KR20160126697A - Novel crystalline varenicline oxalate hydrate, preparation method thereof, and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention relates to a novel crystalline varenicline oxalate hydrate, a manufacturing method thereof, and a pharmaceutical composition for assisting an antismoking agent, comprising the same as an active ingredient. The crystalline varenicline oxalate hydrate of the present invention exhibits excellent thermal stability and produce the same in large quantities with an uniform quality and the high purity, thereby being efficiently used as an antismoking agent.

Description

TECHNICAL FIELD The present invention relates to a novel crystalline form of valenylic oxalic acid salt hydrate, a process for producing the same, and a pharmaceutical composition containing the same. BACKGROUND OF THE INVENTION 1. Field of the Invention [0001]

The present invention relates to a novel crystalline form of barrenicin oxalate salt hydrate, a process for producing the same, and a pharmaceutical composition for a smoking cessation aid containing the same as an active ingredient.

Varenicline is a compound in which the compound is 5,8,14-triazatetracyclo [10.3.1.0 ^2,11 .0 ^4,9 ] -hexadeca-2 (11), 3,5,7,9-penta It is a drug that binds to the neurotrophic acetylcholine receptor to regulate the function of the choline receptor. Barrenicin is an effective treatment for inflammatory bowel disease such as ulcerative colitis, gangrene scarring and Crohn's disease, irritable bowel syndrome, stiff dystonia, chronic pain, acute pain, non-tropical sprue, obesity, vasoconstriction, anxiety, panic disorder, , Bipolar disorder, autism, sleeping paralysis syndrome, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, red bulimia, anorexia, obesity, cardiac arrhythmia, gastric hyperplasia, ulcer, (TBI), obsessive compulsive disorder (OCD), psychosis, depression, psychoses, depression, paralysis, dependence on chemicals (e.g., nicotine), alcohol, benzodiazepines, barbiturates, opioids or cocaine and addiction, headache, migraine, Epilepsy, amyotrophic lateral sclerosis, Huntington's disease, Huntington's chorea, dyskinetic dyskinesia, hyperactivity disorder, schizophrenia, multiple sclerosis, age-related cognitive decline, Dementia, it can be used in Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's syndrome treatment.

5,8,14-triazatetracyclo [10.3.1.0 ^2,11 .0 ^4,9 ] -hexadeca-2 (11), 3,5,7,9-pentaene and its hydrochloride, Compounds that bind to the receptor site are disclosed in International Application No. WO 99/35131.

On the other hand, physicochemical standards such as (1) excellent solubility, (2) excellent stability, (3) non-hygroscopicity, and (4) processability in tablet formulations must be met . Highly stable drugs have the advantage that they do not deteriorate even after storage for a long time. Drugs with high solubility can be expected to have a high effect because they exhibit a high blood concentration even at low doses because fast absorption occurs in stomach and intestines when taken orally .

In addition, the discovery of novel polymorphs and solvates of pharmaceutical products can not only provide the desired processing characteristics, such as ease of handling, ease of processing, storage stability and ease of purification, but also facilitates the conversion to other polymorphs Thereby providing a substance having a desired crystal form. Therefore, it is necessary to study the new crystal form of barrenicin oxalate salt hydrate.

[Patent Document 1] International Application No. WO99 / 35131

Accordingly, an object of the present invention is to provide a novel crystalline varenicline oxalate hydrate of high purity which exhibits excellent thermal stability, is mass-producible and has homogeneous quality.

It is another object of the present invention to provide a process for preparing the barrenicin oxalate salt hydrate.

It is still another object of the present invention to provide a pharmaceutical composition for smoking cessation aids containing the above-mentioned barrenicin oxalate salt hydrate as an active ingredient.

In order to accomplish the above object, the present invention provides a crystalline form of barrenicin oxalic acid salt hydrate represented by the following Formula 1:

[Chemical Formula 1]

In this formula,

n is from 0.5 to 3.

To achieve these and other objects,

(1) reacting barrenicin of the following formula (2) with oxalic acid of the following formula (3) in a solvent, and

(2) obtaining crystals from the solution obtained in the above step (1)

Which comprises reacting a crystalline form of a crystalline form of a crystalline form of a crystalline form of a crystalline form of a crystalline form of the formula

(2)

(3)

[Chemical Formula 1]

In this formula,

n is from 0.5 to 3.

According to another aspect of the present invention, there is provided a pharmaceutical composition for smoking cessation aids, comprising the crystalline type of barrenicin oxalate salt hydrate as an active ingredient.

