KR20090061972A - Crystalline form of bepotastine p-toluenesulfonate, method for preparing same and pharmaceutical composition containing same - Google Patents

Abstract

A crystalline of bepotastine p-toluensulfonate which has effects of anti-histamine or anti-allergy is provided to ensure non-hygroscopicity and optical stability. A crystalline of bepotastine ((S)-4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine-1-yl]butanoic acid)p-toluensulfonate of the chemical formula 1 is formed at the angle of diffraction (2theta±0.2) of 9.0, 10.8, 12.5, 13.3, 14.8, 15.4, 17.9, 18.3, 19.6, 21.2, 21.5, 21.9, 22.3, 22.7, 24.0, 25.4, 26.7, 27.8, and 29.6. The crystalline of bepotastine p-toluensulfonate is produced by reacting and crystallizing a bepotastine and p-toluensulfonate in organic solvent. The organic solvent is methylacetate, ethylacetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethylether, isopropyl ether or tetrahydrofuran. A pharmaceutical composition for anti-histamine or anti-allergy comprises 0.1-95 weight% of bepotastine p-toluensulfonate.

Description

Crystalline form of bepotastine ｐ-toluenesulfonate, a preparation method thereof, and a pharmaceutical composition comprising the same

The present invention provides a crystalline form of ( S ) -4- [4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidin-1-yl] butanoic acid (bepotastine) p-toluenesulfonic acid salt, preparation of the same It relates to a method and a pharmaceutical composition for antihistamine or anti-allergic including the same.

The chemical stability of pharmacologically active ingredients used in pharmaceutical compositions is very important in the pharmaceutical field where high purity quality is to be ensured and maintained during long term storage. In particular, when the pharmacologically active ingredient is composed of one of the optical isomers, optical stability should be secured and maintained. The physicochemical stability of these active ingredients should be maintained throughout the shelf life of the medicinal product, which usually depends largely on the solidity of the active ingredient itself, and generally non-hygroscopic crystalline forms are very desirable.

Bepotastine represented by the following Chemical Formula 2 is a selective antihistaminic agent that shows fast effects after oral administration, little drug interaction, and no side effects such as drowsiness and arrhythmia. Japanese Patent Laid-Open No. 2-25465 discloses bepotastine as a racemate compound for the first time, and is a pharmaceutically acceptable acid addition salt of the racemate compound, such as hydrochloric acid and hydrochloric acid such as hydrobromic acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Organic acids, such as inorganic acid, acetic acid, propionic acid, 2-oxopropanoic acid (pyruvic acid), malonic acid, succinic acid (pump acid), maleic acid, and fumaric acid, are illustrated.

In addition, Japanese Patent Application Laid-Open No. 2000-198784 discloses pharmaceutically acceptable compounds such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, mandelic acid, succinic acid, tartaric acid, hibenzic acid, pendizoic acid, lactic acid and malic acid. An example of preparing bepotastine acid addition salt using an acid is disclosed. However, the majority of existing bepotastine acid addition salts have been obtained in oily, syrup or hygroscopic crystalline forms. Bepotastine salts known as relatively stable and non-hygroscopic crystalline forms include benzenesulfonates and benzoates disclosed in Japanese Patent Application Laid-Open No. 2000-198784. Tarion (Talion®), currently marketed by Tanabe in Japan, is an antihistamine drug containing bepotastine benzenesulfonate as an active ingredient.

However, bepotastine benzenesulfonate was not shown to be sufficiently stable. For example, it has been observed that bepotastine benzenesulfonate is exposed to conventional accelerated test conditions (40 ° C. temperature, 75% relative humidity) to form isomers and degradation products of the R-configuration. Further, Japanese Patent Laid-Open No. 2001-261553 discloses that when bepotastine is formulated using an additive such as an excipient and a binder, which are commonly used in this field, the bepotastine of the S-array is corresponding to R by the moisture in the additive. -It is described as a racemic isomerization of the array, and besides securing bepotastine with high optical purity, a formulation that requires no racemization is described.

Accordingly, there has been a need for a solid body of bepotastine capable of maintaining optical purity under various conditions such as high temperature and high humidity during the storage and distribution periods as well as the formulation process.

Accordingly, the present inventors have found that the specific crystalline form of bepotastine p-toluenesulfonate salt is non-hygroscopic and excellent in physicochemical stability, thus completing the present invention.

[Patent 1] Japanese Patent Application Laid-Open No. 2-25465 (UBE IND. LTD.) 1990. 1. 26.

