KR100536750B1 - Pharmaceutical composition comprising crystalline hemihydrate of sibutramine methanesulfonate - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating or preventing obesity and related diseases, including the novel crystalline Sibutramine methansulfonate hemihydrate of formula (1). The crystalline sibutramine methanesulfonate hemihydrate according to the present invention has excellent solubility in water and excellent stability in water and high temperature compared to conventional sibutramine hydrochloride monohydrate, and thus is useful as an active ingredient of a pharmaceutical composition.

<Formula 1>

Description

PHARMACEUTICAL COMPOSITION COMPRISING CRYSTALLINE HEMIHYDRATE OF SIBUTRAMINE METHANESULFONATE}

The present invention relates to a pharmaceutical composition for treating or preventing obesity, and more particularly to a pharmaceutical composition comprising a crystalline hemihydrate of sibutramine acid-addition salt.

The structure of sibutramine, ie, N, N-dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine, is represented by Formula 2:

Sibutramine is known to be used for the prevention or treatment of depression, Parkinson's disease and obesity (UK Patent No. 2,098,602, Korean Patent Publication No. 90-00274, International Patent Publication No. WO 88/06444 and Korean Patent Publication No. 99 -164435). In addition, sibutramine may be used to reduce insulin resistance or to enhance glucose tolerance, and to prevent diseases such as gout, hyperacidemia, hyperlipidemia, osteoarthritis, anxiety disorders, sleep disorders, sexual dysfunction, chronic fatigue syndrome and cholelithiasis and It is known to be used to treat (US Pat. Nos. 6,174,925, 5,459,164, 6,187,820, 6,162,831, 6,232,347, 6,355,685, 6,365,631, 6,376,554, 6,376,551 and 6,376,552).

However, since such sibutramine is an oily condition that is difficult to handle in pharmaceuticals, it has been required to be converted to acid-addition salt form.

British Patent No. 2,098,602 and Korean Patent Publication No. 90-00274 disclose a process for the preparation of an oily sibutramine and its pharmaceutically acceptable acid-addition hydrochloride anhydride, but such sibutramine hydrochloride anhydride is very hygroscopic and therefore active It is difficult to keep the content of the ingredients constant, and the absorbed moisture can cause hydrolysis and chemical degradation of the active ingredient and eventually affect the quality of the product, making it difficult to use as an active ingredient of the pharmaceutical composition.

In order to solve this problem, the non-hygroscopic sibutramine hydrochloride monohydrate sibutramine hydrochloride of formula (4) has been developed (British Patent No. 2,184,122 and Korean Patent Publication No. 94-08913), the development of such sibutramine hydrochloride monohydrate Sibutramine has become available for medicine. Sibutramine hydrochloride monohydrate is used as an active ingredient in medicines such as Meridia or Reductil, which are known as therapeutic agents for obesity.

On the other hand, it is well known to those skilled in the art that, in addition to the usual requirement that the active ingredients used in the pharmaceutical compositions are not hygroscopic to moisture and have good thermal stability, solubility in water or aqueous solutions over a wide pH range. Because the solubility of the active ingredient in aqueous solution greatly affects the dissolution rate of the composition, which in turn affects the bioavailability of the drug. Generally, solubility of 1 mg / ml or more is preferable in the range of pH 1-7, and considering the disintegration rate in the absorption process, if the solubility is lower than 3 mg / ml, it may be limited in the absorption process during in vivo administration. Can be.

Sibutramine hydrochloride monohydrate, an active ingredient contained in Meridia or reductil, currently marketed as a therapeutic agent for obesity, has a problem of relatively low solubility in water required for use as an active ingredient in pharmaceutical compositions. For example, sibutramine hydrochloride monohydrate shows a low solubility of 2.9 mg / ml in aqueous solution at pH 5.2, below the solubility branch point required for pharmaceutical compositions (Merck Index, 13th Ed, p1522). Accordingly, there is a need for the development of novel salts or hydrates of crystalline sibutramine suitable for use as components of pharmaceutical compositions in terms of stability and non-hygroscopicity to heat and moisture, as well as solubility in water.

Accordingly, the present inventors have completed the present invention by finding crystalline sibutramine methanesulfonate hemihydrate, which is sufficiently hygroscopic and has excellent non-hygroscopicity and stability.

It is an object of the present invention to provide a pharmaceutical composition for treating or preventing obesity and related diseases, comprising as active ingredient sibutramine acid-addition salt, which has increased solubility in water and is stable to water and heat.

Another object of the present invention is to provide a sibutramine acid-addition salt and a method for preparing the same.

In accordance with the above object, the present invention provides a pharmaceutical composition comprising a novel crystalline sibutramine methanesulfonate hemihydrate of Formula 1 below, which is stable to moisture and heat and has high solubility in water.

