 ml of water, a solution in which 1.58 g of strontium hydroxide (8H ₂ O) was dissolved in 25 ml of water was slowly added, and the resulting suspension was stirred at room temperature for 12 hours. The precipitate was filtered to give 4.8 g (yield 86%) of the title compound as a white crystalline powder.

Moisture: 4.2% (Karl-Fischer Moisture Determination, Dihydrate Theoretical 4.01%)

Optical purity: 99.9%

Melting Point: 230 ~ 240 ℃

Test Example 1 Optical Purity Change Test in Harsh Conditions

The bepotastine benzenesulfonate obtained in Reference Example 1 and the bepotastine calcium salt hydrate obtained in Example 1 were exposed to 60 ° C. and 75% relative humidity for 4 weeks in an exposed or closed state, and then optical purity was measured. Isomer changes were compared and the results are shown in Table 5 below.

As can be seen from Table 5, in the case of the known salt bepotastine benzenesulfonate salt after the test, the optical purity of bepotastine was reduced to 95.5% in the exposed state, 97.3% in a closed state, which is very pharmacological efficacy It means that weak isomers of the R- configuration increased by 4.5% and 2.7%, respectively. On the other hand, bepotastine calcium salt hydrate according to the present invention was almost no change in optical purity.

Test Example 2: Hygroscopicity Test

Bepotastine benzenesulfonate obtained in Reference Example 1 and bepotastine calcium salt hydrate obtained in Example 1 were subjected to i) 25 ° C, 75% relative humidity, ii) 40 ° C, 75% relative humidity, and iii) 40 After standing for 15 days in the condition of ℃, 90% relative humidity, the moisture content was measured on the 1st, 3rd, 7th and 15th day, respectively, and the hygroscopicity was compared. The results are shown in Table 6 below.

As can be seen from Table 6, both salts showed no significant increase in moisture content at the relative humidity of 75%. However, at 40 ° C. and 90% relative humidity, bepotastine benzenesulfonate showed an increase in water content of up to 2% or more, whereas bepotastine calcium salt hydrate according to the present invention exhibited an increase in water content of 0.7% or less. It can be seen that it is relatively non-hygroscopic.

Test Example 3: Solubility Measurement Test

The saturation solubility of bepotastine benzenesulfonate obtained in Reference Example 1 and bepotastine calcium salt hydrate obtained in Example 1 was determined in a conventional manner in pH 1.2 buffer solution, which is gastric fluid, and pH 6.8 buffer solution, which is serous. After each measurement, the results are shown in Table 7 below.

As can be seen from Table 7, the solubility of bepotastine calcium salt hydrate according to the present invention is similar to conventional bepotastine benzenesulfonate in pH 2.0 buffer, but more than two times higher in buffer at pH 6.8.

Figure 1 shows the X-ray Powder Diffraction (XRPD) spectrum of the bepotastine calcium salt hydrate according to the present invention,

Figure 2 shows a differential scanning calorimeter of bepotastine calcium salt hydrate according to the present invention (differential scanning calorimeter),

Figure 3 shows the XRPD spectrum of the bepotastine strontium salt hydrate according to the present invention,

Figure 4 shows the differential scanning calorimetry of bepotastine strontium salt hydrate according to the present invention,

Figure 5 shows the XRPD spectrum of the hygroscopic bepotastine sodium salt,

Figure 6 shows the XRPD spectrum of the hygroscopic bepotastine potassium salt.

Claims (12)

Bepotastine metal salt hydrate of the crystalline form represented by Formula 1: <Formula 1>

Wherein M is calcium or strontium. The crystalline bepotastine metal salt hydrate according to claim 1, wherein M is calcium. The crystalline bepotastine metal salt hydrate according to claim 1, wherein M is strontium. In a mixed solvent of water or at least one organic solvent selected from the group consisting of water, methanol, ethanol, 2-propanol, acetonitrile and acetone, a) reacting bepotastine with calcium or strontium hydroxide, b) bepotastine is contacted with a base selected from sodium hydroxide, potassium hydroxide, ammonia and organic amines to produce sodium, potassium, ammonium or organic amine salts of bepotastine, which are then reacted with reactive salts of calcium or strontium. A method for preparing bepotastine metal salt hydrate of the crystalline form of claim 1 comprising recovering the precipitated crystals after the reaction. The method according to claim 4, wherein in step a), calcium hydroxide or strontium hydroxide is used in an amount of 0.5 to 0.75 molar equivalents relative to 1 molar equivalent of bepotastine. The method of claim 4, wherein the base in b) is used in an amount of 1.0 to 1.4 molar equivalents relative to 1 molar equivalent of bepotastine. The method according to claim 4, wherein the reactive salt of calcium or strontium in b) is used in an amount of 0.5 to 0.75 molar equivalents relative to 1 molar equivalent of base. An antihistamine or anti-allergic pharmaceutical composition comprising bepotastine metal salt hydrate of claim 1 as an active ingredient and a pharmaceutically acceptable carrier. 9. The composition of claim 8, wherein the pharmaceutical composition is for the prevention or treatment of allergic rhinitis, urticaria, pruritus, nasal disorders, dermatitis or eczema. 9. A composition according to claim 8, wherein said pharmaceutical composition is formulated in an oral dosage form. 11. A composition according to claim 10, wherein said oral formulation comprises crystalline bepotastine metal salt hydrate in an amount of 0.1 to 95% by weight. 12. The composition of claim 11, wherein the oral dosage form comprises crystalline bepotastine metal salt hydrate in an amount of 1 to 70% by weight.

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