KR20110115343A - Crystalline bepotastine nicotinic acid and the preparation thereof - Google Patents

Abstract

The present invention relates to a bepotastine nicotinate crystalline form having excellent antihistamine activity and anti-allergic activity, a preparation method thereof, and a pharmaceutical composition comprising the same, wherein the bepotastine nicotinate crystalline form according to the present invention is a non-hygroscopic and highly stable compound. to be.

Description

Crystalline Forms of Bepotastine Nicotinate and a Method for Manufacturing the Same {CRYSTALLINE BEPOTASTINE NICOTINIC ACID AND THE PREPARATION THEREOF}

The present invention relates to (S) -4- [4-[(4-chlorophenyl) (2-pyridylmethoxy)] piperidin-1 yl] butanoic acid (bepotastine) nicotinate [Formula 1] It relates to a manufacturing method and a pharmaceutical composition consisting of the active ingredient.

[Formula 1]

Piperidine compounds or salts thereof represented by the following [Formula 2] show selective effects of antagonist H1 receptor antagonism and interleukin-5 production and show high effects on nasal congestion and are not metabolized in the liver. There is no concern about action, and it has excellent therapeutic effect on pruritus (eczema, dermatitis, skin pruritus, yangjin) accompanied by perennial allergic rhinitis and chronic rash and skin disease. It is described. In addition, the compound represented by the following [Formula 2] showed the fastest effect among the second generation antihistamines, minimized side effects such as drowsiness and arrhythmia, and said that the possibility of drug interaction is low.

[Formula 2]

In formula, A represents a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, a lower alkylamino group, a phenyl group, or an alkyl substituted phenyl group.

On the other hand, since the optical isomers are generally known to have different pharmacological activity or stability, and also have different protein binding rates [Pharmacia, 25 (4), pp. 311 to 336, 1989], compounds having optical isomers are more preferable. In order to be prepared as the optical separation of high purity, the optical stability of the obtained optical isomer should be secured and maintained. In addition, these active ingredients must be non-hygroscopic, crystalline forms, and have good physicochemical stability.

Furthermore, Japanese Laid-Open Patent Publication No. 10-237070 discloses that the pharmacological activity of the piperidine derivative of (S) -ester of [Formula 3] is much superior to its optical isomer.

(3)

However, Japanese Patent Laid-Open No. 2001-261553 discloses that bepotastine of S-array is an unstable compound because of its high hygroscopicity. In other words, when formulated using excipients or additives that are commonly used in this field, bepotastine is highly optically purified because bepotastine of S-array is racemized to an isomer of R-array by moisture absorbed by the additive. It is difficult to secure as. Therefore, this patent document emphasizes that development of a formulation in which bepotastine is not racemized is required.

In order to solve this problem, Japanese Patent Laid-Open Nos. Hei 10-237070 and Japanese Patent Laid-Open No. 2000-198784 disclose hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, DL-mandelic acid, succinic acid, L in bepotastine. Bepotastine acid addition salts were prepared using acids such as-(+)-lactic acid, hibenzic acid, pendizoic acid, malic acid and acetamidobenzoic acid. However, in the above patent documents, most of the bepotastine acid adducts are hygroscopic crystalline forms (hydrochloric acid, hydrobromic acid, sulfuric acid), oils (methanesulfonic acid), syrups (fumaric acid, maleic acid, DL-mandelic acid, succinic acid, hibenzic acid, Fendizoic acid, lactic acid, malic acid and acetoamidobenzoic acid) and foamed (L-(+)-lactic acid) forms. Only benzene sulfonate and benzoate have relatively low hygroscopicity and relatively good physicochemical stability. Obtained. Accordingly, Japan's Tanabe Pharmaceuticals currently uses `` tarion tablets '' with bepotastine benzenesulfonate to treat antihistamines of itching (eczema, dermatitis, itching, rash) with perennial allergic rhinitis, chronic urticaria, and skin diseases. I sell zero.

However, according to Korean Patent Publication No. 10-2009-0061972, bepotastine benzenesulfonate also generates isomers and decomposition products of the R-array when exposed to normal accelerated test conditions (temperature: 40 ° C, relative humidity: 75%). Was observed and was not stable enough. In addition, in the storage stability experiment conducted by the present inventors, it was observed that bepotastine benzenesulfonate was converted to the (R) -isomer.

Therefore, high optical purity can be maintained even in various environments, and physicochemically stable addition of bepotastine is required.

