WO2006090999A1

WO2006090999A1 - Anhydrous sibutramine malates and preparation method thereof

Info

Publication number: WO2006090999A1
Application number: PCT/KR2006/000578
Authority: WO
Inventors: Tae-Won Kang; Kwan-Jun Jeon; Hoee-Joo Shon; Won-Kyu Choi; Kwan-Young Chang; Kyung-Yong Jin; Kwang-Seob Lee
Original assignee: Ckd Bio Corp
Priority date: 2005-02-22
Filing date: 2006-02-21
Publication date: 2006-08-31
Also published as: KR20060093564A

Abstract

The present invention relates to a highly soluble and stable non-hydroscopic anhydrous sibutramine malate of formula (1) and a preparation method thereof. The non-hydroscopic anhydrous sibutramine malate according to the present invention has a high solubility in water at various pHs and improved stability to humidity and high temperature, and it is thus useful in the preparation of a pharmaceutical composition for such disease as obesity.

Description

ANHYDROUS SIBUTRAMINE MALATES AND PREPARATION METHOD

THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Korean Patent Application No.10-05-

0014642, filed on February 22, 2005, with the Korea Intellectual Property Office, herein

incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to an anhydride of sibutramine acid addition salt

and a pharmaceutical composition comprising the same as an active ingredient.

BACKGROUND OF THE INVENTION

Sibutramine, N,N-dimethyl-l-[l-(4-chlorophenyl-cyclobutyl)-3-methylbutyl

amine, has the structure represented by formula (II).

(H)

Studies on sibutramine, which has been used for treating depression,

Parkinson's disease and obesity (GB Patent No. 2,098,602), have been widely performed. Furthermore, it has been reported that sibutramine may be used for

reducing the resistance to insulin or enhancing the resistance to sugar, and for

preventing or treating such disease as gout, hyperuricemia, hyperlipidemia,

osteoarthritis, anxiety disorder, somnipathy, sexual dysfunction, chronic fatigue

syndrome, and cholelithiasis.

However, it is required that sibutramine should be used in the form of acid

addition salt in the pharmaceutical application since free base form of sibutramine is an

oil state difficult to handle and its stability is troublesome.

GB patent No.2,098,602 discloses methods for preparing sibutramine and

anhydrous hydrochloride form thereof as a pharmaceutically acceptable acid addition

salt. However, anhydrous sibutramine hydrochloride is highly hygroscopic.

Hygroscopic material is undesirable in preparing drugs because of difficulties in

maintaining constant content of a drug, handling and storing. That is, it is difficult to

prepare a drug containing a hygroscopic active ingredient since controlling consistence

in weight of the hygroscopic active ingredient, which readily absorbs water, in each

dose is difficult.

In order to solve the hygroscopicity of anhydrous sibutramine acid addition salt,

sibutramine acid addition salt has been developed as a hydrate form, which is the final

hygroscopic form of anhydride. For example, sibutramine hydrochloride monohydrate

(GB Patent No.2,184,122) of formula (III) has been reported. Sibutramine hydrochloride monohydrate is used as an active ingredient in a pharmaceutical

composition such as Meradia and Reductile known for treating obesity.

HCI H₂O

(III)

As another known sibutramine acid addition salt, sibutramine methansulfonate

hemihydrate is disclosed in Korea Patent 10-03-53752 which solves the hygroscopic

problem of sibutramine acid addition salt by developing the compound as a hemihydrate

form. As described above, the hygroscopic problem of the sibutramine acid addition

salt has not been fundamentally solved in any known patent. Researches have

conducted only on developing a pharmaceutical composition as a monohydrate or

hemihydrate form of sibutramine.

Meanwhile, to maintain bioavailability of a pharmaceutically active ingredient,

solubility must be great over a broad pH range which highly influences on release rate

of composition in diverse conditions, e.g., stomach, gut or blood when it is administered,

and it is required to maintain internal resorption as release rate of the composition

increases.

