F O R M 2
THE PATENTS ACT, 1970
(SECTION 39 of 1970)
5
COMPLETE SPECIFICATION
(Section 10 and Rule 13)
10
15 “NOVEL PROCESS FOR THE PREPARATION OF (+)-CIBENZOLINE
SUCCINATE”
20 OPTIMUS DRUGS (P) LTD
2nd Floor, Sy No. 37/A & 37/P, Plot No. 6P,
Signature Towers, Kothaguda, Kondapur,
Hyderabad-500084, Telangana, India
.
25
30
The following specification particularly describes and ascertains the nature of this
invention and the manner in which the same is to be performed.
2
“NOVEL PROCESS FOR THE PREPARATION OF (+)-CIBENZOLINE
SUCCINATE”
FIELD OF THE INVENTION:
5
The present invention relates to a crystalline form of (+)-Cibenzoline succinate.
The present invention is also relates to a process for the preparation of (+)-Cibenzoline
succinate with chiral purity greater than 99.9%.
10
The present invention also provides a process for the preparation of (+)-Cibenzoline
succinate and a crystalline form thereof.
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
15 BACKGROUND OF THE INVENTION:
Cibenzoline succinate (Racemic) is chemically known as (±)-2-(2,2-
diphenylcyclopropyl)-2-imidazoline succinate with its structure (formula II) as shown
in Figure-1. It was developed and marketed as Cipralan® by Bristol-Myers Squibb
(BMS) and Exacor® 20 by Laboratory XO in France. Cibenzoline succinate (Racemic) is
Antiarrhythmic drug marketed under the trade names Cipralan and Exacor. Racemic
Cibenzoline succinate was approved in France on October 21, 1983 for treating patients
with arrhythmic heart conditions. Cibenzoline is effective in treating arrhythmia heart
disease (Eur J Clin Pharmacol. 1984;26(3):297-302) and heart failure (Circ J. 2006
25 May;70(5):588-92).
3
HN
N
O
HO
OH
O
Formula (II)
Figure-1. Structure of Cibenzoline succinate
Enantiomerically, each (-)-Cibenzoline salt and (+)-Cibenzoline salt, for example the
crystalline forms thereof are not known anywhere. For example, the crystalline forms
5 of each (-)-Cibenzoline succinate and (+)-Cibenzoline succinate are not known
anywhere.
Tetrahedron: Asymmetry 17 (2006) 3067–3069 discloses a process for the preparation
of (+)-Cibenzoline from (+)-2,2-diphenylcyclopropylmethanol formula (VI) as follows;
10 formula (VI) was oxidized with 2-iodoxybenzoic acid (IBX) in dimethylsulfoxide
(DMSO) to afford the corresponding aldehyde of formula (VII), which was treated with
sodium Chlorite (NaClO2), hydrogen peroxide (H2O2), and sodium dihydrogen
phosphate (NaH2PO4) in acetonitrile-water (MeCN-H2O) to give acid compound of
formula (VIII), further it was condensed with ethylenediamine (H2NCH2CH2NH2) in the
15 presence of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
(PyBOP) and triethylamine (Et3N) in dichloromethane (CH2Cl2) to give the
corresponding amide compound of formula (IX). Finally, the amide of formula (IX)
was converted under reduced pressure (2 mmHg) at 160ºC for 37 hours to obtain (+)-
Cibenzoline.
20
The said synthetic process is illustrated in the following Scheme-I.
4
Ph
Ph
OH
DMSO Ph
Ph CHO
NaClO2
, H2O2
/
NaH2PO4
in MeCN-H2O
Ph
Ph COOH
H2NCH2CH2NH2
PyBOP, Et3N in CH2Cl2
Ph
Ph CONHCH2CH2NH2
160ºC for 37 hours
(2 mmHg)
Ph
Ph
N
H
N
(+)-Cibenzoline
Formula (V)
Formula (VI) Formula (VII) Formula (VIII)
Formula (IX)
I
O
O
OH
(IBX)
Scheme-I
Tetrahedron: Asymmetry (2009), 20(17), 2065-2071 discloses a process for the
preparation of (+)-Cibenzoline and it was synthesized from (+)-2,2-
5 diphenylcyclopropylmethanol formula (VI) as follows; compound of formula (VI) with
76% enantiomeric excess (ee) was reacted with compound of formula (X) in
triethylamine (Et3N), 4-dimethylaminopyridine (DMAP), tetrahydrofuran (THF) to
afford the corresponding ester of formula (XI) with ee of 76% which was recrystallized
using a mixture of ethyl acetate (EtOAc) and hexane to give ester compound of formula
10 (XII) with 98% ee. Ester compound was then treated with sodium ethoxide (EtONa) in
ethanol (EtOH) to give corresponding alcohol compound of formula (VI) with 98% ee
which was oxidized with 2-iodoxybenzoic acid (IBX) in dimethylsulfoxide (DMSO) to
afford the corresponding aldehyde compound of formula (VII). Then, the aldehyde
formula (VII) was reacted with ethylenediamine in iodine (I2), potassium carbonate
15 (K2CO3) in tert-butyl alcohol (tBuOH) to obtain (+)-Cibenzoline.
The said synthetic process is illustrated in the following Scheme-II.
5
Ph
Ph
OH
Ph DMSO
Ph Ph CHO
Ph
N
H
N
R
R1
(+)-Cibenzoline
Formula (V)
Formula (VI)
Formula (VII)
I
O
O
O OH
(IBX)
Ph
Ph
OH
Formula (VI)
Et3N, DMAP in THF
O2N
O2N
COCl
Ph
Ph
O
O
NO2
NO2
Ph
Ph
O
O
NO2
NO2
Recrystallization
from EtOAc and hexane
EtONa in EtOH
H2N
R1
NH2
R
I2
, K2CO3
in tBuOH
(Wherein R, R1 =H)
(76 % ee)
(98 % ee)
Formula (X)
Formula (XI)
Formula (XII)
(Ethylenediamine)
Scheme-II
The advantages of enantiomerically pure drugs use can potentially lead to simpler and
more selective pharmacologic profiles, improved therapeutic indices, simpler
5 pharmacokinetics due to different rates of metabolism of the different enantiomers,
decreased drug interactions, and drug companies are increasingly using chiral switching
as a marketing strategy. Additionally, due to different pharmacological activity,
enantiomers of chiral drugs can differ in toxicity over racemic drugs.
10 Potential advantages of single-enantiomer drugs include: separating unwanted
pharmacodynamic side effects from toxic effects in case these reside exclusively in one
enantiomer, smaller doses of medication; simpler and more selective pharmacodynamic
profile; less complex pharmacokinetic profile; less side-effects because of the
elimination of distomers; reduce drug interactions, fewer adverse effects, one form is
15 more prone to adverse drug interactions; reduced metabolic load over the enzymatic
system; potential for an improved therapeutic index and less complex relationship
between plasma concentration and effect. Further, the advantages of enantiopure drugs
over racemic drugs have varied, depending on the case, and the biological effects of
single enantiomer drugs over their counterpart racemic drugs still remain unclear in
20 some cases. These demands of pure enantiomers Cibenzoline succinate for the clinical
studies followed by commercial supply. Thus we felt a need to develop industrially
6
efficient and economic process for making the enantiomerically pure isomers of
Cibenzoline succinate.
