JEON KWAN-JUN (KR)
SHON HOEE-JOO (KR)
CHOI WON-KYU (KR)
CHANG KWAN-YOUNG (KR)
JIN KYUNG-YONG (KR)
LEE KWANG-SEOB (KR)
KANG TAE-WON (KR)
JEON KWAN-JUN (KR)
SHON HOEE-JOO (KR)
CHOI WON-KYU (KR)
CHANG KWAN-YOUNG (KR)
JIN KYUNG-YONG (KR)
LEE KWANG-SEOB (KR)
WO2004096202A1 | 2004-11-11 | |||
WO1998013034A1 | 1998-04-02 | |||
WO2000056313A1 | 2000-09-28 |
US6331571B1 | 2001-12-18 |
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 Xray diffraction spectrum of crystalline sibutramine malate are: 77±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, 163±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, 211±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, 249±0.2, 25.4±0.2, 25.7±0.2, 26.1±0.2, 27.2±0.2. |
3. | 3 The anhyrous sibutramine malate according to claim 1, wherein the 2Θ values of peaks in the Xray diffraction spectrum of crystalline sibutramine malate are: 84±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, 169±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, 228±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, 277±0.2, 28.3±0.2, 28.5±0.2. |
4. | 4 A pharmaceutical composition comprising anhydrous sibutramine malate according to any of claim 1 to 3 as an effective ingredient. |
5. | 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. | 6 The method of claim 5, wherein 0.55.0 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, npropyls alcohol and nbutyl 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 nonhydrophilic solvent selected from the group consisting of ethyl acetate, npropyl acetate, isopropyl acetate, nbutyl acetate; or one or more ethers selected from the group consisting of diethyl ether, isopropyl ether and tbutyl methyl ether. |
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 H 2 O
(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 H 2 O, 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 1 H-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
1 H-NMR (δ, DMS(W 6 ) : 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 1 H-
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 1 H-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 1 H-
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
acid was added dropwise at room temperature. The reaction mixture was stirred for 2
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,
differential scanning calorimetry analysis and 1 H-NMR were performed and the results
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.
1 H-NMR (δ, DMSOd 6 ) : 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 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
was added dropwise at room temperature. The reaction mixture was stirred for 2 hrs,
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 1 H-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
acid was added dropwise at room temperature. The reaction mixture was stirred for 2
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 1 H-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 1 H-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 1 H-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 D 5 L-
malate of the present invention was found stable even if it was exposed to excess
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.
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