KR20060094621A - Crystalline sibutramin camsylate and process for preparing it - Google Patents

Abstract

The present invention relates to crystalline sibutramine campylate salt and a method for preparing the same, and more particularly, crystalline acid addition salt prepared by reacting sibutramine and camphorsulfonic acid, having excellent stability against heat and moisture, non-hygroscopicity and solubility, and so on. A crystalline sibutramine camsylate salt effective as a pharmaceutically acceptable salt for the preparation of a containing drug and a method for preparing the same.

Sibutramine, Sibutramine Hydrochloride, Crystalline Sibutramine Camsylate Salt, Stability, Non-hygroscopic, Solubility

Description

Crystalline Sibutramine Camsylate Salt and Method for Making the Same {Crystalline Sibutramin Camsylate and Process for Preparing it}

1 is a differential scanning calorimetry analysis of sibutramine campylate salt according to the present invention.

The present invention relates to crystalline sibutramine campylate salt and a method for preparing the same, and more particularly, crystalline acid addition salt prepared by reacting sibutramine and camphorsulfonic acid, having excellent stability against heat and moisture, non-hygroscopicity and solubility, and so on. A crystalline sibutramine camsylate salt effective as a pharmaceutically acceptable salt for the preparation of a containing drug and a method for preparing the same.

Sibutramine (Sibutramin) represented by the following Chemical Formula 1 has a chemical name of N, N -dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine, and depression, Parkinson's disease, obesity, and diabetes It is well known as an active substance effective for the treatment of various diseases such as gout, hyperuricemia, hyperlipidemia, osteoarthritis, anxiety disorder, sleep disorder, sexual dysfunction, chronic fatigue syndrome, gallstones.

However, since sibutramine is obtained in an oil state, it is not preferable to use it directly as an active ingredient for drug preparation. Thus, in the art, sibutramine is generally used in the form of acid added salt.

British Patent No. 2,098,602 and Korean Patent Registration No. 32617 describe a method for preparing sibutramine hydrochloride represented by the following Chemical Formula 1a. However, sibutramine hydrochloride anhydride has high hygroscopicity, which causes the hydrolysis and chemical degradation of the drug by absorbed moisture, thereby reducing the effective content of the drug. Accordingly, sibutramine hydrochloride anhydride represented by the following formula (1a) is not suitable for application as a pharmaceutically acceptable salt for drug preparation.

In order to secure the water stability of sibutramine hydrochloride, British Patent No. 2,184,122 and Korean Patent Registration No. 81418 prepared non-hygroscopic sibutramine hydrochloride monohydrate represented by the following Chemical Formula 1b, thereby using sibutramine hydrochloride as an active ingredient of a pharmaceutical product. It became possible.

However, the sibutramine hydrochloride monohydrate represented by Chemical Formula 1b has a problem in that the solubility in aqueous solution of pH 5.2 is very low as 2.9 mg / mL. Given that solubility in aqueous solution is directly related to the dissolution rate of the drug, sibutramine hydrochloride monohydrate is also unsuitable for use as an active ingredient in pharmaceutical compositions. In general, the solubility required for the active ingredient of the pharmaceutical composition is required to be more than 3 mg / mL in consideration of the rate of disintegration in the absorption process.

In order to solve this solubility problem, Korean Patent Publication No. 04-31574 has prepared a crystalline sibutramine methanesulfonate hemihydrate represented by the following Chemical Formula 1c.

However, methanesulfonic acid used in the preparation of crystalline sibutramine methanesulfonate hemihydrate is not fully tested for non-toxicity in humans, and may be harmful to humans when methanesulfonate is used as a medicine.

Accordingly, the present inventors have studied for a long time to develop a pharmaceutically acceptable sibutramine salt which has sufficient stability and non-hygroscopicity, and at the same time has excellent solubility in water and is effective for preparing a drug containing sibutramine as an active ingredient. Results The sibutramine campylate salt was synthesized using camphorsulfonic acid, which has been thoroughly tested to be non-toxic to humans through toxicology tests, and confirmed that the synthesized sibutramine campylate salt has excellent stability and non-hygroscopicity and solubility in water and heat The present invention has been completed.