The crystalline form of Varianicin oxalate salt hydrate according to the present invention can be effectively used as a pharmaceutical composition for smoking cessation aids since it has excellent thermal stability, good bioavailability, and can be mass-produced with homogeneous quality.

Figs. 1 and 2 show the X-ray diffraction diagram (XRD) and the differential scanning calorimetry curve (DSC) of the crystalline barrenicin oxalate monohydrate according to embodiment 1, respectively.

The present invention provides a crystalline form of valencycline oxalic acid salt hydrate represented by the following formula (1)

In this formula,

n is from 0.5 to 3.

The crystalline barrenicin oxalate salt hydrate was characterized by characteristic 2theta, 2? Diffraction peak peaks observed in X-ray powder diffraction (XRPD) irradiated with Cu-K? It is built.

Crystalline barrenicin oxalate salt hydrate of the present invention was confirmed by X-ray powder diffraction analysis (XRPD) and differential scanning calorimetry (DSC), and the results are shown in FIGS. 1 and 2, respectively.

Specifically, the crystalline form of barrenicin oxalate salt hydrate according to one embodiment of the present invention is characterized by having an XRPD of 7.30, 9.42, 10.79, 11.48, 12.05, 13.37, 13.93, 14.57, 16.36, 16.78, 18.11, 19.46, 20.63, 21.63, 21.83 , 22.69, 22.67, 22.78, 23.91, 24.31, 24.58, 25.20, 25.92, 26.53, 27.08, 28.01, 28.65, 29.29, 29.98, 31.24, 31.91, 32.78, 34.55, 35.25, 35.78, 36.10, 39.24, 39.29, 39.76, , 47.69 and 55.52 (2 &thetas; +/- 0.2) (see Fig. 1).

Further, it is characterized by showing three endothermic peaks at about 62 ° C, 97 ° C and 220 ° C by differential scanning calorimetry (DSC) (see FIG. 2).

The crystalline type Varenicline oxalate salt hydrate according to the present invention has a moisture content of 1 to 12% by weight as measured by a Karl-Fischer titrator (hereinafter referred to as KF). Preferably, the crystalline barrenicin oxalate salt hydrate has a moisture content of about 5.2% by weight and corresponds to a monohydrate.

The crystalline form of the crystalline form of the varicelin oxalate salt according to the present invention may have a melting point ranging from 203 to 208 캜.

The crystalline form of barrenicin oxalate salt hydrate according to the present invention can maintain the monohydrate state by keeping the moisture content at about 5.2% even when it is left to stand for 14 days at 40 캜 and 75% relative humidity.

On the other hand, oxalic acid (C ₂ H ₂ O ₄ ) is in the form of a calcium salt and exists in a small amount in the urine of a person or an animal and is very low in toxicity. US FDA-approved medicines manufactured and distributed using oxalic acid as an additional salt include escitalopram (escitalopram oxalate) and Movant (Naloxegol Oxalate) ).

The crystalline form of barrenicin oxalate salt hydrate according to the present invention can be prepared by reacting barrenicin and oxalic acid in a solvent, as shown in Scheme 1 below:

[Reaction Scheme 1]

In this formula,

n is from 0.5 to 3.

Specifically, the crystalline form of the crystalline form of the valencycline oxalic acid salt represented by formula (1) comprises the steps of (1) reacting valencycline represented by the following formula (2) and oxalic acid represented by the following formula (3) in a solvent, and (2) And obtaining crystals from the obtained solution: < RTI ID = 0.0 >

[Chemical Formula 1]

In this formula,

n is from 0.5 to 3.

In step (1) of the production process of the present invention, the barrenicin of formula (2) and oxalic acid of formula (3) can be reacted in a solvent. The reaction may be carried out at 0 to 65 ° C, preferably at 20 to 55 ° C, for example at 20 to 40 ° C. The reaction may be carried out for 1 to 15 hours, preferably for 1 to 3 hours.

The oxalic acid may be used in an amount of 1 to 2 equivalents, preferably 1 to 1.5 equivalents based on 1 equivalent of valencycline.

The solvent is selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, t -butyl alcohol, sec -butyl alcohol, n -butyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, A solvent selected from the group consisting of acetonitrile, methylene chloride, chloroform, dimethylsulfoxide, dimethylformamide, dimethylacetamide and combinations thereof, or a mixed solvent of the solvent and water may be used.

The solvent is preferably a solvent selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, and combinations thereof, or a mixed solvent of the solvent and water .