No reports are available in the literature for the preparation enantiomerically pure form
5 of Cibenzoline succinate except a stereo selective synthesis for (+)-Cibenzoline base
staring from enantiomerically pure compound of formula (VI) as shown in Schemes 1
and 2. (Tetrahedron: Asymmetry (2009), 20(17), 2065-2071). The major disadvantages
of this process are as follows:
a) The preparation of formula (VI) by stereo selective strategy was giving only 76% ee
10 (enantiomeric excess) purity and required extra effort for purification to get (+)
Cibenzoline, which is not commercially viable process.
b) The reagents used in the process of (+)-Cibenzoline are very expensive and it’s very
difficult to handle at plant scale. Hence it is not industrially feasible process.
c) The multi-step process for the preparation of (+)-Cibenzoline causes a lot of
15 impurities and it leads to loss of yield.
However, there is no publication that discloses a commercially useful synthesis of (+)-
Cibenzoline succinate and a salt of (+)-Cibenzoline. Hence, there is consequently a need
of development of novel methods to sort out issues associated with prior art methods.
20 So, our inventors have developed a method for the preparation of (+) Cibenzoline and a
salt thereof. The present disclosure provides a simple and cost effective industrially
applicable process with high purity and good yield.
OBJECTIVE OF THE INVENTION
25
The present disclosure provides a novel (+)-Cibenzoline·chiral acid salt of formula (IV).
HN
N
Formula (IV)
(+)-Cibenzoline Chiral aicd salt
. Chiral acid salt
7
The present disclosure provides a novel process for the preparation of (+)-Cibenzoline
succinate of formula (I) with high yield and purity.
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
5 The present disclosure provides a crystalline form of (+)-Cibenzoline succinate of
formula (I).
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
The present disclosure provides a process for the preparation of a crystalline form of
10 (+)-Cibenzoline succinate of formula (I).
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
8
SUMMARY OF THE INVENTION
The present disclosure relates to a process for the preparation of (+)-Cibenzoline
succinate of formula (I) by employing novel chiral acid salt of formula (IV). A
5 crystalline form of (+)-Cibenzoline succinate and a process for the preparation thereof
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
HN
N
Formula (IV)
. Chiral acid salt
(+)-Cibenzoline Chiral aicd salt
.
The one embodiment of the present invention provides a novel of (+)-Cibenzoline·chiral
10 acid salt of formula (IV).
HN
N
Formula (IV)
. Chiral acid salt
(+)-Cibenzoline Chiral aicd salt
The second embodiment of the present invention provides a novel process for the
preparation of enantiomerically pure (+)-Cibenzoline succinate of formula (I),
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
15
9
which comprises the steps of:
a) treating the racemic Cibenzoline succinate of formula (II) with a suitable base to
produce the racemic Cibenzoline free base of formula (III);
HN
N
Formula (III)
HN
N
O
HO
OH
O
Formula (II)
5 b) treating the racemic Cibenzoline free base of formula (III) with a suitable chiral
acid in the presence of suitable solvent to obtain racemic Cibenzoline·chiral acid
salt of formula (IIIA);
c) isolating the (+)-Cibenzoline·chiral acid salt of formula (IV);
HN
N
Formula (IV)
. Chiral acid salt
(+)-Cibenzoline Chiral aicd salt
10
d) neutralizing the (+)-Cibenzoline·chiral acid salt of formula (IV) with a suitable
base to produce the (+)-Cibenzoline free base of formula (V); and
10
HN
N
Formula (V)
(+)-Cibenzoline
e) treating the (+)-Cibenzoline free base of formula (V) with succinic acid in
presence of suitable solvent to produce the (+)-Cibenzoline succinate of formula
(I).
5
The third embodiment of the present invention provides a crystalline form of the (+)-
Cibenzoline succinate of formula (I).
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
10 The fourth embodiment of the present invention provides a process for the preparation
of a crystalline form of (+)-Cibenzoline succinate, which comprises the steps of:
a) mixing a solution 1 including (+)-Cibenzoline free base and a solution 2 including
succinic acid to prepare a mixture; and
b) cooling the mixture.
15 .
The fifth embodiment of the present invention provides a process for the preparation of
a crystalline form of (+)-Cibenzoline succinate, which comprises the steps of:
a’) reacting (+)-Cibenzoline free base with succinic acid in the presence of a straight
or branched C1-C5 alcohol to prepare a resultant mixture including (+)-
20 Cibenzoline succinate; and
11
b’) cooling the resultant mixture to obtain solid (+)-Cibenzoline succinate.
The sixth embodiment of the present invention provides a pharmaceutical
composition comprising an effective amount of a crystalline form of (+)-Cibenzoline
5 succinate of formula (I).
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the X-ray powder diffraction pattern of a crystalline form of (+)-
10 Cibenzoline succinate according to Example 4.
Fig. 2 illustrates high-performance liquid chromatography (HPLC) of (+)-Cibenzoline
succinate according to Example 4.
DETAILED DESCRIPTION OF THE INVENTION
15
A process for the preparation of (+)-Cibenzoline succinate of formula (I) by
employing chiral acid salt of formula (IV).
The present disclosure relates to a preparation of (+)-Cibenzoline succinate of formula
20 (I). by employing novel chiral acid salt of formula (IV). A crystalline form of (+)-
Cibenzoline succinate and a process for the preparation thereof.
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
HN
N
Formula (IV)
. Chiral acid salt
(+)-Cibenzoline Chiral aicd salt
.
25
The one embodiment of the present invention provides a novel (+)-Cibenzoline·chiral
acid salt of formula (IV),
12
HN
N
Formula (IV)
. Chiral acid salt
(+)-Cibenzoline Chiral aicd salt
wherein the suitable chiral acid is one selected from the group consisting of L-(+)-
Tartaric acid, D-(−)-Tartaric acid, (R)-(−)-Mandelic acid, (S)-(+)-Mandelic acid,
Dibenzoyl-L-tartaric acid, (+)-2,3-Dibenzoyl-D-tartaric acid, (−)-O,O′-Dibenzoyl-L5 tartaric acid monohydrate, (+)-O,O-Dibenzoyl-D-tartaric acid monohydrate, (−)-O,O′-
Dibenzoyl-L-tartaric acid mono(dimethylamide), Di-p-toluoyl-D-tartaric acid
monohydrate, Di-p-toluoyl-L-tartaric acid monohydrate, (−)-O,O′-Di-p-toluoyl-Ltartaric acid, (+)-O,O′-Di-p-toluoyl-D-tartaric acid, (+)-O,O′-Di-p-toluoyl-D-tartaric
acid, D-Glutamic acid, L-Glutamic acid, L-(−)-Malic acid, D-(+)-Malic acid, (−)-
10 Menthyloxyacetic acid, (+)-Menthyloxyacetic acid, (R)-(+)-α-Methoxy-αtrifluoromethylphenylacetic acid, (S)-(−)-α-Methoxy-α-trifluoromethylphenylacetic
acid, (R)-(−)-5-Oxo-2-tetrahydrofurancarboxylic acid, (S)-(+)-5-Oxo-2-
tetrahydrofurancarboxylic acid, (R)-(+)-N-(1-Phenylethyl)phthalamic acid, (S)-(−)-N-
(1-Phenylethyl)phthalamic acid, (R)-(−)-2-Phenylpropionic acid, (S)-(+)-2-
15 Phenylpropionic acid, L-Pyroglutamic acid, D-Pyroglutamic acid, D-(−)-Quinic acid,
L-(+)-Quinic acid, L-Aspartic acid, D-Aspartic acid, (R)-1,4-Benzodioxane-2-
carboxylic acid, (S)-1,4-Benzodioxane-2-carboxylic acid, N,N-Bis[(S)-(−)-1-
phenylethyl]phthalamic acid, N,N-Bis[(R)-(+)-1-phenylethyl]phthalamic acid, (1S)-
(+)-3-Bromocamphor-10-sulfonic acid hydrate, (1R)-(-)-3-Bromocamphor-10-sulfonic
20 acid hydrate, (1S)-(−)-Camphanic acid, (1R)-(+)-Camphanic acid, (1R,3S)-(+)-
Camphoric acid, (1S,3R)-(−)-Camphoric acid, (1R)-(−)-10-Camphorsulfonic acid, and
(1S)-(+)-10-Camphorsulfonic acid
The second embodiment of the present invention provides a novel process for the
25 preparation of enantiomerically pure (+)-Cibenzoline succinate of formula (I),
13
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
which comprises the steps of:
a) treating the racemic Cibenzoline succinate of formula (II) with a suitable base to
produce the racemic Cibenzoline free base of formula (III);
HN
N
Formula (III)
HN
N
O
HO
OH
O
Formula (II)
5
b) treating the racemic Cibenzoline free base of formula (III) with a suitable chiral
acid in the presence of suitable solvent to obtain racemic Cibenzoline·chiral acid
salt of formula (IIIA);
10 c) isolating (+)-Cibenzoline·chiral acid salt of formula (IV);
HN
N
Formula (IV)
. Chiral acid salt
(+)-Cibenzoline Chiral aicd salt
14
d) neutralizing the (+)-Cibenzoline·chiral acid salt of formula (IV) with a suitable
base to produce the (+)-Cibenzoline free base of formula (V); and
HN
N
Formula (V)
(+)-Cibenzoline
e) treating the (+)-Cibenzoline free base of formula (V) with succinic acid in the
5 presence of suitable solvent to produce (+)-Cibenzoline succinate of formula (I).