In accordance with another object, the present invention provides a crystalline sibutramine methanesulfonate hemihydrate of Chemical Formula 1 and a method for preparing the same.

As used herein, the term sibutramine means sibutramine of racemate unless otherwise specified.

Hereinafter, the present invention will be described in detail.

The crystalline sibutramine methanesulfonate hemihydrate according to the present invention meets the water and heat stability and non-hygroscopicity required as the active ingredient of the pharmaceutical composition, while at the same time has an excellent solubility in water.

Specifically, in the crystalline sibutramine methanesulfonate hemihydrate of Formula 1, the peak values of 2θ when I / I _o ≥ 200 in X-ray diffraction analysis were 8.2 ± 0.2, 10.8 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.4 ± 0.2, 17.8 ± 0.2, 19.0 ± 0.2, 21.2 ± 0.2, 21.9 ± 0.2, 22.2 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, 24.4 ± 0.2, 24.9 ± 0.2, 25.3 ± 0.2, 25.6 ± 0.2, 26.8 ± 0.2.

As a method of preparing the crystalline sibutramine methanesulfonate hemihydrate of Chemical Formula 1, there are two methods as follows.

First, a method of preparing crystalline sibutramine methanesulfonate hemihydrate of Chemical Formula 1 by reacting sibutramine of Chemical Formula 2 with methanesulfonic acid in an organic solvent containing water (hereinafter, referred to as “first method”).

<Formula 2>

In the first method, the amount of methanesulfonic acid may be used in a ratio of 1 to 2 molar equivalents, preferably 1.1 to 1.2 molar equivalents, relative to 1 molar equivalent of sibutramine of the formula (2). Methanesulfonic acid is conventionally added dropwise to the reaction solution as a neat or mixed solution with an organic solvent.

In the first method, the amount of water may be used in a ratio of 0.5 to 5 molar equivalents of water with respect to 1 molar equivalent of sibutramine of Chemical Formula 2.

In the first method, the amount of the organic solvent may be used in a ratio of 3 to 20 ml, preferably 5 to 15 ml, based on 1 g of sibutramine of the formula (2).

As the organic solvent used in the first method, at least one ester solvent selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate; At least one ether solvent selected from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether; Or a mixed solvent of at least one ketone solvent selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone and at least one ether solvent selected from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether Can be used.

When using a mixed solvent of a ketone solvent and an ether solvent as the organic solvent, the volume ratio of the ether solvent to the ketone solvent is preferably 1: 0.5 to 1: 5, more preferably 1: 2 to 1: 3.

The first method is carried out at a reaction temperature in the boiling point range of 0 ° C. to the solvent, preferably in a temperature range of 15 to 35 ° C. Moreover, after adding methanesulfonic acid, it is preferable to maintain the reaction time of 0.5 to 5 hours.

Secondly, i) reacting sibutramine of formula (2) with methanesulfonic acid in anhydrous organic solvent to obtain sibutramine methanesulfonate anhydride of formula (3); And ii) filtering the crystals formed by contacting sibutramine methanesulfonate anhydride of formula (3) with water in an organic solvent (hereinafter, "Second method").

<Formula 2>

<Formula 3>

In the second method, the amount of methanesulfonic acid may be used in a ratio of 1 to 2 molar equivalents, preferably 1.1 to 1.2 molar equivalents, relative to 1.0 molar equivalent of sibutramine of the formula (2). Methanesulfonic acid is conventionally added dropwise to the reaction solution as a neat or mixed solution with an organic solvent.

In the second method, the amount of water may be used in a ratio of 0.5 to 5 molar equivalents of water with respect to 1 molar equivalent of sibutramine methanesulfonate hemihydrate in Chemical Formula 3.

In the steps i) and ii) of the second method, the organic solvent may be used in a ratio of 3 to 20 ml, preferably 5 to 15 ml, based on 1 g weight of each of the sibutramine of formula (2) and sibutramine anhydride of formula (3).

The anhydrous organic solvent of step i) of the second method includes at least one ester solvent selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate; At least one ketone solvent selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone; At least one ether solvent selected from the group consisting of ethyl ether, isopropyl ether and t-butyl methyl ether; toluene; Or a mixed solvent thereof.

The organic solvent of step ii) of the second method comprises at least one ester solvent selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate; At least one ether solvent selected from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether; Or a mixed solvent of at least one ketone solvent selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone and at least one ether solvent selected from the group consisting of diethyl ether, diisopropyl ether and t-butyl methyl ether Can be used.

When using a mixed solvent of a ketone solvent and an ether solvent as the organic solvent, the volume ratio of the ether solvent to the ketone solvent is preferably 1: 0.5 to 1: 5, more preferably 1: 2 to 1: 3.