The solvent may be used in an amount of 1 to 100 times by volume, preferably 3 to 30 times by volume based on the volume of barrenicin.

In step (2) of the production method of the present invention, crystallization can be induced from the solution obtained in step (1) by a conventional method. For example, crystals may be precipitated after cooling the solution obtained in the step (1), or crystallized by adding an anti-solvent to the solution obtained in the step (1).

Specifically, the solution obtained in the above step (1) is cooled to precipitate a solid substance naturally, and the solid precipitated therefrom is separated to obtain barrenicin oxalate salt hydrate.

Alternatively, the solution obtained in the above step (1) may be cooled, a semi-solvent may be added thereto to precipitate a solid, and the precipitated solid may be separated therefrom to prepare barrenicin oxalate salt hydrate.

The cooling process may be performed at 0 to 25 < 0 > C for 5 to 30 minutes.

Wherein the semi-solvent is selected from the group consisting of ethyl acetate, acetonitrile, methylene chloride, chloroform, diethyl ether, methyl t-butyl ether, isopropyl acetate, methyl isobutyl ketone, n-hexane, n-heptane, The selected semi-solvent can be used.

The semi-solvent may be used in an amount of 5 to 30 times by volume, preferably 8 to 20 times by volume based on the volume of barrenicin.

The crystals produced through the above process can be recovered and dried in accordance with a conventional method to obtain the crystalline form of the crystalline form of the barrenicin oxalic acid salt of the present invention.

The thus obtained crystalline form of barrenicin oxalate salt hydrate may be in the form of a hydrate of 0.5 to 3, preferably in the form of a hydrate of 0.5 to 2.

The barrenicin oxalate salt hydrate of the present invention is useful for binding to neuronal nicotinic acetylcholine-specific receptor sites to regulate the function of the choline receptor. Thus, barrenicin oxalate salt hydrates can be usefully used to treat, prevent or ameliorate dependence and addiction to nicotine or tobacco products.

Accordingly, the present invention provides a pharmaceutical composition for a smoking cessation aid comprising the crystalline barrenicin oxalate salt hydrate as an active ingredient.

The pharmaceutical composition of the present invention may further comprise, as an active ingredient, an effective amount of valencycline oxalate hydrate crystals and appropriate carriers, excipients and diluents conventionally used in the production of pharmaceutical compositions. The barrenicin oxalate salt hydrate crystals of the present invention may be formulated together with a pharmaceutically acceptable carrier, diluent or excipient regardless of the dosage form.

Such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In addition, it may further comprise pharmaceutically acceptable additives such as fillers and extenders such as calcium phosphate and silicic acid derivatives; But are not limited to, starch, sugar, mannitol, trehalose, dextrin, amylopectin, sucrose, gluten, arabic gum, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose Binders such as cellulose derivatives, gelatin, alginate, and polyvinylpyrrolidone; Lubricants such as talc, magnesium stearate or calcium, hydrogenated castor oil, talcum powder, and solid polyethylene glycols; Disintegrants such as povidone, sodium croscarmellose, and crospovidone; Surfactants such as polysorbate, cetyl alcohol, and glycerol monostearate; And a combination thereof.

The pharmaceutical composition of the present invention may contain, as an active ingredient, a crystal of valencycline oxalate hydrate in an amount of 0.1 to 95% by weight, preferably 1 to 70% by weight, based on the total weight of the composition.

The pharmaceutical compositions according to the present invention may be administered to a patient in an effective amount via a variety of routes, for example, oral or parenteral routes. Preferably, the compositions of the present invention are prepared in an oral dosage form such as capsules, tablets, dispersions and suspensions. The capsule or tablet may be in enteric coated form or may contain pellets of valencycline oxalate salt hydrate crystals coated with enteric coating.

A typical daily dose of the barrenicin oxalate salt hydrate crystals may range from about 5 to 250 mg / kg body weight, preferably 10 to 100 mg / kg body weight, for mammals, including humans, May be administered in single or divided doses. However, the actual dosage of the active ingredient should be determined in light of various relevant factors, such as the route of administration, the age, sex and weight of the patient, and the severity of the disease, and accordingly, It does not.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Reference example: Equipment used and measurement conditions

The analytical values described in the following examples were measured as follows.