[Document 2] Japanese Patent Application Laid-Open No. 2000-198784 (Tanabe Seiyaku Co., Ltd.) 2000. 7. 18.

[Patent 3] Japanese Patent Application Laid-Open No. 2001-261553 (Tanabe Seiyaku Company Limited, Ube Industry Limited) 2001. 9. 26.

Accordingly, it is an object of the present invention to provide a crystal form of bepotastine p-toluenesulfonate which is excellent in pharmaceutical conditions and non-hygroscopic, a preparation method thereof, and an antihistamine or anti-allergic pharmaceutical composition comprising the same as an active ingredient.

In order to achieve the above object, the present invention provides a crystalline form of bepotastine p-toluenesulfonate of formula (I):

Where

X is 0 or 2.

Since the crystal form of bepotastine p-toluenesulfonate salt according to the present invention is not only excellent in optical stability but also non-hygroscopic, it can be stored for a long time without a decrease in pharmacological activity due to optical purity decrease, and thus an effective component of an antihistamine or anti-allergic pharmaceutical composition It can be usefully used as.

The crystalline form of bepotastine p-toluenesulfonate of formula 1 according to the present invention is divided into anhydride crystalline form and dihydrate crystalline form, and the present invention will be described in detail below.

The crystalline form of bepotastine p-toluenesulfonate of formula 1 according to the present invention can be confirmed by X-ray powder diffraction spectrometry (XRPD) spectrum analysis, the crystal form is irradiated with a CuK _α light source The characteristic 2theta (2θ) diffraction angle peaks shown in the XRPD spectrum, the relative peak intensity (p) for each diffraction angle and the distance (d) between crystal planes. In addition, the determination of the hydrate of bepotastine p-toluenesulfonate salt according to the present invention can be confirmed by the presence or absence of a dehydration point in a Diagram of Differential Scanning Calorimeter (DSC) curve, and thermogravimetric analysis at the dehydration point ( Thermogravity analysis or Karl-Fisher moisture determination can be used to determine the number of water molecules contained and ¹ H Nuclear Magnetic Resonance ( ¹ H-NMR) spectra. The salt of bepotastine and p-toluenesulfonic acid of 1 molecule can be confirmed.

The anhydride crystalline form of bepotastine p-toluenesulfonate salt according to the present invention has a peak having a relative intensity 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) of 9.0, Crystal structures characteristic at diffraction angles (2θ ± 0.2) of 10.8, 12.5, 13.3, 14.8, 15.4, 17.9, 18.3, 19.6, 21.2, 21.5, 21.9, 22.3, 22.7, 24.0, 25.4, 26.7, 27.8 and 29.6 (See FIG. 1). Bepotastine p-toluenesulfonate anhydride crystalline form is endothermic peak that corresponds to melting point without dehydration and thermogravimetry in DSC, and has melting point with onset point of about 156.2 ° C and peak point of about 159.8 ° C. The endothermic peak is shown (see FIG. 2). The moisture content measured by Karl-Fisher moisture determination is about 0.1%, supporting the anhydride crystalline form.

The dihydrate crystalline form of bepotastine p-toluenesulfonate according to the present invention has a peak having a relative intensity of at least 15% in the XRPD (I / I _o ; I is the intensity of each peak; I _o is the intensity of the largest peak). , Diffraction angles (2θ ± 0.2) of 8.5, 9.7, 14.3, 14.6, 15.9, 16.6, 17.9, 19.1, 20.2, 20.5, 21.0, 21.9, 23.4, 24.5, 24.8, 25.2, 25.7, 27.2, 28.8, and 29.4 It has a crystal structure represented by (see FIG. 3). Bepotastine p-toluenesulfonate dihydrate crystalline form simultaneously shows endothermic peaks corresponding to dehydration and melting points at about 74.5 ° C. and about 87.9 ° C. in DSC (see FIG. 4). The moisture content measured by Karl-Fisher moisture measurement is about 5.9%, which is almost the same as the theoretical moisture content (6.0%) of the dihydrate crystalline form.

The present invention also provides a method for preparing the crystalline form of the bepotastine p-toluenesulfonic acid salt.

Bepotastine p-toluenesulfonate anhydride crystalline form is at least one organic selected from the group consisting of methyl acetate, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl ether, isopropyl ether and tetrahydrofuran Bepotastine and p-toluenesulfonic acid in a solvent can be prepared by reacting at a molar ratio of 1: 0.9 to 1: 1.2 to crystallize. If necessary, the obtained bepotastine p-toluenesulfonic acid salt can be recrystallized in the above solvent. Can be.