The second method is generally carried out at a reaction temperature in the range of 0 ° C. to the boiling point of the solvent, preferably at a temperature of 15 to 35 ° C. In addition, after adding methanesulfonic acid in step i), a reaction time of 0.5 to 5 hours is maintained, and in step ii), the time for contacting sibutramine methanesulfonate anhydride of formula 3 with water in an organic solvent is 2 hours to 5 days. This is preferred.

Crystalline sibutramine methanesulfonate hemihydrate of formula (1) prepared by the above two methods, compared to the sibutramine hydrochloride monohydrate of formula (4) used as a conventional sibutramine acid-addition salt, stability against water and heat, and non-absorbent Remained nearly the same, improving solubility in water.

Due to the improvement of the solubility of the crystalline sibutramine methanesulfonate hemihydrate in water in the formula (1), the crystalline sibutramine methanesulfonate hemihydrate has a good dissolution rate from the composition containing it, and thus also has good bioavailability. Done.

Meanwhile, in one embodiment of the present invention, it was confirmed whether the crystalline sibutramine methanesulfonate hemihydrate according to the present invention can be prepared from optical isomers that are (+)-isomers and (-)-isomers of sibutramine (see FIG. 6). ). The fact that the crystalline sibutramine methanesulfonate hemihydrate of the present invention is not easily formed by the (+)-and (-)-isomers of sibutramine, respectively, isolated from the sibutramine of the racemate is as follows. It can be confirmed, which is an example to demonstrate the uniqueness and uniqueness of the crystalline sibutramine methanesulfonic acid salt and the preparation method according to the present invention.

 Specifically, it was confirmed whether the crystalline sibutramine methanesulfonate hemihydrate according to the present invention can be formed by the (+)-and (-)-isomers of sibutramine, respectively separated from the sibutramine of the racemate. To this end, in the present application, according to the method described in US 2002/0006963, US 2002/0006964 or International Patent Publication WO 00/10551, the optical isomerization of sibutramine is carried out by optical division of (+)-sibutramine, which is an optical isomer of sibutramine. And (-)-sibutramine, respectively, followed by preparation of crystalline (+)-sibutramine methanesulfonate hemihydrate or (-)-sibutramine methanesulfonate hemihydrate according to the preparation method according to the present invention and various similar methods. Was intended.

Specifically, the crystals produced by reacting sibutramine of racemate with L-dibenzyl tartaric acid (L-DBTA) in ethyl acetate were collected, which were further purified in ethyl acetate and isopropyl alcohol in turn to obtain 99.3% ee (enantiomer excess). ), A salt of L-DBTA of pure (-)-sibutramine was obtained. The filtrate was reacted with L-dibenzyl tartaric acid (L-DBTA) and filtered, and the filtrate was treated with sodium hydroxide solution and extracted with chloroform to collect (+)-sibutramine, which is mostly composed of (+)-isomers. This was again reacted with D-dibenzyl tartaric acid (D-DBTA) to obtain the resulting crystals, which were then further purified to yield at least 99.3% ee of the salt of D-DBTA of (+)-sibutramine. The resulting salts of L-DBTA of (-)-sibutramine or salts of D-DBTA of (+)-sibutramine were each neutralized with saturated sodium bicarbonate solution and extracted with chloroform to give (-)-sibutramine and (+)- Sibutramine free base was obtained. Crystalline (-)-sibutramine methanesulfonate hemihydrate and (+)-sibutramine methanesulfonate hemihydrate for the above (-)-sibutramine and (+)-sibutramine free bases respectively An attempt was made to produce it, but this could not be obtained.

From the fact that the corresponding sibutramine methanesulfonate hemihydrates are not easily prepared from the optical isomers of each sibutramine as described above, the crystalline sibutramine methanesulfonate hemihydrate according to the present invention cannot be easily prepared by conventional methods. It can be inferred from this that it has intrinsic physicochemical characteristics.

In addition, the present invention provides a pharmaceutical for treating or preventing obesity and related diseases comprising crystalline sibutramine methanesulfonate hemihydrate of Formula 1 as an active ingredient, and additionally including a pharmaceutically acceptable carrier, diluent and excipient. To provide a composition.

In the pharmaceutical composition comprising the crystalline sibutramine methanesulfonate hemihydrate according to the present invention as an active ingredient, the preferred dosage form is oral administration, and such means of administration include tablets or capsules.

Tablets may be prepared by mixing the active ingredient with a carrier, diluent or excipient and the like followed by tableting, examples of suitable carriers, diluents or excipients used include disintegrants such as starch, sugars, and mannitol; Fillers and extenders such as calcium phosphate and silicic acid derivatives; Binders such as carboxymethyl cellulose and other cellulose derivatives, gelatin, and polyvinyl pyrrolidone; Talc, calcium and magnesium stearate, lubricants such as solid polyethylene glycols, and the like. In addition, hard or soft gelatin capsules containing the active ingredient with or without additives such as carriers, diluents or excipients can be prepared according to conventional methods.