However, sibutramine hydrochloride monohydrate shows a low solubility in

water, 2.9 mg/ml at pH 5.2 (Merck index, 13^th Ed, pi 522), which is very low in consideration of an integration rate during the resorption process of a pharmaceutical

composition administered internally in respect of solubility required of the

pharmaceutical composition.

The stability of sibutramine is also an important factor for a pharmaceutical

application, and a remarkable increase in the stability of sibutramine is necessary to

maintain constant content of a drug in diverse pH conditions, e.g., stomach, gut or blood

in respect of internal resorption and bioavailability. The improved stability is also

required for uses as an ingredient in a pharmaceutical composition having high-

temperature stability and high non-hygroscopicity in respect of preparation, storing, and

distribution.

Therefore, there is a need to develop a novel non-hygroscopic anhydrous salt of

sibutramine having a high solubility in water or aqueous solution over a broad pH range

as well as stability to heat and water and non-hygroscopicity, and the preparation

method thereof.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a highly soluble,

stable and non-hygroscopic anhydrous sibutramine malate.

It is another object of the present invention to provide a method for preparing

said anhydrous sibutramine malate. It is further another object of the present invention to provide a pharmaceutical

composition comprising said anhydrous sibutramine malate as an active ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a flow chart illustrating a preparation process of an anhydrous

sibutramine malate from sibutramine and malic acid according to the present invention.

Fig. 2 is a representative X-ray diffraction spectrum of the anhydrous

sibutramine malate crystalline I according to the present invention.

Fig. 3 is a representative differential scanning calorimetry (DSC) of the

anhydrous sibutramine malate crystalline I according to the present invention.

Fig. 4 is a representative X-ray diffraction spectrum of the anhydrous

sibutramine malate crystalline II according to the present invention.

Fig. 5 is a representative differential scanning calorimetry (DSC) of the

anhydrous sibutramine malate crystalline II according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an anhydrous sibutramine malate of formula (I)

which has a high solubility in water or aqueous solution over a broad pH range, as well

as a high stability under high humidity/temperature condition, and non-hygroscopicity.

(I)

The present invention further provides a method for preparing the anhydrous

sibutramine malate.

The present invention further provides a pharmaceutical composition

comprising the anhydrous sibutramine malate as an active ingredient.

Hereinafter, the present invention is described in detail.

The present inventors observed that hydroxyl and carboxyl groups of

sibutramine malate, a product of salt-forming reaction between malic acid and

sibutramine, function like hydroxyl group of H₂O, and solved the hydroscopicity of

sibutraimine salt anhydride using "non-hydration" property of sibutramine malate.

"Non-hydration" of anhydrous sibutramine malate is unique innate property inhibiting

hygroscopicity essentially, which is not observed in any other known sibutramine acid

addition salt.

The present invention provides anhydrous sibutramine malate crystallines I and

II which have a high solubility within a broad body pH range and a high stability to high temperature as well as non-hygroscopic property, which are advantageous in a

pharmaceutical application.

The anhydrous sibutramine malate of the present invention has solved

fundamentally the hygroscopic problem associated with conventional sibutramine acid

addition salt anhydride and is the most harmless (non-toxic) compared to conventional

pharmaceutically acceptable acid additions. Furthermore, it has advantages in a

pharmaceutical application by employing useful and stable malic acid in a reaction

with sibutramine.

Since the anhydrous sibutramine malate of the present invention also has a high

solubility over a broad pH range, e.g., stomach, gut or blood in respect of internal

resorption and bioavailability, and shows a remarkable increase in stability under high

temperature and humidity for maintenance of constant content of a drug for uses as an

ingredient in the pharmaceutical composition.

The present inventors tried to obtain hydrate of sibutramine malate by exposing

sibutramine malate to excess amount of water intentionally or by contacting with water

in the preparing hydrate of salt known in the art. However, hydrate of sibutramine

malate of the present invention is not formed by any known method, so that it may be

concluded that sibutramine malate according to the present invention has innate "non-

hydration" property.

Therefore, it was found that anhydrous sibutramine malate having "non- hydration" property according to the present invention is superior to any other known

sibutramine salts which are converted to the corresponding hydrate salts when they

come in contact with water.