1) Chemical purity (%): High performance liquid chromatography (column: Kromasil C-18 column, internal diameter 4.6 mm x length 250 mm, detection wavelength: 237 nm , Flow rate: 0.6 ml / min, eluent: methyl alcohol: pH 3.0, 0.01 M potassium dihydrogen orthophosphate buffer = 50:50 (v / v), oven temperature: 25 ° C) The chemical purity was calculated from all the peak areas except the peak and the peak area of the barrenicin oxalate salt hydrate.

At this time, the potassium dihydrogen orthophosphate buffer was prepared by adding 0.1 M phosphoric acid to 0.025 M potassium dihydrogen orthophosphate aqueous solution to adjust the pH to 3.0.

2) X-ray diffraction spectrum: Using a D8 Advance X-ray powder diffraction spectrometer (Bruker, Germany), Cu-Kα radiation ? = 1.54050?).

3) The differential scanning calorimetry (DSC) was measured at a rate of + 1 ° C / min using a differential scanning calorimeter (STA S-1000, Scinco, Korea).

4) Dynamic vapor adsorption (DVS): Measured using a dynamic vapor sorption analyzer (SMS, UK).

5) Nuclear magnetic resonance spectrum (NMR): Measured using a 300 MHz FT-NMR spectrometer (Bruker, Germany).

6) Melting point: Measured using an automatic melting point apparatus (Buchi / Swiss, B-545).

7) Infrared absorption spectrum (InfraRed Spectrum): Measured using FT-IR (660 Plus).

Example 1: Preparation of barrenicin oxalate salt hydrate (methyl alcohol)

20 g of Yancheng Shengweier Chemical CO., LTD. Was added to the reaction vessel, 150 ml of methyl alcohol was added thereto, and the mixture was stirred at room temperature for dissolution, followed by membrane filtration. After the temperature of the filtrate was adjusted to about 25 캜, 9.37 g of oxalic acid (Junsei) was added thereto at 25 캜 for 10 minutes. The reaction mixture was stirred for 1 hour while maintaining at 25 < 0 > C. Then, the resulting reaction solution (mother liquor) was filtered, and the filtered crystals were washed with 40 ml of methyl alcohol. The thus-obtained crystals were vacuum-dried at 45 캜 to obtain 23.2 g (yield: 82.5%) of the target compound, valencycline oxalate salt hydrate.

The analytical values of the crystals produced are as follows:

Purity: 99.93% (measured by HPLC)

DSC endothermic peaks: 62 占 폚, 97 占 폚 and 220 占 폚

^{1 H-NMR (DMSO, 300} MHz) δ 8.91 (s, 2H), 8.03 (s, 2H), 3.59 (s, 2H), 3.42 (t, 2H), 3.21 (t, 2H), 2.49 ~ 2.50 ( _{m, -NH 2), 2.19 (} d, 1H)

Moisture content: about 5.4%

Melting point: 203 - 208 캜

The XRD spectrum of the prepared crystals is shown in Fig.

As can be seen from FIG. 1, the crystals were found to be 7.30, 9.42, 10.79, 11.48, 12.05, 13.37, 13.93, 14.57, 16.36, 16.78, 18.11, 19.46, 20.63, 21.63, 21.83, 22.69, 22.67, 22.78, 23.91, The diffraction angles (2 & tilde &thetas; 0.2) of 24.58, 25.20, 25.92, 26.53, 27.08, 28.01, 28.65, 29.29, 29.98, 31.24, 31.91, 32.78, 34.55, 35.25, 35.78, 36.10, 39.24, 39.29, 39.76, 42.20, 47.69 and 55.52 ), Indicating a characteristic peak.

Example 2: Preparation of barrenicin oxalate salt hydrate (ethyl alcohol)

10 g of barrenicin was added to the reaction vessel, 75 ml of ethyl alcohol was added, and the mixture was stirred and dissolved at 45 DEG C, followed by filtration through a membrane. 4.68 g of oxalic acid was added to the filtrate for 10 minutes while maintaining 45 캜. The reaction mixture was slowly cooled to 25 < 0 > C for 40 min and the reaction was stirred at 25 < 0 > C for 1 h. Then, the resulting reaction solution (mother liquor) was filtered, and the filtered crystals were washed with 20 ml of ethyl alcohol. The thus-obtained crystals were dried in vacuo at 45 캜 to obtain 11.5 g (yield: 80.4%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, ¹ H-NMR, moisture content and melting point results were the same as in Example 1.

Example 3: Preparation of barrenicin oxalate salt hydrate (methyl alcohol / acetonitrile)

5 g of barrenicin was added to the reaction vessel, 38 ml of methyl alcohol was added, and the mixture was stirred at room temperature to dissolve and then subjected to membrane filtration.