Accordingly, the present invention is characterized by providing a sibutramine campylate salt as an acid addition salt of camphorsulfonic acid, which is remarkably excellent in stability and non-hygroscopicity as well as water solubility in water and heat, and is completely nontoxic to the human body.

In another aspect, the present invention provides a method for preparing sibutramine campylate salt.

The present invention is characterized by the crystalline sibutramine campylate salt represented by the following formula (1d) and its preparation method.

[Formula 1d]

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

Referring to the present invention in more detail as follows.

The crystalline sibutramine campylate salt represented by Formula 1d according to the present invention is an acid addition salt of camphorsulfonic acid, which is harmless to the human body, and as a pharmaceutically acceptable salt, satisfies water stability and non-hygroscopicity as required for water and heat. It has excellent solubility.

According to the present invention, the crystalline sibutramine camsylate salt represented by Chemical Formula 1d has a residual rate (HPLC measurement) of at least 0.998 after storage for 6 months at a temperature of 60 ° C. and 75% relative humidity, and is stable to moisture and heat. great.

In addition, the crystalline sibutramine camsylate salt represented by Chemical Formula 1d according to the present invention has a moisture content of less than 0.25 as measured by a Kaal-Fisher moisture meter for 20 hours at 40 ° C. and 75% relative humidity. As a non-hygroscopic property, it is excellent.

In addition, the crystalline sibutramine camsylate salt represented by Chemical Formula 1d according to the present invention has a solubility in water (pH 5.2, 25 ° C.) of 20 mg / mL, and the standard solubility required for the active ingredient used in the pharmaceutical composition ( 3 mg / mL).

Therefore, the crystalline sibutramine camsylate salt represented by Formula 1d according to the present invention can be effectively used as a pharmaceutically acceptable salt in the preparation of a drug containing sibutramine as an active ingredient.

Pharmaceutical compositions containing the crystalline sibutramine campylate salt represented by the formula 1d according to the present invention as an active ingredient can be administered orally or parenterally during clinical administration, and can be used in the form of general pharmaceutical preparations. That is, it can be formulated into various formulations for oral and parenteral administration, which are prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like. Such solid preparations are prepared by mixing the active compound with at least one excipient such as starch, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspending agents, solvents, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Dosage to the human body of the pharmaceutical composition according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, 1 day at a predetermined time interval depending on the doctor or pharmacist It may be administered in divided doses or several times. The effective dose of the crystalline sibutramine camsylate salt represented by the above formula (1d) is 1.0 to 10.0 mg / kg, preferably 5.0 to 8.0 mg / kg.

On the other hand, the present invention includes a method for producing sibutramine campylate salt. In the preparation method according to the present invention, as shown in the following Scheme 1, by reacting sibutramine represented by the following formula (1) with camphorsulfonic acid in an organic solvent to prepare a crystalline sibutramine campylate salt represented by the following formula (1d).

The amount of camphorsulfonic acid used in the reaction may be used in a ratio of 1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents, based on 1 mole of sibutramine represented by Chemical Formula 1. In this case, camphorsulfonic acid is conventionally added dropwise to the reaction solution in a mixed solution with a neat or an organic solvent.

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 represented by Chemical Formula 1.

Organic solvents that can be used in the reaction include one or more ketone solvents selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone; At least one acetate solvent selected from the group consisting of ethyl acetate, n- propyl acetate, i -propyl acetate and n- butyl acetate; At least one ether solvent selected from the group consisting of diethyl ether, diisopropyl ether and t- butyl methyl ether; One or more alcohol solvents selected from the group consisting of methyl alcohol, ethyl alcohol, n- propyl alcohol, isopropyl alcohol and n- butyl alcohol are used. The organic solvent may be a single solvent or two or more mixed solvents. In the case where an alcohol solvent and an ether solvent are used as the mixed solvent, the ether solvent is used in a volume ratio of 1: 0.5 to 1: 5, more preferably in a volume ratio of 1: 2 to 1: 3 relative to the alcohol solvent.

The reaction is carried out at a reaction temperature in the boiling point range of 0 ° C. to the solvent, preferably at a temperature in the range of 20 to 50 ° C. The reaction is preferably stirred for 0.5 to 4 hours after the addition of camphorsulfonic acid to maintain the reaction time.