At this time, it is preferable that the crystalline sibutramine methanesulfonate hemihydrate of Formula 1 as the active ingredient of the pharmaceutical composition contains 1 to 50 parts by weight based on 250 parts by weight of the pharmaceutical composition.

For example, 10 mg of crystalline sibutramine methanesulfonate hemihydrate of Formula 1, 115 mg of microcrystalline cellulose, 115 mg of lactose, 5 mg of silicon dioxide and magnesium as active ingredients in the preparation of the pharmaceutical composition according to the present invention having a total weight of 250 mg It can be prepared to contain 5 mg of stearate. However, since the composition ratio of the pharmaceutical composition is only one example, the scope of the present invention is not limited thereto.

Hereinafter, the crystalline sibutramine methanesulfonate hemihydrate according to the present invention and a preparation method thereof will be described in more detail with reference to Examples. However, this is only to help the understanding of the configuration and operation of the present invention, the scope of the present invention is not limited to these examples.

Preparation Example 1 Preparation of Sibutramine Hydrochloride Monohydrate (Compound of Formula 4)

Sibutramine hydrochloride anhydride was prepared according to the method described in British Patent No. 2,098,602 or Korean Patent Publication No. 90-00274. Then, according to the method described in British Patent No. 2,184,122 or Korean Patent Publication No. 94-08913, 10 g of the above prepared sibutramine hydrochloride anhydride was dissolved in a boiling mixture of 110 ml of acetone and 1.2 ml of water, and then the solution was Hot-filtration and 80 ml of solvent were distilled off to reduce the volume of the filtrate. The concentrate was cooled and the resulting solid was collected by filtration and dried in vacuo to yield 9.2 g (yield: 87%) of a compound of formula 4 having a melting point of 195 ° C.

Example 1 Preparation of Sibutramine Methanesulfonate Hemihydrate (Compound of Formula 1) by First Method

1-1) Preparation of sibutramine methanesulfonate hemihydrate 1

30.0 g of sibutramine of formula 2 was dissolved in 120 ml of isopropyl acetate, 1.94 ml of water was added, and then 10.9 g of methanesulfonic acid was slowly added dropwise at room temperature, followed by stirring for 1 hour. After cooling to 0 ° C. and stirring for about 2 hours, the precipitated crystals were filtered off, washed sequentially with 30 ml of isopropyl acetate and 30 ml of isopropyl ether, and dried at 50 ° C. to yield 38.46 g of a white desired compound (yield: 92.5 %) Was obtained.

Melting point: 164-165 ° C. (shrinkage at about 130 ° C.);

Moisture content 2.35% (theoretical value 2.34%); And

¹ H-NMR (δ, DMSO-d6): 8.5 (1H, br.s), 7.7 to 7.2 (4H, dd), 3.7 (1H, t), 2.8 (3H, d), 2.5 (2H, d) , 2.4 (3H, s), 2.3 (2H, d), 2.1 (3H, d), 1.9 (1H, m), 1.7 to 1.6 (2H, m), 1.3 (2H, t), 1.0 (6H, t ).

1-2) Preparation of Sibutramine Methanesulfonate Hemihydrate 2

10.0 g of sibutramine of formula 2 was dissolved in 40 ml of ethyl acetate and 40 ml of t-butyl methyl ether, 0.97 ml of water was added, and then 3.8 g of methanesulfonic acid was slowly added dropwise at room temperature, followed by stirring for 1 hour. After cooling to 0 ° C. and stirring for about 2 hours, the precipitated crystals were filtered off, washed sequentially with 30 ml of isopropyl acetate and 30 ml of isopropyl ether, and dried at 50 ° C. to yield 12.1 g of a white desired compound (yield: 88%). ) Was obtained. The obtained compound had a water content of 2.38% (theoretical value 2.34%) and the melting point and the ¹ H-NMR data were the same as in 1-1).

1-3) Preparation of Sibutramine Methanesulfonate Hemihydrate 3

11.7 g of the white desired compound (yield) in the same manner as in 1-2), except that 30 ml of acetone and 60 ml of t-butyl methyl ether were used instead of 40 ml of ethyl acetate and 40 ml of t-butyl methyl ether. : 85%) was obtained. The water content of the obtained compound was 2.27% (theoretical value 2.34%), and the melting point and the ¹ H-NMR data were the same as in the above 1-1).

Example 2 Preparation of Sibutramine Methanesulfonate Hemihydrate (Compound 1) by Second Method

2-1) Preparation of Sibutramine Methanesulfonate Anhydride (Compound of Formula 3) (Step 1 of Second Method)

As a first step of the second method for preparing sibutramine methanesulfonate hemihydrate, sibutramine methanesulfonate anhydride was prepared from sibutramine in 2-1-1) to 2-1-3), respectively.