In another reaction vessel, 2.34 g of oxalic acid was dissolved in 75 ml of acetonitrile, and then the reaction filtrate of the above-obtained barrenicin and methyl alcohol was gradually added thereto at 25 ° C for 30 minutes. The reaction mixture was cooled to 25 DEG C and stirred for 1-2 hours. Subsequently, the obtained reaction solution (mother liquor) was filtered, and the filtered crystals were washed with 10 ml of methyl alcohol and 10 ml of acetonitrile. The crystals thus obtained were vacuum-dried at 45 캜 to obtain 6.1 g (yield: 85.3%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, ¹ H-NMR, moisture content and melting point results were the same as in Example 1.

Example 4: Preparation of barrenicin oxalate salt hydrate (ethyl alcohol / water)

10 g of barrenicin was added to the reaction vessel, 75 ml of ethyl alcohol was added, and the mixture was stirred and dissolved at 45 DEG C, followed by filtration through a membrane. To the filtrate was added 10 ml of water and 4.68 g of oxalic acid was added for 5 to 10 minutes while maintaining 45 캜. The reaction mixture was slowly cooled to 25 [deg.] C for 40 minutes and the reaction was stirred at 25 [deg.] C for 1 hour. Then, the resulting reaction solution (mother liquor) was filtered, and the filtered crystals were washed with 20 ml of ethyl alcohol. The thus-obtained crystals were dried in vacuo at 45 캜 to give 12.7 g (yield: 89.1%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, ¹ H-NMR, moisture content and melting point results were the same as in Example 1.

Example 5: Preparation of barrenicin oxalate salt hydrate (methyl alcohol / water)

10 g of barrenicin was added to the reaction vessel, 75 ml of methyl alcohol was added, and the mixture was stirred at room temperature for dissolution, followed by filtration through a membrane. The filtrate was slowly cooled to about 25 ° C. 10 ml of water was added thereto, and 4.68 g of oxalic acid was added thereto at a temperature of 25 캜 for 10 minutes. The reaction mixture was stirred at 45 캜 for 20 hours. Subsequently, the obtained reaction solution (mother liquor) was filtered, and the filtered crystals were washed with 20 ml of methyl alcohol. The crystals thus obtained were vacuum-dried at 45 캜 to obtain 11.5 g (yield: 81.7%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, ¹ H-NMR, moisture content and melting point results were the same as in Example 1.

Example 6: Preparation of barrenicin oxalate salt hydrate (isopropyl alcohol / water)

10 g of barrenicin was added to the reaction vessel, 100 ml of isopropyl alcohol was added, and the mixture was stirred at 45 캜 for dissolution, followed by filtration of the membrane. 10 ml of water was added to the filtrate, and 4.68 g of oxalic acid was added thereto at a temperature of 45 캜 for 10 minutes. The reaction mixture is slowly cooled to 25 < 0 > C for 40 minutes. Subsequently, the reaction solution was stirred at 25 DEG C for 1 hour, and the resulting reaction solution (mother liquor) was filtered, and the filtered crystals were dissolved in isopropyl alcohol Lt; / RTI > The thus-obtained crystals were vacuum-dried at 45 캜 to obtain 12.5 g (yield: 88.2%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, ¹ H-NMR, moisture content and melting point results were the same as in Example 1.

Example 7: Preparation of barrenicin oxalate salt hydrate (isopropyl alcohol / water)

5 g of barrenicin was added to the reaction vessel, 50 ml of isopropyl alcohol was added, and the mixture was stirred and dissolved at 45 캜, followed by filtration through a membrane. To the filtrate was added 2.5 ml of water, and 4.68 g of oxalic acid was added thereto at a temperature of 45 캜 for 10 minutes. The reaction mixture was slowly cooled to 25 [deg.] C for 40 minutes. Subsequently, the reaction solution was stirred at 25 DEG C for 1 hour, and the resulting reaction solution (mother liquor) was filtered, and the filtered crystals were dissolved in isopropyl alcohol Lt; / RTI > The thus-obtained crystals were dried in vacuo at 45 캜 to obtain 5.4 g (yield: 76.2%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, ¹ H-NMR, moisture content and melting point results were the same as in Example 1.