The process according to the embodiment of the present invention enables the
preparation of (+)-Cibenzoline succinate of formula (I) with significantly high chiral
purity of pharmaceutically acceptable grade in high yield and therefore is suitable for
mass production and economical.
10 According to the embodiment, the racemic Cibenzoline·chiral acid salt of
formula (IIIA) of the step (b) may include (+)-Cibenzoline·chiral acid salt and (-)-
Cibenzoline·chiral acid salt, wherein (+)-Cibenzoline·chiral acid salt and (-)-
Cibenzoline·chiral acid salt may be diastereomers of each other. For example, if the
chiral acid is L-tartaric acid, the racemic Cibenzoline·chiral acid salt of formula (IIIA)
15 may be racemic Cibenzoline-L-tartrate salt, wherein the racemic Cibenzoline-Ltartrate salt may include (+)-Cibenzoline-L-tartrate salt and (-)-Cibenzoline-L-tartrate
salt, which are diastereomers of each other.
According to the embodiment, the present invention comprises treating the
racemic Cibenzoline succinate of formula (II) with a base over 0-30 minutes at 0-30ºC
20 to produce the racemic Cibenzoline free base of formula (III).
According to the embodiment, the present invention comprises treating the
racemic Cibenzoline free base of formula (III) with a suitable chiral acid at suitable
temperature in the presence of suitable solvent to obtain the racemic
Cibenzoline·chiral acid salts of formula (IIIA), wherein the suitable temperature for
25 the reaction is about 20- 65ºC and the reaction is carried out for 30 minutes to 6 hours.
The (+)-Cibenzoline·chiral acid salt of formula (IV) may be isolated by
suitable techniques such as filtration or centrifugation and the like.
15
The (+)-Cibenzoline·chiral acid salt of formula (IV) may be further dried by
using a tray dryer, vacuum oven, fluidized bed dryer and spin flash dryer.
Further embodiment teaches that the (+)-Cibenzoline·chiral acid salt of
formula (IV) was purified by using various methods like crystallization, precipitation,
5 centrifugation and the like.
According to the embodiment, the present invention comprises neutralizing
the (+)-Cibenzoline·chiral acid salt of formula (IV) with a suitable base to produce
the (+)-Cibenzoline free base of formula (V), wherein the reaction is carried out at a
suitable temperature of 10-50ºC, for 30 minutes to 5 hours.
10 According to the embodiment, the present invention comprises treating the
(+)-Cibenzoline free base of formula (V) with succinic acid at 0-65ºC and stirring for
10 minutes to 5 hours to produce the (+)-Cibenzoline succinate of formula (I).
According to the embodiment, the present invention comprises recrystallizing
the (+)-Cibenzoline succinate from suitable solvents to get optically pure (+)-
15 Cibenzoline succinate of pharmaceutically acceptable grade.
The isolated optically pure (+)-Cibenzoline succinate is dried by using various
techniques like a tray dryer, vacuum oven, fluidized bed dryer and spin flash dryer.
According to the embodiment of the present invention, wherein the suitable
chiral acid is one selected from the group consisting of L-(+)-Tartaric acid, D-(−)-
20 Tartaric acid, (R)-(−)-Mandelic acid, (S)-(+)-Mandelic acid, Dibenzoyl-L-tartaric acid,
(+)-2,3-Dibenzoyl-D-tartaric acid, (−)-O,O′-Dibenzoyl-L-tartaric acid monohydrate,
(+)-O,O-Dibenzoyl-D-tartaric acid monohydrate, (−)-O,O′-Dibenzoyl-L-tartaric acid
mono(dimethylamide), Di-p-toluoyl-D-tartaric acid monohydrate, Di-p-toluoyl-Ltartaric acid monohydrate, (−)-O,O′-Di-p-toluoyl-L-tartaric acid, (+)-O,O′-Di-p25 toluoyl-D-tartaric acid, (+)-O,O′-Di-p-toluoyl-D-tartaric acid, D-Glutamic acid, LGlutamic acid, L-(−)-Malic acid, D-(+)-Malic acid, (−)-Menthyloxyacetic acid, (+)-
Menthyloxyacetic acid, (R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid, (S)-
(−)-α-Methoxy-α-trifluoromethylphenylacetic acid, (R)-(−)-5-Oxo-2-
tetrahydrofurancarboxylic acid, (S)-(+)-5-Oxo-2-tetrahydrofurancarboxylic acid, (R)-
30 (+)-N-(1-Phenylethyl)phthalamic acid, (S)-(−)-N-(1-Phenylethyl)phthalamic acid, (R)-
(−)-2-Phenylpropionic acid, (S)-(+)-2-Phenylpropionic acid, L-Pyroglutamic acid, DPyroglutamic acid, D-(−)-Quinic acid, L-(+)-Quinic acid, L-Aspartic acid, D-Aspartic
acid, (R)-1,4-Benzodioxane-2-carboxylic acid, (S)-1,4-Benzodioxane-2-carboxylic
acid, N,N-Bis[(S)-(−)-1-phenylethyl]phthalamic acid, N,N-Bis[(R)-(+)-1-
16
phenylethyl]phthalamic acid, (1S)-(+)-3-Bromocamphor-10-sulfonic acid hydrate,
(1R)-(-)-3-Bromocamphor-10-sulfonic acid hydrate, (1S)-(−)-Camphanic acid, (1R)-
(+)-Camphanic acid, (1R,3S)-(+)-Camphoric acid, (1S,3R)-(−)-Camphoric acid, (1R)-
(−)-10-Camphorsulfonic acid, and (1S)-(+)-10-Camphorsulfonic acid.