2-1-1) Preparation of Sibutramine Methanesulfonate Anhydride 1

10 g of sibutramine of formula 2 was dissolved in 70 ml of acetone, and 3.75 g of methanesulfonic acid was added dropwise at room temperature, followed by stirring for 1 hour. After cooling the reaction suspension to 0 ° C. and stirring for about 2 hours, the precipitated crystals were filtered off, washed with 30 ml of ether and dried at 50 ° C. to give 11.7 g (yield: 87%) of the title compound as a white crystal. .

Melting point 164 to 165 ° C;

Moisture content 0.2%; And

¹ H-NMR (δ, DMSO-d6): 8.5 (1H, br.s), 7.5 (4H, dd), 3.7 (1H, t), 2.8 (3H, d), 2.5 (2H, d), 2.3 (3H, s), 2.3 (2H, d), 2.1 (3H, d), 1.9 (1H, m), 1.7 to 1.6 (2H, m), 1.4 (2H, t), 1.0 (6H, t).

2-1-2) Production 2 of sibutramine methanesulfonate anhydride

After dissolving 10 g of sibutramine of Formula 2 in 80 ml of toluene, 3.75 g of methanesulfonic acid was added dropwise at room temperature, followed by stirring for 2 hours. After cooling the reaction suspension to 0 ° C. and stirring for about 2 hours, the precipitated crystals were filtered off, washed with 20 ml of ether and dried at 50 ° C. to give 12.8 g of a white desired compound (yield: 95%). The water content of the obtained compound was 0.1%, melting point and ¹ H-NMR data were the same as in 2-1-1).

2-1-3) Preparation of Sibutramine Methanesulfonate Anhydride 3

Except for using isopropyl acetate instead of toluene, the same procedure as in the above 2-1-2) was carried out to obtain 12.5 g of a white desired compound (yield: 93%). The water content of the obtained compound was 0.1%, melting point and ¹ H-NMR data were the same as in 2-1-1).

2-2) Preparation of Sibutramine Methanesulfonate Hemihydrate (Compound of Formula 2) (Step 2 of Method 2)

In the following 2-2-1) and 2-2-2), sibutramine methanesulfonate hemihydrate was prepared from the sibutramine methanesulfonate anhydride prepared in 2-1-1) to 2-1-3).

2-2-1) Preparation of sibutramine methanesulfonate hemihydrate

5.0 g of sibutramine methanesulfonate anhydride of Formula 3 prepared in 2-1-1) to 2-1-3) was added to a mixed solvent of 50 ml of ether and 25 ml of acetone, and 0.72 ml of water was added to the resulting suspension. Stir at 18 h. The precipitated crystals were filtered off, washed with 10 ml of a mixed solvent having a volume ratio of ether: acetone of 2: 1, and dried at 50 ° C. to yield 3.89 g (yield: 76%) of the title compound as white crystals. The water content of the obtained compound was 2.30% (theoretical value 2.34%), and the melting point and the ¹ H-NMR data were the same as in 1-1).

2-2-2) Preparation of sibutramine methanesulfonate hemihydrate

144 g of sibutramine methanesulfonate anhydride of Chemical Formula 3 prepared in 2-1-1) to 2-1-3) was added to a mixed solvent of 100 ml of ether and 40 ml of methyl isobutyl ketone. Was added and stirred at room temperature for 24 hours. The precipitated crystals were filtered, washed with 30 ml of a mixed solvent having a volume ratio of ether: methyl ethyl ketone of 2: 1, and air dried to give 7.5 g (yield: 73%) of the title compound as white crystals. The water content of the obtained compound was 2.32% (theoretical value 2.34%), and the melting point and the ¹ H-NMR data were the same as in 1-1).

Example 3: Qualitative Identification of the Structure of Crystalline Sibutramine Methanesulfonate Hemihydrate

X-ray diffraction spectroscopy of sibutramine methanesulfonate hemihydrate of Formula 1 prepared in Examples 1 and 2, sibutramine methanesulfonate anhydride of Formula 3 and sibutramine hydrochloride monohydrate of Formula 4 prepared in Preparation Example 1 From the differential scanning calorimetry, it can be seen that the sibutramine methanesulfonate hemihydrate according to the present invention has a different crystal form from the known sibutramine hydrochloride monohydrate or sibutramine methanesulfonate anhydride (see FIGS. 1 to 5).

The characteristic peaks of the sibutramine methanesulfonate hemihydrate shown in the powder X-ray diffractogram spectrum of FIG. 1 are shown in Table 1, where "2θ" is a diffraction angle and "d" is a distance between crystal planes. "I / I _o " means the relative strength of the peak.

Experimental Example 1: Measurement of Solubility in Water

The solubility of the sibutramine methanesulfonate hemihydrate of Formula 1 prepared in Examples 1 and 2 with the sibutramine hydrochloride monohydrate of Formula 4, which is used as an active ingredient in the pharmaceutical composition of sibutramine, to date, was compared.