Accordingly, the present inventors conducted various salt addition studies of bepotastine to solve this problem, but most acid addition salts are obtained in the form of syrup without forming crystals, but bepotastine nicotinate is crystalline, non-hygroscopic and high optical. Confirming that the purity is maintained, the present invention has been completed.

It is an object of the present invention to provide a crystal form of bepotastine nicotinate and a method for preparing the same, which maintain high optical purity, have excellent physicochemical stability, and are non-hygroscopic.

The present invention provides the following formula (S) -4- [4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidin-1-yl] butanoic acid (bepotastine) nicotinate ] To give the crystalline form.

[Formula 1]

In the present invention, bepotastine nicotinate may be an anhydride crystalline form or a hydrate crystalline form, with anhydride crystalline form being even more preferred.

In addition, the present invention, in the X-ray powder diffraction spectrogram, when the light source wavelength is 1.5406 피크, the peaks represented by the diffraction angle (2θ ± 0.2 °) are 10.0, 12.4, 12.9, 13.2, 14.0, 15.4, 16.1, 18.1, 19.3 , 19.9, 20.7, 22.2, 24.1, 25.1, 25.6, 26.8, 28.2, 29.5 and 30.4 provide the crystalline form of bepotastine nicotinate (see FIG. 1).

In addition, the bepotastine nicotinate crystal form 1 of the present invention has a purity of about 99.8%, and an endothermic peak appears at a point of 124.0 ° C. when the DSC (differential scanning thermal analysis) value has a temperature rising rate of 10 ° C./min. Referring to Figure 2), Karl-Fisher (Karl-Fisher) water through the water molecules to check the results, it was confirmed that the water content of bepotastine nicotinate crystalline Form 1 is anhydrous 0.12%.

The present invention also relates to bepotastine in 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. Provided is a method for preparing a crystalline form of bepotastine nicotinate comprising reacting and crystallizing salicylic acid.

In the preparation method of the present invention, bepotastine may be used commercially available or manufactured by a known method (US Pat. No. 6,307,052), and nicotinic acid may also be commercially available.

In the preparation method of the present invention, the reaction molar ratio of bepotastine and nicotinic acid may be 1: 0.5 to 3.0, and it is preferable that it is 1: 1.0 to 2.0 in terms of saving of reagent, improved product yield, and economic efficiency of purification method. Even more preferred is from 1.1 to 2.0, even more preferably from 1: 1.0 to 1.2.

In the production method of the present invention, the reaction solvent can be used as long as it is a solvent that does not participate in the bepotastine nicotinate formation reaction. For example, esters (methyl acetate, ethyl acetate, etc.), nitriles (acetonitrile, pro) Pionitrile, etc.), alcohols (methanol, ethanol, 1-propanol, 2-propanol, butanol, etc.), ketones (acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), ethers (ethyl ether, isopropyl ether and tetra) Hydrofuran and the like). Preferably, acetone, ethyl acetate, acetonitrile, ethanol and 2-propanol are used. The solvent used in the present invention is preferably used alone, but it is also possible to use two or more kinds of arbitrary solvents. The amount of the solvent used for the bepotastine nicotinate production reaction is 0.5 to 30 times by weight (w / v), preferably 5 to 20 times by weight (w / v), based on 1 weight of bepotastine.

In the production method of the present invention, the temperature of the bepotastine nicotinate production reaction is 0 to 70 ° C, preferably 10 to 40 ° C, and the temperature at which the salt is precipitated is -30 to 40 ° C, preferably 0 to 25 ° C.

In the manufacturing method of the present invention, the method of adding nicotinic acid to bepotastine is not particularly limited, but after adding bepotastine in a solvent and stirring to dissolve it, the nicotinic acid solid may be added at a time or the solid may be divided into nicotinic acid. It may be added by dissolving in a reaction solvent.

In the production method of the present invention, the resulting crystals can be obtained by filtration, washing and drying in accordance with conventional methods in the art. If necessary, the obtained bepotastine nicotinate can be recrystallized in the above reaction solvent, and acetonitrile is preferred as the recrystallization solvent.

In another aspect, the present invention provides a pharmaceutical composition for antihistamine or anti-allergic including bepotastin nicotinate crystal form as an active ingredient.

In the present invention, the antihistamine or anti-allergic pharmaceutical composition means a pharmaceutical composition for preventing or treating allergic rhinitis, urticaria, pruritus and nasal obsrtuction, dermatitis and eczema. do.