The anhydrous sibutramine malate according to the present invention has a high

solubility at body pH having an effect on bioavailability and a high stability against a

high temperature and humidity during storage and distribution and it has a lot of

advantages in the pharmaceutical application.

Also, "non-hydration" and "non-hygroscopicity" of the anhydrous sibutramine

malate according to the present invention prevents humidity from causing hydrolysis

and degradation of active ingredients in pharmaceutical compositions. As a result, it is

possible to maintain constant drug content.

The anhydrous sibutramine malate of formula I according to the present

invention can be obtained in 2 different crystalline types, crystallines I and II.

2Θ values of peaks observed in the X-ray diffraction spectrum of crystalline I

are:

7.7±0.2, 10.4±0.2, 11.5±0.2, 12.4±0.2, 13.5±0.2, 14.1±0.2, 14.8±0.2, 15.4±0.2,

16.3±0.2, 16.7±0.2, 17.2±0.2, 18.0±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 20.5±0.2,

21.1±0.2, 21.7±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.4±0.2, 24.2±0.2, 24.5±0.2,

24.9±0.2, 25.4±0.2, 25.7±0.2, 26.1±0.2, 27.2±0.2. :Θ values of peaks observed in the X-ray diffraction spectrum of crystalline II

are:

8.4±0.2, 8.7±0.2, 9.7±0.2, 10.0±0.2, 11.4±0.2, 11.6±0.2, 12.1±0.2, 15.8±0.2, 16.3±0.2,

16.9±0.2, 17.4±0.2, 17.8±0.2, 19.4±0.2, 19.9±0.2, 21.3±0.2, 21.7±0.2, 22.0±0.2,

22.8±0.2, 23.4±0.2, 24.1±0.2, 25.0±0.2, 25.4±0.2, 25.8±0.2, 26.9±0.2, 27.2±0.2,

27.7±0.2, 28.3±0.2, 28.5±0.2.

A preparation method of the anhydrous sibutramine malate of the present

invention comprises the steps of:

a) dissolving sibutramine of formula (II) in a first solvent which is used as a

salt-forming reaction solvent and stirring a mixture after adding malic acid to the

solution; and

b) precipitating crystalline of I or II by adding a second solvent after

concentrating the mixture.

Fig. 1 is a flow chart of a preparation process of the anhydrous sibutramine

malate from sibutramine and malic acid according to the present invention.

(H)

The first solvent is one or more alcohols selected from the group consisting of

methanol, ethanol, isopropyl alcohol, n-propyl alcohol and n-butyl alcohol solvent which are water miscible organic solvent. When sibutramine is dissolved in the first

solvent, water may be add to the solvent.

The second solvent used in the preparation of the crystalline I is one or more

ketones which are hydrophilic selected from the group consisting of acetone, methyl

ethyl ketone and methyl isobutyl ketone; or one or more ethers which are water miscible

selected from the group consisting of tetrahydrofuran and dioxane.

The second solvent used in the preparation of the crystalline II is one or more

esters which are non-hydrophilic selected from the group consisting of ethyl acetate, n-

propyl acetate, isopropyl acetate, n-butyl acetate; or one or more ethers, which are non-

hydrophilic selected from the group consisting of diethyl ether, isopropyl ether and t-

butyl methyl ether.

In the reacting step a), the first solvent may be employed in an amount of 5-20

parts by weight, more preferably 7-15 parts by weight, based on 1 part by weight of

sibutramine of formula (II). In the precipitating step b), the second solvent may be

employed in an amount of 5-35 parts by weight, more preferably 10-30 parts by weight,

based on 1 part by weight of sibutramine of formula (II).

Also, in the reacting step a), reaction temperature and reaction time are

dependent on boiling point of a solvent used. Particularly, the reaction is performed at

a reaction temperature ranging from 0 ^°C to the boiling point of the solvent, preferably

from 10 ^°C to 85 ^°C , for 0.5-5 hrs after adding malic acid. The precipitating process may be performed at -15^°C to 65 ^°C, preferably at

0°C to 35^°C for 0.5-7 hrs, more preferably at 25 ^°C for 1.5-3 hrs.