After dissolving each of the sibutramine methanesulfonate hemihydrate and sibutramine hydrochloride monohydrate of the formula (1) at pH 5.2 to reach saturation, the solution was analyzed by high performance liquid chromatography (HPLC) based on the sibutramine base (free base). The amount dissolved was measured, and the comparative measurement results are shown in Table 2 below.

As shown in Table 2 above, sibutramine methanesulfonate hemihydrate exhibited significantly improved solubility in water compared to known sibutramine hydrochloride monohydrate. From these results, it is predicted that crystalline sibutramine methanesulfonate hemihydrate is better than sibutramine hydrochloride monohydrate in bioavailability.

Experimental Example 2 Stability Test for Moisture and Heat

The thermal stability of the active ingredients used in the pharmaceutical composition is a very important factor in the long-term storage of the product as well as in the manufacturing process of tablets and capsules, and therefore the crystalline sibutramine methanesulfonate hemihydrate over time at high temperatures. The stability between known sibutramine hydrochloride monohydrate (compound of formula 4) was compared. Specifically, each compound is stored at a temperature of 60 ° C. and the relative stability is measured by high performance liquid chromatography (HPLC) after 1 month, 2 months, 3 months and 6 months to determine the residual ratio of the initial active ingredient value. The results are shown in Table 3.

As shown in the results of Table 3, the sibutramine hydrochloride monohydrate of Formula 4 tends to decrease slightly after 6 months, whereas the sibutramine methanesulfonate hemihydrate of Formula 1 does not degrade after 6 months. And so stable that the absolute content remains the same as the initial one. From this result, it can be confirmed that the crystalline sibutramine methanesulfonate hemihydrate is a substance that is as stable or more stable as known sibutramine hydrochloride monohydrate.

Experimental Example 3: Non-hygroscopic Test

The crystalline sibutramine methanesulfonate hemihydrate of Formula 1 and the known sibutramine hydrochloride monohydrate prepared in Examples 1 and 2 were continued for 1 day, 2 days and 5 days at 40 ° C. and 75% relative humidity, respectively. After exposure, each moisture content was measured by a Kahl-Fisher moisture meter, and the results are shown in Table 4 below. The measured values in Table 4 represent the moisture content (% by weight) of the water content in the active ingredient. In addition, the degree of dissociation of the crystal water contained in the hydrate was measured by testing at a temperature of 40 ° C. and a relative humidity of 10% with little moisture, thereby confirming whether or not it was a stable hydrate in which crystal water was not released. On the other hand, in order to prove that the crystalline sibutramine methanesulfonate hemihydrate is characteristically stable against moisture, the hygroscopicity of the sibutramine methanesulfonate anhydride obtained by preparing according to a conventional pharmaceutically acceptable salt is also measured. The results were compared.

As shown in Table 4, it was confirmed that the crystalline sibutramine methanesulfonate hemihydrate of the formula (1) is a non-hygroscopic salt that does not absorb water in the same manner as the known hydrochloride monohydrate even in high humidity conditions, and also in low humidity conditions It was confirmed that it was a stable hydrate that did not release the crystal water of.

Therefore, the crystalline sibutramine methanesulfonate hemihydrate of Formula 1 has excellent solubility in water and is very stable against heat and moisture, and thus may be usefully used as an active ingredient of the pharmaceutical composition.

Experimental Example 4: Confirmation of the weight loss effect of crystalline sibutramine methanesulfonate hemihydrate

In order to determine the effect of treating or preventing obesity of the crystalline sibutramine methanesulfonate hemihydrate of Formula 1 prepared in Examples 1 and 2, the experiment was carried out as follows.

16 growing obese Zuker rats (fa / fa) from Charles River Japan, Biogenome Co., Ltd. and dry Zuker rats (Fa / Fa) from Charles River Japan (Charles River Japan, Biogenome)

Each rat was divided into a drug administration group and a control group, and the weight of each individual was measured before the test, and the drug administration group used the crystalline sibutramine methanesulfonate hemihydrate of Formula 1 for 3 mg / kg for 21 days. Daily oral administration and the control group received vehicle only. At this time, high-fat foods were freely consumed throughout the test period. After 21 days, the weight change of each subject was measured, and the weight gain of the control group and the drug administration group was measured as an average value, and the weight loss effect was calculated and shown in Table 5 below.

Test group Obese Zuker Rat Skinny Zuker Rat Drug administration group Control Drug administration group Control Average weight before test (g: A) 332.2 333.2 245.0 244.8 Average weight after test (g: B) 455.6 486.2 303.4 323.6 Weight gain (g: B-A) 123.4 153.0 58.4 78.8 Weight loss effect (g: control group-drug administration group) 29.6 20.4

As shown in Table 5, the rats receiving the crystalline sibutramine methanesulfonate hemihydrate of Formula 1 showed a significant decrease in weight gain compared to the control group, and thus the crystalline sibutramine methanesulfonate hemihydrate was obese. It can be usefully used for treatment or prevention.