5 According to the embodiment of the present invention, wherein the suitable base
is selected from an inorganic base like alkali metal hydroxides, such as sodium
hydroxide, lithium hydroxide or potassium hydroxide and the like, or alkali metal
carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate or lithium
carbonate and the like, or alkali metal bicarbonates such as sodium bicarbonate or
10 potassium bicarbonate and the like or mixtures thereof.
According to the embodiment of the present invention, wherein the suitable
solvent is selected from alcohols, such as methanol, ethanol, n-propanol, isopropanol,
n-butanol, tert-butanol and the like, or esters, such as ethylacetate, methylacetate, butyl
acetate, isopropyl acetate, methoxy ethyl acetate and the like, or aliphatic hydrocarbons,
15 such as heptane, hexane and the like, or ketones, such as acetone, methyl isobutyl ketone,
2-pentanone, ethylmethylketone, diethylketone and the like, or aromatic hydrocarbons,
such as benzene, toluene, xylene, chlorobenzene and the like, or halogenated
hydrocarbons, such as chloroform, dichloromethane and the like, or ethers, such as
methyl tert-butyl ether, diethyl ether, tetrahydrofuran, dioxane and the like, or aprotic
20 polar solvents, such as dimethylformamide, dimethylsulfoxide, acetonitrile or water and
or mixtures thereof.
The present invention provides a process for the preparation of (+)-Cibenzoline
succinate with high optical purity by using tartaric acid.
The process for the preparation of (+)-Cibenzoline succinate according to the
25 embodiment of the present invention includes the following steps:
reacting racemic Cibenzoline free base of formula (III) with L-tartaric acid in
the presence of a solvent to obtain a mixture including racemic Cibenzoline-L-tartrate
salt; and
17
isolating (+)-Cibenzoline-L-tartrate salt from the mixture including the racemic
Cibenzoline-L-tartrate salt.
In embodiments of the present invention, the racemic Cibenzoline-L-tartrate salt
5 may be prepared in the presence of a solvent.
In embodiments of the present invention, preparing racemic Cibenzoline-Ltartrate salt in the presence of the solvent may include the following steps:
adding a solution 2 including L-tartaric acid to a solution 1 including racemic
Cibenzoline free base to preparing a mixture; and
10 adding an organic solvent dropwise to the mixture to prepare the racemic
Cibenzoline-L-tartrate salt.
In embodiments of the present invention, the solution 2 may be slowly added
dropwise to the solution 1 in the step of preparing the mixture.
In embodiments of the present invention, the additional organic solvent may be
15 slowly added dropwise to the mixture in the step of adding the organic solvent to the
mixture.
In embodiments of the present invention, the solution 1 may be prepared by
dissolving racemic Cibenzoline free base in acetonitrile and the solution 2 may be
prepared by dissolving L-tartaric acid in water.
20 In embodiments of the present invention, the additional organic solvent may be
methyl tert butyl ether.
In embodiments of the present invention, the solvent may be acetonitrile, water,
and methyl tert butyl ether in the step of preparing racemic Cibenzoline-L-tartrate salt
in the presence of the solvent.
25 In embodiments of the present invention, the volumetric ratio between
acetonitrile and methyl tert butyl ether may be about 0.5:1 to 1.5:1, particularly, about
0.7:1 to 1.3:1, in the step of preparing the racemic Cibenzoline-L-tartrate salt in the
18
presence of the solvent. For example, the volumetric ratio between acetonitrile and
methyl tert butyl ether may be approximately 1:1 or 1:1.
In embodiments of the present invention, the reaction after adding the additional
organic solvent may be carried out at room temperature, and it may be heated to a
5 temperature of 40-60°C after the reaction at room temperature to accelerate reaction,
more particularly approximately equal to or higher than 45°C, or more particularly
approximately equal to or higher than 50°C, or even more particularly approximately
50-55°C.
In embodiments of the present invention, the additional organic solvent may be
10 added dropwise for 15 minutes or more; the dropwise addition time may differ
depending on the scale of reaction, but it can be added dropwise for 20 minutes, 30
minutes, 1 hour, and 2 hours. In addition, after the dropwise addition of the additional
organic solvent, it may be stirred for 2 hours or more; the stirring time may differ
depending on the scale of reaction, but it can be stirred for 2.5 hours, 3 hours, 3.5 hours,
15 and 4 hours.
In embodiments of the present invention, the step of isolating (+)-CibenzolineL-tartrate salt from the mixture including the racemic Cibenzoline L-tartrate salt may be
obtaining solid (+)-Cibenzoline-L-tartrate salt from the mixture including the racemic
Cibenzoline L-tartrate salt.
20 In embodiments of the present invention, the step of isolating (+)-CibenzolineL-tartrate salt from the mixture including the racemic Cibenzoline L-tartrate salt may
further include:
heating the mixture including the racemic Cibenzoline L-tartrate salt; and
cooling the mixture.
25 In embodiments of the present invention, the heating may be carried out at a
temperature of approximately equal to or higher than 45°C, or more particularly
approximately equal to or higher than 50°C, or even more particularly approximately
50-55°C.
In embodiments of the present invention, the isolating (+)-Cibenzoline-L-tartrate
30 salt may additionally include a stirring step after the heating step. The stirring may be
carried out for 30 or more minutes, and the duration of stirring may differ depending on
the scale of reaction, but it can be stirred for 1 hour, 2 hours, 3 hours, 4 hours, and 5
hours.
19
In embodiments of the present invention, the cooling may be carried out at a
temperature of approximately 20-30°C, particularly approximately 25-30°C.
In embodiments of the present invention, the isolating (+)-Cibenzoline-L-tartrate
salt may additionally include a stirring step after the cooling step. The stirring may be
5 carried out for 30 or more minutes, and the duration of stirring may differ depending on
the scale of reaction, but it can be stirred for 1 hour, 2 hours, 3 hours, 4 hours, and 5
hours.
In embodiments of the present invention, the process for the preparation of (+)-
Cibenzoline succinate may further include purifying the (+)-Cibenzoline-L-tartrate salt.
10 In embodiments of the present invention, the racemic Cibenzoline free base may
be prepared by reacting the racemic Cibenzoline succinate with a base.
In embodiments of the present invention, the type of the base may be as
described above.
In embodiments of the present invention, the process for the preparation of (+)-
15 Cibenzoline succinate may further include the following steps:
reacting (+)-Cibenzoline-L-tartrate salt with a base to obtain (+)-Cibenzoline
free base; and
reacting the (+)-Cibenzoline free base with succinic acid.
In embodiments of the present invention, the type of the base may be as
20 described above.
The (+)-Cibenzoline succinate obtained by the process according to the
embodiment of the present invention has pharmaceutically acceptable grade optical
purity and may be a single crystalline form.
25 A crystalline form of (+)-Cibenzoline succinate and a process for the preparation
thereof
The third embodiment of the present invention is to provide a crystalline form of (+)-
Cibenzoline succinate of formula (I).
20
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
According to the embodiment of the present invention, the crystalline form of
(+)-Cibenzoline succinate has an X-ray powder diffraction (XRPD) pattern including
diffraction peaks at 11.1°, 12.9°, 14.1°, 14.6°, 23.0°, and 24.2° (2θ±0.2°).
5 According to the embodiment of the present invention, the crystalline form of
(+)-Cibenzoline succinate has an X-ray powder diffraction (XRPD) pattern including
diffraction peaks at 11.14°, 12.83°, 14.09°, 14.62°, 22.97°, and 24.21° (2θ).