Hereinafter, the crystalline sibutramine camsylate salt represented by Chemical Formula 1d according to the present invention and a method for preparing the same will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples. .

Example 1 Preparation of Sibutramine Kamsylate Salt

10 g of sibutramine was dissolved in 60 mL of ethyl acetate, and 8.3 g of camphorsulfonic acid were slowly added dropwise at room temperature, followed by stirring at 50 ° C. for 1 hour. After cooling to 0 ° C. and stirring for about 2 hours, the precipitated crystals were filtered, washed with 40 mL of ethyl acetate, and dried at 50 ° C. to give 17.3 g of a white sibutramine camsylate salt (yield: 95.2%).

Melting point 179-181 ° C. (shrinkage at about 177 ° C.); ¹ H-NMR (DMSO-d ₆ , ppm) δ 7.5 (4H, m), 3.7 (1H, t), 2.8 (3H, d), 2.7 (1H, t), 2.5 (3H, m), 2.4 ( 1H, s), 2.3 (3H, m), 2.2 (1H, t), 2.1 (3H, d), 1.9 (1H, d), 1.9 (1H, m), 1.8 (1H, d), 1.7 (2H , m), 1.4 (2H, s), 1.3 (2H, d), 1.1 (3H, s), 1.0 (6H, dd), 0.7 (3H, s),

Moreover, the differential scanning calorimetry figure of the sibutramine camsylate salt obtained by the said method was attached as FIG.

Example 2: Preparation of Sibutramine Kamsylate Salt

20 g of sibutramine were dissolved in 80 mL of isopropyl alcohol and 120 mL of diethyl ether, and 18.2 g of camphorsulfonic acid were slowly added dropwise at room temperature, followed by stirring at 40 ° C. for 1 hour. After cooling to 0 ° C. and stirring for about 2 hours, the precipitated crystals were filtered off, washed with 40 mL of isopropyl alcohol, and dried at 50 ° C. to yield 34.4 g of a white sibutramine campylate salt (yield 94%). . Melting point and ¹ H-NMR data of the obtained compound were the same as in Example 1.

Example 3: Preparation of Sibutramine Kamsylate Salt

20 g of sibutramine were dissolved in 80 mL of acetone, and 8.2 g of camphorsulfonic acid was slowly added dropwise at room temperature, followed by stirring at 40 ° C. for 1 hour. After cooling to 0 ° C. and 80 mL of methyl ethyl ketone were added dropwise, the mixture was stirred for about 2 hours, and then the precipitated crystals were filtered, washed with 50 mL of acetone, and dried at 50 ° C. to yield 33.6 g of white sibutramine campylate salt (yield). 92%) was obtained. Melting point and ¹ H-NMR data of the obtained compound were the same as in Example 1.

Comparative Example: Preparation of Sibutramine Hydrochloride Monohydrate

Sibutramine hydrochloride anhydride was prepared according to the method described in British Patent No. 2,098,602 and Korean Patent Registration No. 32617. Then, sibutramine hydrochloride monohydrate was prepared according to the method described in British Patent No. 2,184,122 and Korean Patent Registration No. 81418 by the following method.

10 g of sibutramine hydrochloride anhydride was dissolved in a boiling mixture of 110 mL acetone and 1.2 mL water, then the filtrate was hot-filtered and 80 mL of solvent was 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 sibutramine hydrochloride monohydrate having a melting point of 195 ° C.

Experimental Example 1 Measurement of Solubility in Water

In order to compare the solubility of the sibutramine camsylate salt prepared in Example 1 with the sibutramine hydrochloride monohydrate prepared in Comparative Example, the following experiment was performed.

After dissolving each of the sibutramine salts to be saturated at pH 5.2, the solution was analyzed by high performance liquid chromatography (HPLC) to determine the amount dissolved, and the results are shown in Table 1, respectively.

Sibutramine salt Solubility in water (mg / mL, pH 5.2, 25 ° C) Sibutramine-HCl-H ₂ O (Formula 1b) 2.9 Sibutramine campylate salt (Formula 1d) 20

As shown in Table 2, sibutramine camsylate salt (Formula 1d) showed increased solubility in water compared to known sibutramine hydrochloride monohydrate (Formula 1b). Given that the solubility required for the active ingredient of the pharmaceutical composition is at least 3 mg / mL, the sibutramine camsylate salt of the present invention has sufficient solubility to be used as the active ingredient of the drug.