The pharmaceutical composition of the present invention may contain one or more active ingredients exhibiting the same or similar functions in addition to the bepotastine nicotinate of the present invention.

The pharmaceutical composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above components for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, it may be suitably formulated according to the administration purpose or the additive ingredient by a suitable method in the art or using a known method (e.g., Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, 19th Ed., 1995). .

The pharmaceutical composition for oral administration of the present invention may contain, as an active ingredient, bepotastine nicotinate of the present invention at 0.1 to 95% by weight, preferably 1 to 70% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or topically) according to a desired method, and the dosage may be weight, age, sex, or health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The daily dose of bepotastine of the present invention is about 5 to 30 mg / 24hrs, preferably 10 to 20mg / 24hrs, and can be administered once to several times a day.

As described above, the crystalline form of bepotastine nicotinate according to the present invention is not only excellent in physicochemical stability but also non-hygroscopic, so that it is useful as an active ingredient of an antihistamine or an antiallergic agent without a decrease in pharmacological activity due to optical purity decrease. Can be used.

In addition, the method for producing bepotastine nicotinate crystal form of the present invention is relatively economical and commercially available because it provides a relatively high yield of the product.

Figure 1 shows the spectrum according to the X-ray powder diffraction analysis of the bepotastine nicotinate crystal form prepared in the present invention.
Figure 2 shows the curve of the differential scanning calorimetry (DSC) of the bepotastine nicotinate crystal form prepared in the present invention.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

Unless otherwise specified, Sigma-Aldrich Co., Ltd. was used.

In addition, the measuring machine, the measuring method and the measurement conditions used to confirm the physical properties of the compound prepared below are as follows.

1) Differential Scanning Calorimetry (DSC)

Model Name (Manufacturer): DSC Q100 V8.2 Build 268

-Heating rate: 10 ℃ / min.

Sample usage: 5.0mg

2) X-ray powder diffraction spectrophotometer

-Model Name: PANalytical X'Pert PRO

-X-ray source: Tension-40kV, Current-30mA

Source: Fixed Divergence Slit

-Detector: X'clerator

-Wavelength of light source of X-ray: 1.5406 1.5

-Measurement of sample: Put 0.5g of sample on 'Zerobackground' and measure by 'Gonio' Scan

3) Karl-Fischer Moisture Measurement

-Model: Mettler Toledo DL38

-Accurately weigh 0.3 g of the sample.

4) ¹ H-NMR

-Model name: ¹ H NMR (500 MHz) is Varian Inova 500MHz FT-NMR

Analyze 10 mg of sample in DMSO-d ⁶ .

5) Optical purity measurement method by HPLC

  Model Name: Jasco UV 2075 plus

 - column ; ULTRON ES-OVM (4.6 × 150mm)

 -Detector: UV Detector

 Mobile phase: 20 mM KH2PO4: EtOH (9: 1 (v / v))

 Flow rate: 0.5 mL / min.

 Detection wavelength: 223nm

Injection volume: 10

Bepotastine was prepared by reference to the method described in US Pat. No. 6,307,052 as in Scheme 1.

Scheme 1

[ Manufacturing example  1] (S) -2-[(4- Chlorophenyl ) (Piperidine-4- Iloxy ) methyl ] Pyridine [ III Manufacture of

89.1 g of 2-[(4-chlorophenyl) (piperidin-4-yloxy) methyl] pyridine [I] was dissolved in 370 ml of ethyl acetate and 36.6 g of N-acetyl-L-phenylalanine [II] was added. The mixed solution was heated to 50 ~ 60 ℃ to make a clear solution and then slowly cooled to 20 ~ 25 ℃. The resulting crystals were filtered and washed with 50 ml of ethyl acetate. 150 ml of 2N hydrochloric acid was added while stirring the obtained crystal and 300 ml of purified water, followed by stirring for 1 hour. The reaction mixture was filtered to remove N-acetyl-L-phenylalanine, and 90 ml of 28% NH ₄ OH was added to the aqueous layer, followed by stirring for 30 minutes. 360 ml of ethyl acetate was added thereto, stirred for 1 hour, the layers were separated, and the organic layer was recovered and concentrated under reduced pressure to give 40.5 g (yield 45.4%) of the title compound as a brown liquid.