Bepotastine p-toluenesulfonate dihydrate crystalline form is obtained by recrystallizing anhydride crystalline form in a mixed solvent of water or at least one organic solvent selected from the group consisting of methanol, ethanol, 2-propanol, acetonitrile and acetone, or in water. It can manufacture. This is only to help the understanding of the present invention, the manufacturing method of the present invention is not limited thereto.

Bepotastins of the S-arrays used in the preparation of bepotastine p-toluenesulfonate crystalline forms of the present invention can be prepared according to the method described in US Pat. No. 6,307,052 or a similar or new preparation method.

The bepotastine p-toluenesulfonate of formula (1) thus obtained is a non-hygroscopic crystalline form having a high optical purity of 99.5% or more, and has superior optical stability as compared to the conventional bepotastine benzenesulfonate, and a pharmaceutical comprising the same. Since the composition can maintain high optical purity even under various conditions such as high temperature and high humidity, it is advantageous for distribution and storage and thus can maintain high purity for a long time.

Accordingly, the present invention further provides a pharmaceutical composition for antihistamine or anti-allergic, comprising a crystalline form of bepotastine p-toluenesulfonate of formula 1 as an active ingredient 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, 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. The most preferred form is for oral administration, and specific examples thereof include tablets, capsules, granules, and syrups. Can be mentioned.

Such oral compositions may be prepared by mixing the crystalline form of bepotastine p-toluenesulfonate 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 Excipients such as starch, sugar 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 can be prepared according to conventional methods known in the art, including, without additives, such as carriers, diluents or excipients, or in combination with additives, 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 is a crystalline form of bepotastine p-toluenesulfonate of formula 1 according to the present invention as an active ingredient, based on the total weight of the composition, 0.1 to 95% by weight, preferably 1 to 70 It may be contained in an amount of% by weight.

As an active ingredient The crystalline form of bepotastine p-toluenesulfonate of formula (I) 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.

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 Comparative Examples, Examples and Test Examples, the optical purity was determined by the following chiral high-performance liquid chromatography (chiral HPLC) under the following analytical conditions. Calculated by

<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

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.

EXAMPLE

Comparative Example 1: Preparation of Bepotastine Benzenesulfonate

a) 5.0 g of bepotastine was dissolved in 250 ml of ethyl acetate according to the method described in US Pat. No. 6,307,052, 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 and left for about 1 week to obtain some crystallization. The crystals were scraped with a spatula, left to stand, and the resulting crystals were filtered and then recrystallized with 50 ml of acetonitrile to give a white color. 4.2g of the title compound of crystalline powder were obtained.

b) 45 g of bepotastine was dissolved in 450 ml of acetonitrile, followed by addition of 16 g of benzenesulfonic acid monohydrate and inoculated with the benzenesulfonic acid salt obtained in a) above. After stirring for 12 hours at room temperature, the resulting crystals were filtered to give 33 g of the title compound as an off-white crystalline powder. This was used for comparative testing.

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

Moisture: 0.4% (Karl-Fischer Moisture Measurement)

Optical purity: 99.9%

X-ray powder diffraction spectroscopy (XRPD) of the crystalline powder confirmed the 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), It was a crystalline form having a diffraction angle peak as shown in Table 1.

Example  One: Bepotastine  p- Toluenesulfonate  Preparation of Anhydride Crystalline Form

5.0 g of bepotastine was dissolved in 50 ml of acetonitrile, 2.2 g of p-toluenesulfonic acid monohydrate was added thereto, and the resulting bepotastine p-toluene sulfonate crystals were filtered and recrystallized in acetonitrile. 4.3 g of the title compound was obtained as a white crystalline powder.

Moisture: 0.1% (Karl-Fischer Moisture Measurement)

Optical purity: 99.9%

Melting Point: 154 ~ 156 ℃

Luminous intensity [α] _D ²⁵ : +5.3 (c = 0.5, methanol)

Content: 99.9%

¹ H-NMR (DMSO-d ⁶ , ppm): δ 8.5 (d, 1H), 7.8 (t, 1H), 7.6 (m, 1H), 7.5 (d, 2H), 7.4 (m, 4H), 7.3 (m, 1H), 7.1 (d, 2H), 5.7 (s, 1H, benzyl position peak of (4-chlorophenyl) -2-pyridylmethoxy), 3.7 (bs, 1H), 3.4 (m, 6H) , 3.1 (m, 4H), 2.3 (s, 3H, methyl peak of p-toluenesulfonic acid), 2.2-1.7 (m, 4H).

IR (KBr, cm ⁻¹ ): 3340, 2922, 2742, 1715, 1589, 1472, 1439, 1228, 1154, 1121, 1066, 1031, 1007, 818, 808, 774, 682, 571.