Comparative Example: Preparation of (+)-Isomer and (-)-Isomer Methanesulfonate of Sibutramine

From the optical isomer of sibutramine, it was confirmed whether or not the corresponding sibutramine methanesulfonate hemihydrate can be prepared as follows.

(1) Optical division of sibutramine [(+)-isomer and (-)-isomer of compound of formula 2]

12.3 g of sibutramine of racemate was dissolved in 85 ml of ethyl acetate, to which was added L-dibenzyl tartaric acid (L-DBTA) dissolved in 85 ml of ethyl acetate. The reaction mixture was heated to reflux, cooled to room temperature and filtered to collect crystals (ee of salt about 85%). The solid was then suspended in 220 ml of ethyl acetate and heated at reflux for 30 minutes to yield a solid at least 95% ee. This solid salt was further crystallized in 450 ml of isopropyl alcohol to obtain a salt of L-DBTA of (-)-sibutramine of at least 99.3% ee. The obtained salt of L-DBTA of (-)-sibutramine was neutralized with saturated sodium bicarbonate solution to pH 8.5 and extracted with chloroform to give a (-)-sibutramine free base.

After the reaction with the L-dibenzyl tartaric acid (L-DBTA) and filtered, the filtrate was neutralized to pH 8.5 with sodium hydroxide solution and extracted with chloroform to obtain (+)-sibutramine, which is mostly composed of (+)-isomers This was followed by the addition of D-dibenzyl tartaric acid (D-DBTA) followed by harvesting the crystals, which were further purified in 450 ml of isopropyl alcohol to obtain at least 99.3% ee of the salt of D-DBTA of (+)-sibutramine. Obtained. The obtained salt of D-DBTA of (+)-sibutramine was neutralized with saturated sodium bicarbonate solution to pH 8.5 and extracted with chloroform to obtain a (+)-sibutramine freebase.

(2) Preparation of methanesulfonate of (+)-and (-)-isomers of sibutramine

Methanesulfonate anhydride of each isomer was prepared by treating each of the (+)-isomer or (-)-isomer free base of sibutramine obtained in (1) in the same manner as in Example 2-1-2). Was:

(+)-Sibutramine methanesulfonate: melting point 156.5-157.5 ° C., water content 0.30;

(-)-Sibutramine methanesulfonate: melting point 156.5-157.5 ° C., water content 0.05%.

(3) Attempts to prepare methanesulfonate hemihydrates of (+)-and (-)-isomers of sibutramine

The method of Example 2-2 of Example 2, wherein the methanesulfonate anhydride of the (+)-isomer or (-)-isomer obtained in the above (2) is a method of the present invention for preparing sibutramine methanesulfonate hemihydrate. The same treatment as, but no solid production.

The solvent was evaporated again under reduced pressure and toluene was added to collect the resulting crystals, respectively. However, the collected crystals had the same melting point and water content as the methanesulfonate anhydride of each of the sibutramine isomers prepared in (2) above.

In addition, methanesulfonate anhydride of each of the (+)-isomer or (-)-isomer of sibutramine prepared in the above (2) was allowed to stand for 1 day at 75% relative humidity and room temperature conditions. Within 2 hours, the cream melted, and after 1 day it became a clear liquid.

The experimental result that the corresponding sibutramine methanesulfonate hemihydrate is not prepared from the optical isomers of each sibutramine as described above can be easily prepared by the conventional preparation method for the crystalline sibutramine methanesulfonate hemihydrate. This is an example of proof of absence.

The crystalline sibutramine methanesulfonate hemihydrate, which is the methanesulfonic acid-addition salt of sibutramine according to the present invention, has a good solubility in water as compared to known sibutramine hydrochloride monohydrate, and is the same or superior in stability and nonhygroscopicity. To prepare a pharmaceutical composition comprising a therapeutically or prophylactically effective amount thereof, it can be usefully used for the treatment or prevention of obesity and related diseases.

Figure 1 shows a powder X-ray Diffraction Spectrum of crystalline sibutramine methanesulfonate hemihydrate according to the present invention.

Figure 2 shows the powder X-ray diffraction spectrum of sibutramine methanesulfonate anhydride.

Figure 3 shows the powder X-ray diffraction spectrum of sibutramine hydrochloride monohydrate.

Figure 4 shows a differential scanning calorimeter thermogram of the crystalline sibutramine methanesulfonate hemihydrate according to the present invention.

Figure 5 shows the differential scanning calorimetry of sibutramine methanesulfonate anhydride.