<Example 8> Preparation of barrenicin oxalate salt hydrate (tetrahydrofuran / water)

5 g of barrenicin was added to the reaction vessel, 50 ml of tetrahydrofuran was added, and the mixture was stirred and dissolved at 45 ° C, followed by filtration through a membrane. To the filtrate was added 5 ml of water and 4.68 g of oxalic acid was added thereto at a temperature of 45 캜 for 10 minutes. The reaction mixture was slowly cooled to 25 &lt; 0 &gt; C for 40 min and stirred at 25 &lt; 0 &gt; C for 1 h. Then, the obtained reaction solution (mother liquor) was filtered, and the filtered crystals were dissolved in tetrahydrofuran Lt; / RTI &gt; The thus obtained crystals were dried in vacuo at 45 캜 to obtain 11.8 g (yield: 82.7%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, ¹ H-NMR, moisture content, and melting point results were the same as in Example 1.

Example 9: Preparation of barrenicin oxalate salt hydrate (dimethyl sulfoxide / methyl alcohol)

5 g of barrenicin was added to the reaction vessel, 50 ml of dimethylsulfoxide was added, and the mixture was stirred at room temperature for dissolution, followed by filtration through a membrane.

In another reaction vessel, 2.34 g of oxalic acid was dissolved in 20 ml of methyl alcohol, and the reaction filtrate of the above obtained varenicline and dimethyl sulfoxide was gradually added thereto at 25 ° C for 30 minutes. The reaction mixture was kept at 25 DEG C and stirred for 1 hour. Then, the obtained reaction solution (mother liquor) was filtered, and the filtered crystals were washed with 10 ml of methyl alcohol. The thus obtained crystals were dried in vacuo at 45 캜 to obtain 5.9 g (yield: 83.3%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, ¹ H-NMR, moisture content and melting point results were the same as in Example 1.

Example 10: Preparation of barrenicin oxalate salt hydrate (tetrahydrofuran / ethyl alcohol)

5 g of barrenicin was added to the reaction vessel, 42 ml of tetrahydrofuran was added thereto, and the mixture was stirred at room temperature for dissolution, followed by filtration through a membrane.

In another reaction vessel, 2.34 g of oxalic acid was added to 20 ml of ethyl alcohol, and the solution was dissolved at 40 占 폚. The reaction filtrate of the above-obtained barrenicin and tetrahydrofuran obtained above was gradually added thereto at 25 占 폚 for 30 minutes. The reaction mixture was kept at 25 DEG C and stirred for 1 hour. Then, the obtained reaction solution (mother liquor) was filtered, and the filtered crystals were dissolved in ethyl alcohol Lt; / RTI &gt; The crystals thus obtained were vacuum-dried at 45 캜 to obtain 6.1 g (yield: 85.3%) of the target compound, valencycline oxalate salt hydrate.

Purity, DSC endothermic peak, &lt; ¹ &gt; H-NMR and moisture content were the same as in Example 1. [

&Lt; Comparative Example 1 > Preparation of barrenicin tartrate salt (methyl alcohol)

Tartaric acid (15.6 g) was added to the first reaction vessel, and 150 ml of methyl alcohol was added thereto, followed by stirring and dissolution, followed by membrane filtration.

In a second reaction vessel, 20 g of barrenicin was added, 150 ml of methyl alcohol was added and dissolved, and the mixture was kept at 25 캜 and filtered to prepare a second reaction product. The second reaction reagent was added to the first reaction vessel over 45 minutes. The reaction mixture was stirred overnight at 25 &lt; 0 &gt; C. Subsequently, the obtained reaction solution (mother liquor) was filtered, and the obtained crystals were dried in vacuo at about 45 캜 to give 30.4 g of the crude crystals of tartaric acid salt (yield: 89.3%).

Purity: 99.91% (measured by HPLC)

Endothermic peak of DSC: 217 ° C

Moisture content: 5.2%

&Lt; Comparative Example 2 > Preparation of Barrenicin oxalate anhydride (isopropyl alcohol)

The reaction solvent, the crystallization temperature, and the agitation time were changed to prepare barrenicin oxalate anhydride.

5 g of barrenicin was added to the reaction vessel, 50 ml of isopropyl alcohol was added, and the mixture was stirred at 45 캜 for dissolution, followed by filtration through a membrane. To the filtrate was added 2.34 g of oxalic acid for 10 minutes while maintaining 45 캜. The reaction mixture was stirred for 1 hour while maintaining the temperature at 45 DEG C, and then the reaction mixture was slowly cooled to about 25 DEG C and stirred for 15 hours. Then, the resulting reaction solution (mother liquor) was filtered, and the filtered crystals were washed with 10 ml of isopropyl alcohol. The thus obtained crystals were dried in vacuo at 45 캜 to obtain 23.2 g (yield: 93.7%) of the target compound, valencycline oxalate anhydride.