The prepared bepotastine p-toluenesulfonic acid salt was confirmed by ¹ H-NMR spectrum and was salt of ¹ molecule of bepotastine and 1 molecule of p-toluenesulfonic acid, and it was confirmed that it was anhydrous crystalline form by Karl-Fischer moisture measurement. . X-ray powder diffraction spectroscopy (XRPD) confirmed 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). The same result was obtained.

Example  2: Bepotastine  p- Toluenesulfonate  Preparation of Dihydrate Crystal Form

50 g of bepotastine was dissolved in 500 ml of acetonitrile, and 22 g of p-toluenesulfonic acid hydrate was added. Bepotastine p-toluene sulfonate crystals prepared in Example 1 were inoculated in small amounts and stirred at room temperature for 12 hours. The resulting solid was filtered to yield 45 g (69% yield) of white crystalline bepotastine p-toluenesulfonate anhydride crystalline form.

Moisture: 0.1% (Karl-Fischer Moisture Measurement)

Optical purity: 99.9%

Melting Point: 154 ~ 156 ℃

12 g of the bepotastine p-toluenesulfonate anhydride crystalline form was added to 120 ml of water, heated to 60 ° C to dissolve, cooled to room temperature, and stirred for 6 hours. The resulting solid was filtered to yield 9.0 g (yield 75%) of the title compound as white crystalline.

Moisture: 5.9% (Karl-Fischer Moisture Determination, Dihydrate Theoretical Value: 6.04%)

Optical purity: 99.9%

Melting Point: 77 ~ 78 ℃

Luminous intensity [α] _D ²⁵ : +5.0 (c = 0.5, methanol)

Content: 99.8%

¹ H-NMR (DMSO-d ⁶ , ppm): δ 8.5 (d, 1H), 7.8 (t, 1H), 7.6 (m, 1H), 7.5 (d, 2H), 7.4 (m, 4H), 7.3 (m, 1H), 7.1 (d, 2H), 5.8 (s, 1H), 3.7 (bs, 1H), 3.3 (m, 6H), 3.0 (m, 4H), 2.3 (s, 3H), 2.1 to 1.8 (m, 4 H).

IR (KBr, cm ⁻¹ ): 3513, 3025, 1732, 1596, 1488, 1438, 1226, 1168, 1123, 1080, 1035, 1011, 820, 801, 770, 683, 569.

The prepared bepotastine p-toluenesulfonic acid salt was confirmed by ¹ H-NMR spectrum and was salt of ¹ molecule of bepotastine and 1 molecule of p-toluenesulfonic acid, and was determined to be a dihydrate crystalline form by Karl-Fischer moisture measurement. It became. X-ray powder diffraction spectroscopy (XRPD) confirmed peaks with 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). The same result was obtained.

The following is an example of the preparation of the formulation of the composition using the crystalline bepotastine p-toluenesulfonate salt according to the present invention, but the composition according to the present invention is not limited thereto.

Preparation Example 1 Preparation of Bepotastine Tablets 10mg

After mixing the above components was prepared by tableting by dry or wet method according to the conventional tablet production method.

Preparation Example 2 Preparation of Bepotastine Tablets 10mg

After mixing the above components was prepared by tableting by dry or wet method according to the conventional tablet production method.

Preparation Example 3 Preparation of Bepotastine Tablets 10mg

After mixing the above components was prepared by tableting by dry or wet method according to the conventional tablet production method.

Preparation Example 4 Preparation of Bepotastine Capsule 10mg

After mixing the above ingredients was filled in gelatin capsules according to the conventional capsule preparation method to prepare a capsule.

Preparation Example 5 Preparation of Bepotastine Oral Suspension Powder 100mg / g

The above ingredients were mixed and prepared according to a conventional method for preparing oral powder, and then filled into containers such as bottles.

Test Example 1 Optical Purity Change Test in Harsh Conditions

The conventional bepotastine benzenesulfonate crystalline form and the bepotastine p-toluenesulfonate anhydride and dihydrate crystalline form according to the present invention prepared in Examples 1 and 2, respectively, were exposed or closed at 60 ° C. and 75% relative humidity. After 4 weeks, the optical purity was measured and the degree of change to the isomer was compared (Table 9).

As shown in Table 9, in the case of the conventional bepotastine benzenesulfonate crystalline form, the optical purity of bepotastine was lowered to 95.5% in the exposed state and 97.3% in the closed state after the test. This means that the isomers of the R-array with very weak pharmacological efficacy increased by 4.5% and 2.7%, respectively. In comparison, the bepotastine p-toluenesulfonate dihydrate crystalline form and the bepotastine p-toluenesulfonate anhydride crystalline form according to the present invention can be seen that less or little change in optical purity.