Malic acid in the forms of D-malic acid, L-malic acid or D-,L-malic acid may

be employed in an amount of 0.5-5.0 mol equivalents, preferably 1-2 mol equivalents,

more preferably 1.1-1.5 mol equivalents, based on 1 mol equivalents of sibutramine.

Malic acid and sibutramine are added dropwise to the reaction solution as neat or a

mixture of organic solvent.

The anhydrous sibutramine malate according to the present invention can be

useful for a pharmaceutical composition comprising sibutramine as an active ingredient.

Therefore, the present invention provides a pharmaceutical composition

comprising sibutramine malate as an active ingredient. The pharmaceutical

composition of the present invention may further comprise pharmaceutically acceptable

carriers, diluents and excipients. Preferably, the pharmaceutical composition of the

present invention is administrated orally in the form of a tablet or a capsule.

Hereinafter, the present invention is described in further detail by example.

The following examples are intended to further illustrate the present invention without

limiting its scope.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Preparation example 1 : Preparation of sibutramine hydrochloride monohydrate

Anhydrous sibutramine hydrochloride was prepared according to the method

disclosed in GB Patent No. 2,098,602 or Korean Patent Publication No. 90-00274. 15g

of the anhydrous sibutramine hydrochloride was dissolved in a boiling mixture of

acetone (165ml) and water (1.8ml) and hot-filtered. The filtrate was concentrated by

distilling 120ml of the solvent, according to method disclosed in GB Patent No.

2,184,122 or Korean Patent Publication No. 94-08913. The concentrate was cooled

and filtered to obtain solids, and the solids were dried under a vacuum to obtain 14.3g

of a title compound having 195 ^°C of melting point (yield: 90%).

Example 1: Preparation and analysis of anhydrous sibutramine L-malate

crystalline I

5.Og of sibutramine was dissolved in 50ml of methanol and 2.6g of L-malic acid

was added dropwise at room temperature. The reaction mixture was stirred for 2 hrs,

15ml of the solvent in the mixture was removed under reduced pressure, and then 100ml

of acetone was added thereto. 30ml of the solvent in the mixture was removed again

under reduced pressure, the residue was stirred for 2 hrs and then filtered to obtain

crystals. The crystals were dried at 50 °C for 12 hrs to obtain 7.Og of a title compound

(yield: 94%). After measuring water content of the title compound, X-ray diffraction analysis,

differential scanning calorimetry analysis and ¹H-NMR were performed and the results

were described below. Fig. 2 shows a representative X-ray diffraction spectrum of the

anhydrous sibutramine malate crystalline I according to the present invention. Fig. 3

shows a representative differential scanning calorimetry (DSC) of anhydrous

sibutramine malate crystalline I according to the present invention. According to Fig.

2 and Fig. 3, the crystalline form of sibutramine malate of the present invention is

different from those of known sibutramine hydrochloride monohydrate or sibutramine

methanesulfonate.

Water content: 0.01%

2Θ values of peaks observed in the X-ray diffraction spectrum of crystalline

sibutramine malate: 7.7±0.2, 10.4±0.2, 11.5±0.2, 12.4±0.2, 13.5±0.2, 14.1±0.2,

14.8±0.2, 15.4±0.2, 16.3±0.2, 16.7±0.2, 17.2±0.2, 18.0±0.2, 18.2±0.2, 18.7±0.2,

19.2±0.2, 20.5±0.2, 21.1±0.2, 21.7±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.4±0.2,