FIG. 6 is a schematic diagram showing a process for preparing (+)-sibutramine methanesulfonate hemihydrate or (-)-sibutramine methanesulfonate hemihydrate, which is an optical isomer of sibutramine from sibutramine of racemate.

Claims (15)

In the X-ray diffractogram, the diffraction angle (2θ) is 8.2 ± 0.2, 10.8 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.4 ± 0.2 , 17.8 ± 0.2, 19.0 ± 0.2, 21.2 ± 0.2, 21.9 ± 0.2, 22.2 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, 24.4 ± 0.2, 24.9 ± 0.2, 25.3 ± 0.2, 25.6 ± 0.2, 26.8 ± 0.2 A pharmaceutical composition for treating and preventing obesity comprising a crystalline sibutramine methanesulfonate hemihydrate of the formula (1) below. <Formula 1> delete The method of claim 1, A composition further comprising a pharmaceutically acceptable carrier, diluent or excipient. The method of claim 1, A composition comprising 1 to 50 mg of crystalline sibutramine methanesulfonate hemihydrate. In the X-ray diffractogram, the diffraction angle (2θ) is 8.2 ± 0.2, 10.8 ± 0.2, 11.7 ± 0.2, 12.0 ± 0.2, 12.3 ± 0.2, 15.8 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.4 ± 0.2 , 17.8 ± 0.2, 19.0 ± 0.2, 21.2 ± 0.2, 21.9 ± 0.2, 22.2 ± 0.2, 22.8 ± 0.2, 23.3 ± 0.2, 24.4 ± 0.2, 24.9 ± 0.2, 25.3 ± 0.2, 25.6 ± 0.2, 26.8 ± 0.2 Crystalline sibutramine methanesulfonate hemihydrate of the formula (1) below. <Formula 1> delete Sibutramine of the formula (2) is added 0.5 to 5 molar equivalents of water to 1 molar equivalent of sibutramine, and C ₁ -C ₄ alkyl acetate, C ₁ -C ₄ alkylC ₁ -C ₄ alkylether, and 1: 0.5 to 1:05 volume ratio of a C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl ketones and C ₁ -C ₄ alkyl, C ₁ -C ₄ with respect to the sibutramine 1 g weight is selected, from a mixture of alkyl ethers of 3 to 20 mixed with a The crystalline sibutramine methanesulfonate of claim 5, comprising reacting 1 to 2 molar equivalents of methanesulfonic acid with a molar equivalent of sibutramine for 1 to 2 molar equivalents for 0.5 to 5 hours at a temperature of 0 ° C to the boiling point of the solvent. Method for the preparation of hemihydrates. <Formula 2> delete delete The method of claim 7, wherein C ₁ -C ₄ alkyl acetate is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate, and C ₁ -C ₄ alkyl C ₁ -C ₄ alkyl ether is diethyl ether, di It is selected from the group consisting of isopropyl ether and t-butyl methyl ether, characterized in that the C ₁ -C ₄ alkylC ₁ -C ₄ alkyl ketone is selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone Way. i) Sibutramine of formula 2, consisting of anhydrous C ₁ -C ₄ alkyl acetate, C ₁ -C ₄ alkyl C ₁ -C ₄ alkyl ketone, C ₁ -C ₄ alkyl C ₁ -C ₄ alkyl ether and toluene 1 to 2 molar equivalents of methanesulfonic acid with respect to 1 molar equivalent of sibutramine and 0.5 to 5 hours at a temperature of boiling point of the solvent in 1 to 2 molar equivalents of sibutramine selected from the group Obtaining sibutramine methanesulfonate anhydride of Formula 3; And ii) Sibutramine methanesulfonate anhydride of the formula (3) containing 0.5 to 5 molar equivalents of water relative to 1 molar equivalent of sibutramine methanesulfonate anhydride, C ₁ -C ₄ alkyl acetate, C ₁ -C ₄ alkyl C _1- C ₄ alkyl ether, and a mixed solvent of C ₁ -C ₄ alkyl C ₁ -C ₄ alkyl ketone and C ₁ -C ₄ alkyl C ₁ -C ₄ alkyl ether mixed in a volume ratio of 1: 0.5 to 1: 5. Stirring for 2 hours to 5 days at a temperature of from 0 ° C. to the boiling point of the solvent, in 3-20 ml of an organic solvent, based on 1 g weight of sibutramine methanesulfonate anhydride selected from the group, A process for producing the crystalline sibutramine methanesulfonate hemihydrate according to claim 5. <Formula 2> <Formula 3> delete delete The method of claim 11, C ₁ -C ₄ alkyl acetate is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate and n-butyl acetate, and C ₁ -C ₄ alkyl C ₁ -C ₄ alkyl ether is diethyl ether, di It is selected from the group consisting of isopropyl ether and t-butyl methyl ether, characterized in that the C ₁ -C ₄ alkylC ₁ -C ₄ alkyl ketone is selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone Way. delete