According to the embodiment of the present invention, the crystalline form of
(+)-Cibenzoline succinate has an X-ray powder diffraction (XRPD) pattern including
10 diffraction peaks at 11.1°, 12.9°, 14.1°, 14.6°, 22.1°, 22.6°, 23.0°, 24.2° and 26.0°
(2θ±0.2°).
According to the embodiment of the present invention, in addition to XRPD
diffraction peaks at 11.1°, 12.9°, 14.1°, 14.6°, 23.0°, and 24.2° (2θ±0.2°), the
crystalline form of (+)-Cibenzoline succinate may have an XRPD pattern including
15 one or more diffraction peaks selected from the group consisting of 22.1°, 22.6°, 23.1°,
and 26.0° (2θ±0.2°).
According to the embodiment of the present invention, in addition to XRPD
diffraction peaks at 11.14°, 12.83°, 14.09°, 14.62°, 22.97°, and 24.21° (2θ), the
crystalline form of (+)-Cibenzoline succinate may have an XRPD pattern including
20 one or more diffraction peaks selected from the group consisting of 22.08°, 22.60°,
23.09°, and 25.96° (2θ).
According to the embodiment of the present invention, the crystalline form of
(+)-Cibenzoline succinate may have an XRPD pattern including diffraction peaks at
9.53°, 11.14°, 12.83°, 14.09°, 14.62°, 16.07°, 17.29°, 18.11°, 19.24°, 21.31°, 22.42°,
25 22.08°, 22.60°, 22.97°, 23.09°, 24.21°, 25.37°, 25.96°, 26.31°, and 27.59° (2θ), as
described in Table 1 below.
21
[Table 1]
(+)-Cibenzoline succinate
2-theta (°) Intensity %
9.53 4.1
11.14 100
12.83 13.0
14.09 16.2
14.62 16.5
16.07 3.7
17.29 6.8
18.11 3.0
19.24 4.8
21.31 4.0
22.42 6.2
22.08 12.4
22.60 8.6
22.97 28.0
23.09 9.4
24.21 14.7
25.37 7.3
25.96 9.6
26.31 4.1
27.59 2.4
According to the embodiment of the present invention, the crystalline form of
(+)-Cibenzoline succinate may have an XRPD pattern with diffraction peaks at 5.41°,
8.98°, 9.53°, 10.04°, 11.14°, 11.95°, 12.83°, 13.29°, 14.09°, 14.62°, 16.07°. 17.29°,
5 18.11°, 19.24°, 19.77°, 21.31°, 22.08°, 22.42°, 22.60°, 22.97°, 23.09°, 24.21°, 25.37°,
25.96°, 26.31°, 27.59°, and 29.26° (2θ).
In the embodiments of the present invention, the crystalline form of (+)-
Cibenzoline succinate has an optical rotation of [α]D 132.17, is a pure optical isomer,
and may have an IR spectrum with peaks at 1675.44 cm-1 (Acid C=O stretching
vibration) and 2954.1 cm-1
10 (sp3 stretching vibration).
According to the embodiment of the present invention, the crystalline form of
22
(+)-Cibenzoline succinate may have an XRPD pattern of Figure 1.
According to the embodiment of the present invention, the XRPD pattern
might have been be measured by using Cu-Kα or Cu-Kβ radiation, more particularly,
Cu-Kα radiation, even more particularly, Cu-Kα1, Cu-K α2, Cu-Kβ, or Cu-K α1 and Cu5 K α2 radiation. For example, the XRPD pattern might have been be measured by using
Cu-Kα radiation.
According to the embodiment of the present invention, identification by FTIR of the crystalline form of (+)-Cibenzoline succinate may have 1675 ±5 cm-1
and
2954±5 cm-1
, for example, 1675cm-1
and 2954cm-1
.
10 In addition, the crystalline form of (+)-Cibenzoline succinate of the present
invention may be defined in terms of additional physical properties such as solid CNMR, a specific diffraction peak at crystal lattice plane spacing, the shape of solid
crystalline form in microscopic image, or particle size or particle size distribution (Dvalue) of solid crystalline form in microscopic image.
15 The crystalline form of (+)-Cibenzoline succinate of the present invention may
have low hygroscopicity, may be remarkably stable at the accelerated conditions and
long-term storage conditions and may be stably maintained with no change in content
for long term. Accordingly, the crystalline form of (+)-Cibenzoline succinate of the
present invention may be obtained as a raw material having high purity and may
20 maintain high purity and its crystalline form for long term even when stored for long
periods of time.
In addition, the crystalline form of (+)-Cibenzoline succinate of the present
invention may be obtained in high purity and yield without complicated purification
process, such as column chromatography, and may be therefore easily applicable for
25 mass production and commercial purposes.
Besides, the crystalline form of (+)-Cibenzoline succinate of the present
invention may remarkably stable and therefore may have an excellent
pharmacological effect, making it useful as an active ingredient for preventing or
treating a disease selected from the group consisting of heart disease, arrhythmia heart
30 disease, and heart failure.
The crystalline form of (+)-Cibenzoline succinate may be formulated into a
form selected from the group consisting of powder, granule, tablet, capsule,
suspension, emulsion, syrup, aerosol, ointment, cream, suppository, eye drop, and
injection according to conventional formulation methods recognized by those skilled
23
in the art.
The fourth embodiment of the present invention provides a process for the preparation
of a crystalline form of (+)-Cibenzoline succinate of formula (I).
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
5
According to the embodiment of the present invention, the process for the
preparation of the crystalline form of (+)-Cibenzoline succinate comprises the
following steps of:
a) mixing solution 2 including succinic acid and solution 1 including (+)-
10 Cibenzoline free base of formula (V) to prepare a mixture; and
HN
N
Formula (V)
(+)-Cibenzoline
b) cooling the mixture to prepare the crystalline form of (+)-Cibenzoline succinate
of formula (I).
24
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
According to the embodiment of the present invention, the mixture may be
prepared by adding the solution 2 to the solution 1 in the step (a).
5 According to the embodiment of the present invention, the solution 1 may be
prepared by dissolving (+)-Cibenzoline free base in a straight or branched C1-C5
alcohol.
According to the embodiment of the present invention, the solution 2 may be
prepared by dissolving succinic acid in a straight or branched C1-C5 alcohol.
10 According to the embodiment of the present invention, the straight or
branched C1-C5 alcohol may be methanol, ethanol, straight or branched propanol,
straight or branched butanol, straight or branched pentanol, or a mixture thereof,
particularly, methanol, ethanol, straight or branched propanol, or a mixture thereof,
more particularly methanol, straight or branched propanol, or a mixture thereof.
15 According to the embodiment of the present invention, the solution 1 may be
prepared by using isopropanol as solvent and the solution 2 may be prepared by using
methanol as solvent. In this case, the volumetric ratio between isopropanol and
methanol may be 1:1-5, more particularly 1:1-3.
According to the embodiment of the present invention, the mixing in the step
20 (a) may be carried out at a temperature of 20-60ºC, particularly 20-50ºC, more
particularly 20-35ºC.
According to the embodiment of the present invention, the cooling of the step
(b) may be carried out at a temperature of 0-10ºC.
According to the embodiment of the present invention, filtration and drying
25 steps may be additionally carried out following cooling in the step (b) to obtain a solid
crystalline form of (+)-Cibenzoline succinate.