24.2±0.2, 24.5±0.2, 24.9±0.2, 25.4±0.2, 25.7±0.2, 26.1±0.2, 27.2±0.2

¹H-NMR (δ, DMS(W₆) : 7.3~7.2(4H, dd), 4.2(1H, dd), 3.1(1H, t), 2.6(1H, dd),

2.4(3H, dd), 2.3~2.1(9H, m), 1.9(1H, m), 1.7(1H, m), 1.5(1H, m), 1.2(1H, m), 0.9(3H,

d), 0.8(3H, d) Example 2: Preparation and analysis of anhydrous sibutramine D-malate

crystalline I

lO.Og of sibutramine was dissolved in 100ml of methanol and 5.3g of D-malic

acid was added dropwise thereto at room temperature. The reaction mixture was

5 stirred for 2 hrs, 15ml of the solvent in the mixture was removed under reduced pressure,

and then 50ml of tetrahydrofuran was added thereto. 30ml of the solvent in the

mixture was removed again under reduced pressure, the residue was stirred for 2 hrs and

then filtered to obtain crystals. The crystals were dried at 50 ^°C for 12 hrs to obtain

13.3g of a title compound (yield: 90%). The water content of the title compound was

10 0.01%, and the 2Θ values of peaks observed in the X-ray diffraction spectrum and ¹H-

NMR data thereof were the same as those observed in example 1.

Example 3: Preparation and analysis of anhydrous sibutramine D,L-malate

crystalline I

₍ 15 8.0g of sibutramine was dissolved in 80ml of methanol and 4.2g of D,L-malic

acid was added dropwise at room temperature. The reaction mixture was stirred for 2

hrs, 13ml of the solvent in the mixture was removed under reduced pressure, and then

50ml of dioxane was added thereto. 30ml of the solvent in the mixture was removed

again under reduced pressure, and the residue was stirred for 2 hrs and then filtered to

20 obtain crystals. The crystals were dried at 50 ^°C for 12 hrs to obtain 10.9g of a title compound (yield: 92%). The water content of the title compound was 0.01%, and the

2Θ values of peaks observed in the X-ray diffraction spectrum and ¹H-NMR data

thereof were the same as those observed in example 1.

Example 4: Preparation and analysis of anhydrous sibutramine L-malate

crystalline I

5.Og of sibutramine was dissolved in 50ml of methanol, 0.96ml of water (3

equivalents) was added and then 2.6g of L-malic acid was added dropwise to the

reaction mixture at room temperature. The mixture was stirred for 2 hrs, 15ml of the

solvent in the mixture was removed under reduced pressure, and then 100ml of acetone

was added thereto. 30ml of the solvent in the mixture was removed again under

reduced pressure, and the residue was stirred for 2 hrs and then filtered to obtain crystals.

The crystals were dried at 40 "C for 12 hrs to obtain 6.3g of a title compound (yield:

86%). The 2Θ values of peaks observed in the X-ray diffraction spectrum and ¹H-

NMR data thereof were the same as those observed in example 1. The water content

of the title compound was 0.01-0.03% and no crystal water was found in the crystalline.

As a result, it was found that the title compound is obtained in the form of anhydrous

compound even though water was added during the preparation process. Example 5: Preparation and analysis of anhydrous sibutramine L-malate

crystalline II

15.Og of sibutramine was dissolved in 150ml of methanol and 7.9g of L-malic

hrs, 25ml of the solvent in the mixture was removed under reduced pressure, and then

50ml of isopropyl acetate was added thereto. 50ml of the solvent in the mixture was

removed again under reduced pressure, the residue was stirred for 4 hrs and then filtered

to obtain crystals. The crystals were dried at 50 °C for 12 hrs to obtain 20.2g of a title

compound (yield: 91%).

After measuring water content of the title compound, X-ray diffraction analysis,

were described below. Fig. 4 shows a representative X-ray diffraction spectrum of the

anhydrous sibutramine malate crystalline II according to the present invention. Fig. 5

shows a representative differential scanning calorimetry (DSC) of the anhydrous

sibutramine malate crystalline II according to the present invention. According to Fig.

4 and Fig. 5, the crystalline form of sibutramine malate of the present invention is

different from those of known sibutramine hydrochloride monohydrates or sibutramine

methanesulfonates.