Experimental Example 2 Stability Test for Moisture and Heat

In order to compare the stability of water and heat for each of the sibutramine camsylate salt prepared in Example 1 and the sibutramine hydrochloride monohydrate prepared in Comparative Example, the following experiment was performed.

Each of the above-described sibutramine salts was stored for 1 month, 2 months, 3 months and 6 months at 60 ° C. and 75% relative humidity, and then the residual ratio of the initial active ingredient value was determined by high performance liquid chromatography (HPLC). The results of comparing the relative stability is shown in Table 2 below.

Sibutramine salt Early 1 month 2 months 3 months 6 months Sibutramine-HCl-H ₂ O (Formula 1b) 1.000 1.000 0.999 0.999 0.992 Sibutramine campylate salt (Formula 1d) 1.000 1.000 0.999 0.998 0.999

As shown in the results of Table 2, the sibutramine hydrochloride monohydrate (Formula 1b) tends to decrease slightly after 6 months, whereas the sibutramine camsylate salt (Formula 1d) is characterized by the present invention. ) 6 months later, the active ingredient appeared almost the same as the initial.

Experimental Example 3: Non-hygroscopic Test

In order to compare the hygroscopicity of the sibutramine camsylate salt prepared in Example 1 and the sibutramine hydrochloride monohydrate prepared in Comparative Example, the following experiment was performed.

Each of the sibutramine salts was measured by a Kaal-Fisher moisture meter at 40 ° C. and 75% relative humidity under time, and is shown in Table 3 below.

Sibutramine salt Moisture content (%) Early 24 hours later 48 hours later 120 hours later Sibutramine-HCl-H ₂ O (Formula 1b) 5.40 5.40 5.45 5.48 Sibutramine campylate salt (Formula 1d) 0.20 0.20 0.25 0.25

As shown in Table 3, it can be seen that the crystalline sibutramine camsylate salt (Formula 1d) according to the present invention is a non-hygroscopic salt like the known sibutramine hydrochloride monohydrate (Formula 1b).

As described above, the crystalline sibutramine campylate salt according to the present invention is an acid addition salt of camphorsulfonic acid, which is non-toxic to the human body, and has excellent solubility in water compared to known sibutramine hydrochloride monohydrate, and is excellent in heat and moisture. It has been found that it is effective as a pharmaceutically acceptable salt for the preparation of a drug containing sibutramine as an active ingredient because it sufficiently secures stability and nonhygroscopicity.

Claims (7)

Crystalline sibutramine campylate salt represented by the following formula (1d). [Formula 1d]

The crystalline sibutramine campylate salt according to claim 1, wherein the residual ratio (HPLC measurement) after storage for 6 months at a temperature of 60 ° C and 75% relative humidity is 0.998 or more. 2. The crystalline sibutramine campylate salt of claim 1, wherein the water content is less than 0.25% as measured by a Kaal-Fisher moisture meter for 20 hours at 40 ° C and 75% relative humidity. 2. The crystalline sibutramine camsylate salt according to claim 1, wherein the solubility in water at 25 DEG C and pH 5.2 is 20 mg / mL. A process for preparing the crystalline sibutramine campylate salt represented by the following Chemical Formula 1d, which is prepared by reacting sibutramine represented by the following Chemical Formula 1 with camphorsulfonic acid in an organic solvent. [Formula 1]

[Formula 1d]

The method according to claim 5, wherein camphorsulfonic acid is used in a ratio of 1 to 2 molar equivalents based on 1 mole of sibutramine represented by Chemical Formula 1. The method of claim 5, wherein the organic solvent is at least one ketone solvent selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone; At least one acetate solvent selected from the group consisting of ethyl acetate, n- propyl acetate, i -propyl acetate and n- butyl acetate; At least one ether solvent selected from the group consisting of diethyl ether, diisopropyl ether and t- butyl methyl ether; And one or more alcohol solvents selected from the group consisting of methyl alcohol, ethyl alcohol, n- propyl alcohol, isopropyl alcohol and n- butyl alcohol, wherein the solvent is used alone or in combination of two or more. Way.

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