According to the embodiment of the present invention, the mixing of step (a)
25
may be carried out for 5 minutes or more, and the duration of stirring may differ
depending on the scale of reaction, but it can be stirred for 10 minutes, 20 minutes,
30 minutes, and 1 hour.
According to the embodiment of the present invention, the cooling of step (b)
5 may be carried out for 1 hour or more, and the duration of stirring may differ
depending on the scale of reaction but it can be stirred for 2 hours, 3 hours, 4 hours,
and 5 hours.
The fifth embodiment of the present invention provides a process for the preparation
10 of a crystalline form of (+)-Cibenzoline succinate of formula (I).
According to the embodiment of the present invention, the process for the
preparation of a crystalline form of (+)-Cibenzoline succinate including the following
steps of:
a’) reacting (+)-Cibenzoline free base with succinic acid in the presence of a
15 straight or branched C1-C5 alcohol to prepare a resultant mixture, and
b’) cooling the resultant mixture to obtain solid (+)-Cibenzoline succinate.
According to the embodiment of the present invention, the straight or
branched C1-C5 alcohol may be methanol, ethanol, straight or branched propanol,
straight or branched butanol, straight or branched pentanol, or a mixture thereof, more
20 particularly methanol, ethanol, straight or branched propanol, or a mixture thereof,
even more particularly methanol, straight or branched propanol, or a mixture thereof.
According to the embodiment of the present invention, the straight or
branched C1-C5 alcohol may be isopropanol and methanol. The volumetric ration
between isopropanol and methanol may be 1:1-5, more particularly 1:1-3 even more
25 particularly, 2:1.
According to the embodiment of the present invention, the mixing in the step
(a’) may be carried out at a temperature of 20-60ºC, more particularly 20-50ºC, even
more particularly 20-35ºC at room temperature.
According to the embodiment of the present invention, the cooling of the step
30 (b’) may be carried out at a temperature of 0-10ºC and the cooling forms a solid form
of Cibenzoline succinate crystalline form.
According to the embodiment of the present invention, filtration and drying
steps may be additionally carried out following cooling in the step (b’) to obtain a
solid Cibenzoline succinate crystalline form.
26
According to the embodiment of the present invention, the mixing of step (a’)
may be carried out for 5 or more minutes, and the duration of stirring may differ
depending on the scale of reaction but it can be stirred for 10 minutes, 20 minutes, 30
minutes, and 1 hour.
5 According to the embodiment of the present invention, the cooling of step (b’)
may be carried out for 1 or more hours, and the duration of stirring may differ depending
on the scale of reaction but it can be stirred for 2 hours, 3 hours, 4 hours, and 5 hours.
A pharmaceutical composition comprising a crystalline form of (+)-Cibenzoline
10 succinate
The sixth embodiment of the present invention provides a pharmaceutical
composition comprising an effective amount of a crystalline form of (+)-Cibenzoline
succinate of formula (I) as an active ingredient together with a pharmaceutically
15 acceptable carrier, diluent, or excipient.
The composition may be formulated into a form selected from the group
consisting of powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol,
ointment, cream, suppository, eye drop, and injection according to conventional
formulation methods recognized by those skilled in the art.
20 The composition may be effective in preventing or treating at least one disease
selected from the group consisting of heart disease, arrhythmia heart disease, and
heart failure.
The pharmaceutical composition according to embodiment of the present
invention may be formulated by using a pharmaceutically acceptable carrier
25 according to a method that can be practiced by those skilled in the art without
difficulty and prepared in a unit dosage form or supplied in a multi-dose container.
The content of additive included in the pharmaceutical composition according
to embodiment of the present invention is not specifically restricted and may be
adjusted appropriately within a scope that is conventionally applied for formulation.
30 The pharmaceutical composition according to embodiment of the present
invention may be administered to a patient in an effective amount via the various
routes, e.g., the oral route or the non-oral route. Preferably, the inventive composition
is prepared in the oral administration form such as a capsule, a tablet, a dispersion,
and a suspension.
27
The preferable dose volume and duration of the pharmaceutical composition
according to embodiment of the present invention may vary depending on a patient’s
weight, age, gender, health condition, diet, administration time, administration
method, administration duration or interval, excretion rate, constitutional specificity,
5 the property of formulation, and the severity of disease and be selected appropriately
by those skilled in the art.
The process details of the invention are provided in the examples given below, which
are provided by way of illustration only and therefore should not be construed to limit
10 the scope of the invention.
EXPERIMENTAL PROCEDURE:

15
1. Chiral purity (HPLC) analysis
Chiral purity (e.e) of the prepared compound was measured by high-performance
liquid chromatography (HPLC) with measurement conditions as below.
[Table 2]
HPLC condition
Column Chiralpak IC, 250 X 4.6mm, 5µm, column temperature: 35°C.
Mobile
phase
a mixture of n-Hexane, Isopropyl alcohol, Ethanol and Diethyl amine
in the ratio of 80:10:10:0.1 (v/v/v/v)
flow rate 0.8 mL / min.
detection 220 nm.
Instrument
details
System make: Shimadzu. LC-2030C, i-services.
20
2. 1H NMR and 13C NMR analysis
The nuclear magnetic resonance spectrum of (+)-Cibenzoline succinate was obtained
by using Bruker advance-III FT-NMR. 1H NMR was measured at 400 MHz (in
DMSO-D6) and 13C NMR was measured at 400 MHz (in CD3OD).
25
3. IR analysis
IR analysis of (+)-Cibenzoline succinate was performed on a PerkinElmer spectrum
FT-IR spectrophotometer. IR spectrum was recorded by using a KBr disc.
28
4. Mass spectral analysis
Mass spectral analysis of (+)-Cibenzoline succinate was performed on an Agilent
LCQ Fleet Thermo-ion trap mass spectrometer with Electro Spray Ionization (ESI).
5 5. UV-Visible spectroscopy analysis
UV-visible spectroscopy analysis of (+)-Cibenzoline succinate was performed by
using a UV visible spectrophotometer of Perkin-Elmer (model Lambda 25). A
solution of 10 μg/ml was prepared by dissolving (+)-Cibenzoline succinate in
methanol as solvent and scanned from 200nm to 400nm.
10
6. Specific Optical Rotation Analysis
Specific optical rotation analysis of a (+)-Cibenzoline succinate solution whose
concentration is 1.401g/100ml (in methanol) was performed on Agilent Autopol V,
Serial #81225 at room temperature.
15

Example 01:
Preparation of (±)-Cibenzoline free base:
20 A suspension of (±)-Cibenzoline succinate (50 g) was stirred in water (200 ml) and
basified with 10% sodium hydroxide solution to pH 10.5-10.8 over 30 minutes at 25-
30ºC and extracted with ethyl acetate (400 ml). The obtained organic layer was dried
over anhydrous sodium sulphate, followed by concentration under reduced pressure
(400- 20 mm of Hg) at below 45°C to afford a white solid as (±)-Cibenzoline free base
25 (30 g).