Water content: 0.01% 2Θ values of peaks observed in the X-ray diffraction spectrum of crystalline

sibutramine malate: 8.4±0.2, 8.7±0.2, 9.7±0.2, 10.0±0.2, 11.4±0.2, 11.6±0.2, 12.1±0.2,

15.8±0.2, 16.3±0.2, 16.9±0.2, 17.4±0.2, 17.8±0.2, 19.4±0.2, 19.9±0.2, 21.3±0.2,

21.7±0.2, 22.0±0.2, 22.8±0.2, 23.4±0.2, 24.1±0.2, 25.0±0.2, 25.4±0.2, 25.8±0.2,

26.9±0.2, 27.2±0.2, 27.7±0.2, 28.3±0.2, 28.5±0.2.

¹H-NMR (δ, DMSOd₆) : 7.3~7.2(4H, dd), 4.2(1H, dd), 3.1(1H, t), 2.6(1H, dd),

d), 0.8(3H, d)

Example 6: Preparation and analysis of anhydrous sibutramine D-malate

crystalline II

5.Og of sibutramine was dissolved in 50ml of methanol and 2.6g of D-malic acid

14ml of the solvent in the mixture was removed under reduced pressure, and then 50ml

of diisopropyl ether was added thereto. 50ml of the solvent in the mixture was

removed again under reduced pressure, and the residue was stirred for 4 hrs and then

filtered to obtain crystals. The crystals were dried at 50 "C for 12 hrs to obtain 6.5g of

a title compound (yield: 88%). The water content of the title compound was 0.01%,

and the 2Θ values of peaks observed in the X-ray diffraction spectrum and ¹H-NMR

data thereof were the same as those observed in example 5. Example 7: Preparation and analysis of anhydrous sibutramine D,L-malate

crystalline II

7.Og of sibutramine was dissolved in 70ml of methanol and 3.7g of D,L-malic

hrs, 20ml of the solvent in the mixture was removed under reduced pressure, and then

30ml of diisopropyl acetate and 50ml of diisopropyl ether were added thereto. 50ml of

the solvent in the mixture was removed again under reduced pressure, the residue was

stirred for 4 hrs. After adding 40ml of methanol and 100ml of isopropyl acetate

thereto, 30ml of solvent in the mixture was removed under reduced pressure and the

residue was stirred for 4 hrs and then filtered to obtain crystals. The crystals were

dried at 50 °C for 12 hrs to obtain 9.3g of a title compound (yield: 90%). The water

content of the title compound was 0.01%, and the 2Θ values of peaks observed in the

X-ray diffraction spectrum and ¹H-NMR data thereof were the same as those observed

in example 5.

Example 8: Formulation in capsule containing sibutramine malate

120mg of microcrystalline cellulose, 110.5mg of lactose, 4.5g of aerosil, and

5mg of magnesium stearate were mixed with lOmg of anhydrous sibutramine malate for

5-15 minutes. After making particles evenly, it was encapsulated into capsules.

Experimental example 1 : Non-hygroscopicity test

Non-hygroscopic salt is desirable for stable formulation and constant content of a

drug since hygroscopicity of an active ingredient may cause hydrolysis and chemical

degradation. Non-hydroscopicity of the anhydrous sibutramine malate crystalline I

prepared according to examples 1 to 3 and the anhydrous sibutramine malate crystalline

II prepared according to examples 5 to 7 was determined, and compared them with that

of the sibutramine hydrochloride monohydrate prepared according to preparation

example 1.

Crystalline sibutramine malates were each exposed to a high

temperature/humidity condition of 40 °C and 75% relative humidity for 0, 3 and 6 days,

and the water content thereof was measured by employing a Kaal-Fisher moisture

analyzer. The water content (weights %) of each compound are shown in Table 1. Table 1: Non-hydroscopicity at 40 ^°C, 75% of humidity

As shown in Table 1, it was noted that anhydrous sibutramine malate of formula

(I) was stable non-hygroscopic compound as similar as sibutramine hydrochloride

monohydrate even if it was exposed to a high temperature/humidity condition of 40 ^°C

and 75% relative humidity.