Purity: 99.94% (measured by HPLC)

Endothermic peak of DSC: 212 ° C

Water content: 5.4%

<Test Example>

In order to determine whether the novel barrenicin oxalate salt hydrate obtained according to the preparation method of the present invention can be used for medicinal use, various tests were carried out as follows.

Hygroscopicity test with dynamic vapor adsorption (DVS)

From the pharmaceutical point of view, it is desirable to maintain the initial moisture and shape without absorbing moisture even in a high moisture environment.

The barrenicin oxalate salt hydrate prepared in the examples was tested by a DVS analyzer and showed non-hygroscopicity.

Solubility test

The solubility of the barrenicin oxalate salt hydrate obtained in Example 1 was measured at 25 占 폚 in distilled water or at various pH (1.2, 4.0, 5.2 and 6.8) solvents. And the results of the barrenicin tartrate acid salt of Comparative Example 1 and the barrenicin oxalic acid salt anhydride of Comparative Example 2 were compared.

As a result, the barrenicin oxalate salt hydrate of Example 1 showed an increase in solubility more than two times at pH 1.2, as compared with the comparative substance, varenicline tartrate salt. Compared with barrenicin oxalate anhydride, it showed excellent solubility under all conditions.

In view of the fact that a solubility of 1 mg / ml or more is generally required for an oral drug, the barrenicin oxalate salt hydrate of the present invention exhibits an improved solubility of at least two times at a pH lower than that of the existing barrenicin tartrate, It can be said that it has acceptable solubility.

Thermal stability test

The DSC results of the barrenicin oxalate salt hydrates prepared in Examples 1 to 9 show that the endothermic peaks measured at about 62 ° C, 97 ° C and 220 ° C were DSC results of barrenicin tartrate according to Comparative Example 1 Endothermic peak: 217 占 폚) and the DSC result (endothermic peak: 212 占 폚) of barrenicinic oxalate anhydride.

In order to compare the thermal stability of the compounds prepared in Example 1 and Comparative Examples 1 and 2, the relative retention time (RRT) impurity content was measured after storage for 14 days at relative humidity of 75% and 40 ° C . The results are shown in Tables 1 to 3 below.

Thermal stability of barrenicin oxalate salt hydrate water(%) Change (%) RRT 0.8 impurity
(weight%) RRT 0.85 Impurity (wt%) RRT 2.19 Impurities (wt%) Initial (Initial) 99.93 - 0.003 - 0.057 3 days 99.92 0.01 0.013 - 0.057 7 days 99.92 - 0.013 - 0.058 14 days 99.92 - 0.013 - 0.058

Thermal stability of barrenicin tartrate water(%) Change (%) RRT 0.8 impurity
(weight%) RRT 0.85 Impurity (wt%) RRT 2.19 Impurities (wt%) Initial (Initial) 99.913 - 0.014 0.062 0.018 3 days 99.89 0.02 0.006 0.066 0.015 7 days 99.89 0.02 0.006 0.066 0.015 14 days 99.89 0.02 0.006 0.066 0.015

Thermal Stability of Barrenicinic Oxalate Anhydride water(%) Change (%) RRT 0.8 impurity
(weight%) RRT 0.85 Impurity (wt%) RRT 2.19 Impurities (wt%) Initial (Initial) 99.94 - 0.018 - 0.037 3 days 99.91 0.03 0.018 - 0.061 7 days 99.91 0.03 0.018 - 0.061 14 days 99.91 0.03 0.018 - 0.061

The compounds prepared in Example 1 and Comparative Examples 1 and 2 were stored at 60 DEG C for 14 days, and the resulting impurity content was measured. The results are shown in Tables 4 to 6 below.