[Chiral purity measured by chiral HPLC: mixture of (-)-Cibenzoline 48.76% and (+)-
Cibenzoline 51.24%]
Example 02:
30 Preparation of (+) Cibenzoline-L- tartrate:
(±)-Cibenzoline free base (15.0 g, Example 1) was dissolved in acetonitrile (250 ml),
stirred at 25-30°C for 15 min and then added L-(+)-tartaric acid (1.0 m. eq.) solution in
water (30 ml) over a period of 20 min at 25-30°C. The resultant mixture was stirred for
30 min, followed by addition of methyl tert butyl ether (MTBE, 250 ml) over a period
29
of 20 min and then stirred for 2.5 hours at room temperature. The reaction mixture was
heated to 50-55°C and stir for 1 hour and then allowed to cool at 25-30°C and stir for 1
hour. The obtained solid was filtered and washed with acetonitrile (22.5 ml) to afford
(+)-Cibenzoline-L-tartrate salt (6.1 g) with 99.0% chiral purity measured by chiral
5 HPLC. (yield: 39(w/w)%)
1H-NMR (400 MHz, DMSO-D6): 9.31 (s, 2H), 7.4 (m, 2H), 7.3 (m,7H), 7.2 (m, 1H),
3.77 (s, 1H), 3.62 (m, 2H), 3.41 (m, 2H), 2.75 (t, 1H), 2.37 (t, 1H), 1.82 (t, 1H) ppm.
10 Example 03:
Preparation of (+) Cibenzoline free base:
(+)-Cibenzoline-L-tartrate salt (5.5 g, example 2) was added in water (27.5 ml) and
basified with saturated sodium bicarbonate solution (55 ml) at 25-30ºC and extracted
with dichloromethane (220 ml). The extracted dichloromethane layer was dried over
15 anhydrous sodium sulphate and followed by distillation under reduced pressure (500-
20 mm of Hg) at below 40°C to get the semisolid as a (+)-Cibenzoline free base (3.3 g)
with [α]D +155.7 and 99.49% chiral purity measured by chiral HPLC.
Example 04:
20 Preparation of (+) Cibenzoline Succinate:
(+)-Cibezoline base (10 g, example 3) was dissolved in isopropanol (100 ml) and stirred
at 50-55°C, followed by addition of succinic acid (1.0 m. eq.) solution in methanol (50
ml) over a period of 10 min and then stirred at 25-30°C for 30 min, allowed to cool at
0-5°C for 1.5 hours. The resultant white solid was filtered, washed with isopropanol (15
25 ml) and then dried at 40-45°C under vacuum to afford pure (+)-Cibezoline Succinate
(11 g) with 99.9% chiral purity measured by chiral HPLC (Fig. 2).
1H-NMR (400 MHz, CD3OD): 7.39 (m, 2H), 7.29 (m, 7H), 7.20 (m, 1H), 3.58 (m, 2H),
3.37 (m, 2H), 2.70 (t, 1H), 2.34 (t, 1H), 2.24 (s, 4H), 1.79 (t, 1H) ppm.
13 30 C-NMR (100 MHz, CD3OD): 179.31, 170.72, 144.70, 139.84, 130.75, 129.85, 129.73,
128.94, 128.71, 128.24, 45.50, 42.50, 32.98, 23.12, 20.10 ppm.
IR (cm−1): 1675.44 (Acid C=O stretching vibration), 2925.1 (Sp3 C-H stretching
vibration)
m/z of (-)-Cibenzoline: 263.35(theoretical), 263.29(observed)
35 UV absorption: 0.9171 absorption at 202.7 nm
Specific Optical Rotation: [α]D +132.17; Rotation +VE.
30
Example 05:
Preparation of (±) Cibenzoline-D-Tartrate salt:
(±)-Cibenzoline free base (17.0 g, Example 1) was dissolved in acetonitrile (280 ml),
5 stirred at 25-30°C for 15 min and then added D-(-) tartaric acid (1.0 m. eq.) solution in
water (40 ml) over a period of 10-15 min at 25-30°C and stir for 30 min, further added
methyl tertiary butyl ether (265 ml) over a period of 20 min and stirred mixture for 2.5
hours at the same temperature. The obtain mixture was heated to 50-55°C for 1.5 hours
and allow to cool at 25-30°C stir for 1 hour at same temperature. The resultant solid was
10 filtered and washed with acetonitrile (42 ml) to afford of (-)-Cibenzoline-D-tartrate (6.5
g) with 99% purity by chiral HPLC and then filtrate was distilled out under reduced
pressure to get the oil residue of (±)-Cibenzoline-D-Tartrate salt
[In which content mixture of ~70% (+)-Cibenzoline-D-Tartrate salt and ~30% (-)-
Cibenzoline-D-Tartrate salt]
15
Example 06:
Preparation of (±) Cibenzoline free base:
(±)-Cibenzoline-D-Tartrate salt (70g, Example 5) was added in water (250 ml) and
20 basified with saturated aqueous sodium bicarbonate solution (400 ml) over 30 minutes
then extracted with dichloromethane (770 ml). The extracted dichloromethane layer was
dried over anhydrous sodium sulphate and followed by distillation under reduced
pressure (500- 20 mm of Hg) at below 40°C to get the semisolid of (±)-Cibenzoline free
base (43.0 g).
25
Example 07:
Preparation of (+)-Cibenzoline-L-tartrate Salt:
(±)-Cibenzoline free base (40 g, example 6) was dissolved in acetonitrile (670 ml) and
stirred at 25-30°C for 15 min, followed by addition of one molar equivalent aqueous L30 (+)-tartaric acid (80 ml) over a period of 15 min at 25-30°C. The resultant solution was
stir for 30 min and then added methyl tert butyl ether (670 ml) over a period of 20 min,
stirred for 2.5 hours at room temperature. The obtained mixture was heated to 50-55°C,
stir for 1 hour and then allowed to cool at 25-30°C. The resultant solid was filtered and
31
washed with acetonitrile (60 ml) to afford of (+)-Cibenzoline-L-tartrate salt (25 g) with
90-99% chiral purity measured by chiral HPLC.
Example 08:
5 Purification of (+)-Cibenzoline-L-tartrate Salt:
A suspension of crude (+)-Cibenzoline-L-tartrate salt (10.0 g, example 7) in mixture of
acetonitrile (55 ml) and water (6.5 ml) at 50-55°C, followed by addition of methyl tertbutyl ether (55 ml) and stir for 30 minutes. The resultant suspension was allowed to cool
at 25-30°C. The obtained solid was filtered, washed with mixture of (1:1) acetonitrile:
10 methyl tert-butyl ether (12.2 ml), water (0.8 ml) and dried at 45-50°C to afford the pure
(+)-Cibenzoline-L-tartrate Salt (9.3 g) with ≥ 99% chiral purity measured by Chiral
HPLC.
Example 09:
15 Preparation of (+)-Cibenzoline free base:
(+)-Cibenzoline-L-tartrate salt (20 g, example 7 or 8) was added in water (100 ml) and
basified with saturated sodium bicarbonate solution (200 ml) and extracted with
dichloromethane (420 ml). The extracted layer was dried over anhydrous sodium
sulphate and followed by distillation to get the semisolid as a (+)-Cibenzoline free base
20 (12.5 g) with ≥99% chiral purity measured by chiral HPLC.
Example 10:
Preparation of (+)-Cibenzoline Succinate:
A solution of (+)-Cibezoline free base (10 g, example 9) in isopropanol (100 ml), was
25 stirred at 50-55°C, followed by addition of succinic acid (1.0 m. eq.) solution in
methanol (50 ml) over a period of 10 min and then stirred at 25-30°C for 30 min, allowed
to cool at 0-5°C for 1 hours. The resultant white solid was filtered and dried at 40-45°C
under vacuum to afford pure (+)-Cibenzoline Succinate (13.9g) with ≥99% chiral purity
measured by chiral HPLC.