Therefore, it further proved that the anhydrous sibutramine malate according to

the present invention resolved hygroscopic problems of conventional sibutramine acid-

addition salt anhydrides, so that side reactions associated with absorption of water in the

preparation and distribution of a pharmaceutical composition were fundamentally

blocked.

Experimental example 2-1: Non-hydration test 6.Og of anhydrous sibutramine L-malate prepared according to example 1 was

dissolved in 60ml of methanol, 1.16ml of water (3 equivalents) was added, and the

mixture was stirred for 24 hrs at room temperature. After removing the solvent under

reduced pressure, the residue was filtered to obtain crystals. The crystal was dried at

40 ^°C for 12 hrs to obtain 7.8g of a white solid compound (yield: 88%). The ¹H-NMR

data thereof was the same as that observed in example 1.

The crystal water content and the degree of dissociation of adsorption water of

the compound were measured by employing a Kaal-Fisher moisture analyzer. The

water content of the compound was 0.01-0.03% and this anhydrous sibutramine L-

malate of the present invention was found stable even if it was exposed to excess

amount of water.

Experimental example 2-2: Non-hydration test

5.Og of anhydrous sibutramine D,L-malate prepared according to example 3 and

(or?) 7 was added to the mixture of 50ml of isopropyl acetate and 10ml of methanol,

and followed by addition of 3.2ml of water (10 equivalents). The mixture was stirred

for 24 hrs at room temperature and filtered to obtain crystals. The crystal was dried at

40 °C for 12 hrs to obtain 6.2g of a white solid compound (yield: 84%). The ¹H-NMR

data thereof was the same as that observed in example 1. The crystal water content and the degree of dissociation of adsorption water of

the compound were measured by employing a Kaal-Fisher moisture analyzer. The

water content of the compound was 0.01-0.03% and the anhydrous sibutramine D₅L-

amount of water.

As shown in the experimental examples, to prove the distinguished "non-

hydration" characteristics of the anhydrous sibutramine malate of the present invention,

the anhydrous sibutramine malate was intentionally exposed to excess amount of water

during the preparation process to determine if the corresponding sibutramine malate

hydrate is formed. More concretely, the anhydrous sibutramine malate was exposed to

an organic solvent containing 0.5 equivalents to 10 equivalents of water during the

reaction to obtain sibutramine malate hydrate containing water in the form of crystals.

Also, as shown in example 4, excess amount of water was added to the reaction mixture

to obtain sibutramine malate hydrate. Further, the water content determined was 0.01-

0.03%, anhydrous sibutramine malate hydrate having crystal water or adsorption water

was not obtained. As a result, it is noted that the anhydrous sibutramine malate of the

present invention exhibits unique non-hydration property which is not provided in any

known sibutramine anhydride.

Experimental example 3 : Solubility in a body pH range The solubility, significantly influencing on bioavailability of a pharmaceutically

active ingredient and release rate of a composition, was tested in various pH conditions,

close to the pHs of the gut (pH 5.2), the stomach (pH 1.2) and blood (pH 7.4). The

solubilities of the anhydrous sibutramine malate crystalline I prepared according to

examples 1 to 3, the anhydrous sibutramine malate crystalline II prepared according to

examples 5 to 7, and the sibutramine hydrochloride monohydrate prepared according to

preparation example 1 were compared with one another within a pH range required for

absorption into the human body.

In each pH condition, after the anhydrous sibutramine malate and sibutramine

hydrochloride monohydrate were dissolved to reach a saturation state, the saturated

solution was analyzed using a high performance liquid chromatography (HPLC) to

measure the amount dissolved, based on sibutramine base (free base). The results are

shown in Table 2.

Table 2 : Solubility in a body pH range

The anhydrous sibutramine malate crystallites I and II of the present invention

showed significantly higher solubility than the sibutramine hydrochloride monohydrate

prepared by a conventional method, particularly at pH 5.2, they showed 200 times or

higher solubility than sibutramine hydrochloride monohydrate.