Thermal stability of barrenicin oxalate salt hydrate water(%) Change (%) RRT 0.8 impurity
(weight%) RRT 0.85 Impurity (wt%) RRT 2.19 Impurities (wt%) Initial (Initial) 99.93 - 0.003 - 0.057 3 days 99.93 - 0.007 - 0.06 7 days 99.93 - 0.007 - 0.06 14 days 99.93 - 0.007 - 0.06

Thermal stability of barrenicin tartrate acid salt water(%) Change (%) RRT 0.8 impurity
(weight%) RRT 0.85 Impurity (wt%) RRT 2.19 Impurities (wt%) Initial (Initial) 99.913 - 0.014 0.062 0.006 3 days 99.87 0.043 0.02 0.078 0.018 7 days 99.87 0.043 0.02 0.078 0.018 14 days 99.87 0.043 0.02 0.078 0.018

Thermal Stability of Barrenicinic Oxalate Anhydride water(%) Change (%) RRT 0.8 impurity
(weight%) RRT 0.85 Impurity (wt%) RRT 2.19 Impurities (wt%) Initial (Initial) 99.94 - 0.018 - 0.037 3 days 99.91 0.03 0.018 - 0.061 7 days 99.89 0.03 0.029 0.072 14 days 99.89 0.03 0.029 0.072

As can be seen from the results of Tables 1 to 6, the barrenicin oxalate salt hydrate exhibited both purity and impurity content at 40 &lt; 0 &gt; C and 75% It showed excellent thermal stability compared with the salt anhydride.

Especially at 60 ° C, the results were much more stable than those of Comparative Examples 1 and 2. The RRT 0.85 and RRT 2.19 impurity contents remained much lower than the barrenicin tartrate and barrenicin oxalate anhydrides.

Accordingly, the barrenicin oxalate salt hydrate according to the present invention has improved stability compared to the conventional barrenicin tartrate salt and barrenicin oxalate anhydride, and can be provided to patients as a higher purity drug.

Claims (10)

A crystalline varenicline oxalate hydrate represented by the following formula (1):
[Chemical Formula 1]

In this formula,
n is from 0.5 to 3.
The method according to claim 1,
The crystalline barrenicin oxalate salt hydrate was identified as 7.30, 9.42, 10.79, 11.48, 12.05, 13.37, 13.93, 14.57, 16.36, 16.78, 18.11, 19.46, 28.65, 29.29, 29.98, 31.24, 31.91, 32.78, 34.55, 35.25, 35.78, 36.10, 39.24, 24.64, 22.69, 22.67, 22.78, 23.91, 24.31, 24.58, 25.20, 25.92, 26.53, Crystalline barrenicin oxalate hydrates, which show peaks at diffraction angles (2 &amp;thetas; +/- 0.2) of 39.29, 39.76, 42.20, 47.69 and 55.52.
The method according to claim 1,
Wherein the crystalline barrenicin oxalate salt hydrate exhibits an endothermic peak at 62 ° C, 97 ° C and 220 ° C in differential scanning calorimetry (DSC) analysis.
(1) reacting barrenicin of formula (2) and oxalic acid of formula (3) in a solvent, and
(2) A process for producing a crystalline form of a crystalline form of a crystalline form of a crystalline form of a crystalline oxalic acid represented by the following formula (1), which comprises obtaining a crystal from the solution obtained in the step (1)
(2)

(3)

[Chemical Formula 1]

In this formula,
n is from 0.5 to 3.
5. The method of claim 4,
Wherein the solvent is selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, t -butyl alcohol, sec -butyl alcohol, n -butyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate Which is a solvent selected from the group consisting of tetrahydrofuran, acetonitrile, methylene chloride, chloroform, dimethylsulfoxide, dimethylformamide, dimethylacetamide and combinations thereof, or a mixed solvent of said solvent and water, &Lt; / RTI &gt;
6. The method of claim 5,
Wherein the solvent in step (1) is selected from the group consisting of a solvent selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran, dimethyl sulfoxide and combinations thereof, or a mixed solvent of the solvent and water, &Lt; / RTI &gt;
5. The method of claim 4,
Wherein the reaction in step (1) is carried out at a temperature of 0 to 65 占 폚.
5. The method of claim 4,
Characterized in that the step (2) is carried out by cooling the solution obtained in the step (1) and then precipitating crystals, or crystallizing the solution by adding an anti-solvent thereto. Process for the production of lignic acid oxalate salt hydrate.
9. The method of claim 8,
Wherein the semi-solvent is selected from the group consisting of ethyl acetate, acetonitrile, methylene chloride, chloroform, diethyl ether, methyl t-butyl ether, isopropyl acetate, methyl isobutyl ketone, n-hexane and n-heptane, &Lt; / RTI &gt; wherein the concentration of the oxalic acid salt is selected from the group consisting &lt; RTI ID = 0.0 &gt; of: &lt; / RTI &
A pharmaceutical composition for a smoking cessation aid, comprising the crystalline form of a crystalline form of Varenicline oxalate salt according to any one of claims 1 to 3 as an active ingredient.

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