[ Manufacturing example  2] (S) -ethyl 4- (4-((4- Chlorophenyl ) (Pyridin-2-yl) Methoxy Piperidin-1-yl) Butanoate [ IV Manufacture of

40.5 g of (S) -2-[(4-chlorophenyl) (piperidin-4-yloxy) methyl] pyridine [III] prepared in Production Example 1 was dissolved in 600 ml of acetone and ethyl 4-bromobutyrate After adding 31.5 g of ester and 25.5 g of potassium carbonate, the mixture was heated to 65-66 ° C. and refluxed for 7 hours. After the reaction was completed, the reaction mixture was slowly cooled to 20-25 ° C., filtered, and concentrated under reduced pressure to obtain 45.6 g (yield 81.7%) of the title compound as light brown.

[ Manufacturing example  3] Bepotastine [V] manufacturing

45.6 g of (S) -ethyl 4- (4-((4-chlorophenyl) (pyridin-2-yl) methoxy) piperidin-1-yl) butanoate [IV] prepared in Preparation Example 2 18.0 g of sodium hydroxide dissolved in 450 ml of ethanol and dissolved in 300 ml of purified water was added, followed by stirring at 20-25 ° C. for 12 hours. After neutralizing by adding 23.3 ml of concentrated hydrochloric acid, 700 ml of ethyl acetate was added thereto, followed by stirring for 30 minutes. After layer separation, the organic layer was concentrated under reduced pressure to obtain 38.1 g (yield 90.0%) of light yellow bepotastine.

[ Example  One] Bepotastine Nicotinate  Produce

10.0 g (25.7 mmol) of bepotastine prepared in Preparation Example 3 was dissolved in 80 ml of ethyl acetate at room temperature, 2.85 g (23.1 mmol) of nicotine was temporarily added in a solid state and stirred at 20-25 ° C. for 24 hours. . The resulting bepotastine nicotinate crystals were filtered off and washed with 30 ml of ethyl acetate. 50 ml of acetonitrile was added to the obtained crystals, and the mixture was refluxed for 30 minutes, and then cooled to 10 ° C. The resulting crystals were filtered, washed with 30 ml of acetonitrile, and dried under reduced pressure (20 mmHg) at 35 ° C. for 8 hours to obtain 10.3 g (20.1 mmol, yield 87.0%) of the title compound as a white crystalline powder. Is as follows.

DSC melting point: 124.0 ℃

Moisture: 0.12% (Karl-Fischer Moisture Measurement)

Optical purity: 99.8%

Radiance: [α] _D ²⁵ = 5.0 (c = 5, methanol)

¹ H-NMR (DMSO-d ⁶ , ppm), δ 9.0 (s, 1H), 8.7 (s, 1H), 8.5 (d, 1H), 8.2 (d, 1H), 7.8 (t, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4 (m, 4H), 7.2 (t, 1H), 5.7 (s, 1H), 3.5 (bs, 1H), 2.8 (bs, 2H), 2.6 ( bs, 2H), 2.4 (bs, 2H), 2.2 (t, 2H), 1.9 (m, 2H), 1.7 (m, 4H)

X-Ray Powder Diffraction Spectroscopy (XRPD)

TABLE 1

Claims (7)

(S) -4- [4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidin-1-yl] butanoic acid (bepotastine) nicotinate crystalline form of the formula (1):
[Formula 1]

The bepotastine nicotinate crystal form according to claim 1, wherein the crystalline form is an anhydride crystalline form. 3. The X-ray powder diffractogram shows that when the light source wavelength is 1.5406 Hz, the peaks represented by the diffraction angle (2θ ± 0.2 °) are 10.0, 12.4, 12.9, 13.2, 14.0, 15.4, 16.1, 18.1, Bepotastine nicotinate crystalline form, characterized by the appearance of 19.3, 19.9, 20.7, 22.2, 24.1, 25.1, 25.6, 26.8, 28.2, 29.5 and 30.4. The bepotastine nicotinate crystal form according to claim 2, wherein the DSC value is 124.0 ° C when the temperature increase rate is 10 ° C / min. It is determined by reacting bepotastine and nicotinic acid in at least one organic solvent selected from the group consisting of methyl acetate, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl ether, isopropyl ether and tetrahydrofuran. Method for producing bepotastine nicotinate crystal form comprising the step of. The method according to claim 5, wherein the molar ratio of bepotastine and nicotinic acid is 1: 1.1 to 2. A pharmaceutical composition for antihistamine or anti-allergy, comprising the bepotastine nicotinate crystalline form of claim 1 as an active ingredient.

Images