Test Example  2: hygroscopic test

After the conventional bepotastine benzenesulfonate crystalline form and the bepotastine p-toluenesulfonate anhydride and dihydrate crystalline form according to the present invention were allowed to stand for 28 days under conditions of 40 ° C and 75% relative humidity, Moisture content was measured at 15, 21 and 28 days, respectively, to compare hygroscopicity (Table 10).

From the results of Table 10, it can be seen that the water content increase of the anhydride and dihydrate crystalline form of the bepotastine p-toluenesulfonate of the present invention is lower than the conventional bepotastine benzenesulfonate.

Figure 1 shows the X-ray Powder Diffraction (XRPD) spectrum of the bepotastine p-toluenesulfonate anhydride crystalline form according to the present invention,

Figure 2 shows a differential scanning calorimeter (DSC) curve of the bepotastine p-toluenesulfonate anhydride crystalline form according to the present invention,

Figure 3 shows the XRPD spectrum of the bepotastine p-toluenesulfonate dihydrate crystalline form according to the present invention,

Figure 4 shows the DSC curve of the bepotastine p-toluenesulfonate dihydrate crystalline form according to the present invention.

Claims (13)

Beoformin (( S ) -4- [4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidin-1-yl] butanoic acid) of formula (1): p-toluenesulfonate Formula 1

Where X is 0 or 2. The method of claim 1, X is an anhydride crystalline form as 0, The crystalline form of bepotastine p-toluenesulfonate. The method of claim 2, Peaks with relative intensities of 15% or more in the X-ray powder diffraction spectra were 9.0, 10.8, 12.5, 13.3, 14.8, 15.4, 17.9, 18.3, 19.6, 21.2, 21.5, 21.9, 22.3, 22.7, 24.0, 25.4, 26.7 , Crystalline form of bepotastine p-toluenesulfonate, characterized by appearing at diffraction angles (2θ ± 0.2) of 27.8 and 29.6. The method of claim 1, Crystalline form of bepotastine p-toluenesulfonate, wherein X is a dihydrate crystalline form as 2. The method of claim 4, wherein Peaks with a relative intensity of at least 15% in the X-ray powder diffraction spectra are 4.8, 8.5, 9.7, 14.3, 14.6, 15.9, 16.6, 17.9, 19.1, 20.2, 20.5, 21.0, 21.9, 23.4, 24.5, 24.8, 25.2 Crystalline form of bepotastine p-toluenesulfonate, characterized by appearing at diffraction angles (2θ ± 0.2) of 25.7, 27.2, 28.8 and 29.4. Bepotastine and p-toluenesulfonic acid were selected from one or more organic solvents selected from the group consisting of methyl acetate, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl ether, isopropyl ether and tetrahydrofuran. A method for producing a crystalline form of bepotastine p-toluenesulfonate according to claim 2 comprising reacting and crystallizing. The method of claim 6, A method for producing a crystalline form of bepotastine p-toluenesulfonic acid salt, wherein p-toluenesulfonic acid is used in an amount of 0.9 to 1.2 molar equivalents based on 1 molar equivalent of bepotastine. A fourth solvent comprising recrystallization of bepotastine p-toluenesulfonate anhydride in a mixed solvent of water or at least one organic solvent selected from the group consisting of methanol, ethanol, 2-propanol, acetonitrile and acetone, or water Method for producing a crystalline form of bepotastine p-toluenesulfonate salt of the claim. An antihistamine or anti-allergic pharmaceutical composition comprising the crystalline form of bepotastine p-toluenesulfonate of claim 1 as an active ingredient. The method of claim 9, Allergic rhinitis, urticaria, pruritus, nasal disorders, dermatitis and eczema, characterized in that for the prevention or treatment of diseases selected from the group, antihistamine or anti-allergic pharmaceutical composition. The method of claim 9, An oral administration agent, characterized in that the antihistamine or anti-allergic pharmaceutical composition. The method of claim 11, A pharmaceutical composition for antihistamine or anti-allergy, comprising crystalline form of bepotastine p-toluenesulfonate in an amount of 0.1 to 95% by weight, based on the total weight of the composition. The method of claim 12, A pharmaceutical composition for antihistamine or anti-allergy, comprising crystalline form of bepotastine p-toluenesulfonate in an amount of 1 to 70% by weight, based on the total weight of the composition.

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