Experimental example 4: Stability under a pH/ high temperature condition

The stability of the anhydrous sibutramine malate crystallines I and II of the

present invention was determined under the pH/temperature condition shown in Table 3

and compared with that of the sibutrmine hydrochloride monohydrate of the preparation example 1. On 0, 7 and 18 days after storing each compound at 50 ^°C, pH 5.2, the

remaining rates of an active ingredient were measured using HPLC and the relative

stabilities as relative ratio of area (%) were compared with one another. The results

are shown in Table 3.

Table 3 : Stability under a pH / high temperature condition

It is necessary that a pharmaceutical composition should have high temperature

stability and remarkable increase in stability to maintain constant content of a drug

within body pH in respect of bioavailability. This stability of an active ingredient is an

important factor for the pharmaceutical application. It has been proved that the

sibutramine malate of the present invention is more stable than the conventional

sibutramine hydrochloride monohydrate by testing the salt in stringent condition and

determining degradation of the anhydrous sibutramine malate of the present invention

which nearly did not occur at 7 and 18 days.

INDUSTRIAL APPLICABILITY

The anhydrous sibutramine malate according to the present invention shows

excellent non-hydroscopicity and non-hydration property contrasting with conventional

sibutramine salts, so that it fundamentally eliminates the hygroscopic property of a

pharmaceutical composition. Moreover, it shows a remarkable increase in solubility

and stability within a body pH range required in respect of bioavailability and internal

resorption process, which contrasts with known sibutramine hydrochloride

monohydrates. Therefore, the sibutramine malate of the present invention may be used in the pharmaceutical composition for the treatment or prevention of various diseases,

for which sibutramine is used as a pharmaceutically active ingredient.

Claims

WHAT IS CLAIMED IS:

1. An anhydrous sibutramine malate of formula 1.

(I)

2. The anhydrous sibutramine malate according to claim 1, wherein the 2Θ values of

peaks in the X-ray diffraction spectrum of crystalline sibutramine malate are:

24.9±0.2, 25.4±0.2, 25.7±0.2, 26.1±0.2, 27.2±0.2.

3. The anhyrous sibutramine malate according to claim 1, wherein the 2Θ values of

peaks in the X-ray diffraction spectrum of crystalline sibutramine malate are:

16.9±0.2, 17.4±0.2, 17.8±0.2, 19.4±0.2, 19.9±0.2, 21.3±0.2, 21.7±0.2, 22.0±0.2, 22.8±0.2, 23.4±0.2, 24.1±0.2, 25.0±0.2, 25.4±0.2, 25.8±0.2, 26.9±0.2, 27.2±0.2,

27.7±0.2, 28.3±0.2, 28.5±0.2.

4. A pharmaceutical composition comprising anhydrous sibutramine malate according

to any of claim 1 to 3 as an effective ingredient.

5. A method of preparing anhydrous sibutramine malate comprising reacting

sibutramine of formula II with malic acid in a first solvent which is a water miscible

organic solvent.

6. The method of claim 5, wherein 0.5-5.0 mol equivalents of the malic acid is used

relative tol mol equivalent of sibutramine of formula II.

7. The method of claim 5, wherein the first solvent which is a water miscible organic

solvent is one or more alcohols selected from the group consisting of methanol, ethanol,

isopropyl alcohol, n-propyls alcohol and n-butyl alcohol.

8. The method of claim 5, further comprising precipitating crystalline anhydrous

sibutramine malate by addition of a second solvent.

9. The method of claim 8, wherein the second solvent is one or more ketones which is

hydrophilic solvent selected from the group consisting of acetone, methyl ethyl ketone

and methyl isobutyl ketone; or one or more ethers which are water miscible selected

from the group consisting of tetrahydrofuran and dioxane.

10. The method of claim 8, wherein the second solvent is one or more esters which is

non-hydrophilic solvent selected from the group consisting of ethyl acetate, n-propyl

acetate, isopropyl acetate, n-butyl acetate; or one or more ethers selected from the group

consisting of diethyl ether, isopropyl ether and t-butyl methyl ether.