30
32

Experimental example 1: X-ray powder diffraction (XRPD) analysis
The X-ray powder diffraction (XRPD) pattern of (+)-Cibenzoline succinate of Example
5 4 was measured under below conditions and the results are presented in Figure 1.
[Table 3]
XRPD condition
Start 2.000
End 49.998
Step Size 0.018
Time per Step (sec/step) 92.40
Temperature 25 ℃ (Room)
Goniometer Radius 141.0
2-theta (°) 2.000
Theta (°) 1.000
Phi 0.00
Anode Cu
ka1 1.54060
ka2 1.54439
ka2 Ratio 0.50000
kß 1.39222
Generator kV 30.0
Generator mA 10.0
Detector Name LynxEye
PSD Opening 5.015
Sample rotation speed 15.000
Divergence Slit n.a
Anliscatter Slit n.a.
SUt Mode n.a.
X-Offset 0.000
Displacement 0.000
Y-Scale Factor 1
Y-Offset 0
Humidity n.a.
Curvature 1.000
As shown in Figure 1, (+)-Cibenzoline succinate of Example 4 has an XRPD pattern
with peaks at specific 2θ values and is therefore the crystalline form.
10
Experimental example 2: Long-term storage stability test
Long-term storage stability of the crystalline form of (+)-Cibenzoline succinate of
Example 4 was tested under long-term storage conditions. And related substances was
measured under by HPLC below conditions.
33
[Table 4]
Related substances by HPLC (% w/w):
Instrumentation:
a) A High Performance Liquid Chromatography system with gradient elution
capability, a Spectrophotometric UV detector and an auto sampler (Waters
Alliance 2695 separations module, Waters 2487 dual  absorbance detector or
equivalent).
b) Data handling system (Waters Empower work station or equivalent).
Column Imtakt Unison UK-Phenyl, 250 x 4.6 mm, 3.0 m
Flow rate 1.0 mL / min
UV Detector 230 nm
Buffer 10 mm Potassium dihydrogen orthophosphate (KH2PO4) in to 1000
mL of water ph 4.5.
Mobile phase-A Buffer
Solution-A Transfer about 1 mL of Orthophosphoric acid (~85%) in to a 1000
mL of Acetonitrile and mix well.
Mobile phase-B Prepare a degassed mixture of Solution-A and Water in the ratio of
70:30 (v/v)
Diluent Prepare a degassed mixture of Acetonitrile and Water in the ratio of
50:50 (v/v)
< Packing details>
5 - Primary packing: (+)-Cibenzoline succinate obtained by Example 4 shall be packed in
transparent LDPE bag, twist and tie with Strip seal.
- Secondary packing: The above bag shall be kept in Black color LDPE bag, twist and
tie with Strip seal.
- Tertiary packing: The above bag shall be kept Triple laminated aluminum bag with
10 heat seal. Keep this bag in HDPE drum and close with lid.
Specifically, the crystalline form of Example 4 was packed in three levels and subjected
to the test at a temperature of 25±2 °C and a relative humidity of 60±5%. The results are
provided in Table 5.
15
34
[Table 5]
Parameter Specific
ation
Initial 1-
month
2-
month
3-
month
6-
month
Description
A White
to offwhite
crystalli
ne
powder
A
White
crystall
ine
powder
A
White
crystall
ine
powder
A
White
crystall
ine
powder
A
White
crystall
ine
powder
A
White
crystall
ine
powder
Identification by IR
The
infrared
absorpti
on peaks
observe
d at
1674
±5cm-1
and
2954
±5cm-1
Compli
es
Compli
es
Compli
es
Compli
es
Compli
es
Loss on drying at 105℃
for 3 hours(% w/w)
Not
more
than
0.50
0.11 0.03 0.09 0.11 0.11
Assay by potentiometry
(% w/w, on dried basis)
Not less
than
98.0 and
not
more
than
102.0
100.7 100.4 98.9 100.5 100.2
Chiral purity by HPLC
(% Area normalization)
R-Isomer Content
Not less
than
99.0
99.9 99.9 99.9 99.8 99.9
Related
Substance
by HPLC(%
w/w)
Any other
individual
impurity
Not
more
than
0.15
0.01
Not
detecte
d
Not
detecte
d
Not
detecte
d
0.01
Total
impurity
Not
more
than
0.50
0.01
Not
detecte
d
Not
detecte
d
Not
detecte
d
0.01
5
35
As shown in Table 5, a white crystalline powder form was uniformly maintained for six
months under long-term storage conditions.
With respect to the loss on drying at 105°C for 3 hours, the loss rate (%w/w) at the initial
stage was 0.11%, which is less than 0.5%. After 1-6 months under long-term storage
5 conditions, the loss rate after drying at 105°C for 3 hours was on a similar level as
observed at the initial stage.
The (R)-form ((+)-Cibenzoline) of Example 4 was not changed to (S)-form ((-)-
Cibenzoline) under long-term storage conditions and stably maintained, demonstrating
a remarkably excellent stability.
10 In addition, as confirmed from the potentiometry analysis results, it was measured
between equal to or more than 98% and 102% at the initial stage and even after storing
for 1-6 months, demonstrating that the initial level was maintained.
Impurities were nearly not detected under long-term storage conditions, demonstrating
that the crystalline form of (+)-Cibenzoline succinate according to Example 4
15 maintained high purity with no change even under long-term storage conditions and
therefore had an excellent stability.
Experimental example 3: Accelerated stability test
Accelerated stability of the crystalline form of (+)-Cibenzoline succinate of Example 4
20 was tested under accelerated test conditions. And related substances was measured by
HPLC under below conditions.
[Table 6]
Related substances by HPLC (% w/w):
Instrumentation:
c) A High Performance Liquid Chromatography system with gradient elution
capability, a Spectrophotometric UV detector and an auto sampler (Waters
Alliance 2695 separations module, Waters 2487 dual  absorbance detector or
equivalent).
d) Data handling system (Waters Empower work station or equivalent).
Column Imtakt Unison UK-Phenyl, 250 x 4.6 mm, 3.0 m
Flow rate 1.0 mL / min
UV Detector 230 nm
36
Buffer 10 mm Potassium dihydrogen orthophosphate (KH2PO4) in to 1000
mL of water ph 4.5.
Mobile phase-A Buffer
Solution-A Transfer about 1 mL of Orthophosphoric acid (~85%) in to a 1000
mL of Acetonitrile and mix well.
Mobile phase-B Prepare a degassed mixture of Solution-A and Water in the ratio of
70:30 (v/v)
Diluent Prepare a degassed mixture of Acetonitrile and Water in the ratio of
50:50 (v/v)
< Packing details>
- Primary packing: (+)-Cibenzoline succinate obtained by Example 4 shall be packed
in transparent LDPE bag, twist and tie with Strip seal.
5 - Secondary packing: The above bag shall be kept in Black color LDPE bag, twist
and tie with Strip seal.
- Tertiary packing: The above bag shall be kept Triple laminated aluminum bag with
heat seal. Keep this bag in HDPE drum and close with lid.
10 Specifically, the crystalline form of Example 4 was packed in three levels and subjected
to the test at a temperature of 40±2 °C and a relative humidity of 75±5%. The results are
provided in Table 7.
[Table 7]
Parameter Specific
ation
Initial 1-
month
2-
month
3-
month
6-
month
Description
A White
to offwhite
crystalli
ne
powder
A
White
crystall
ine
powder
A
White
crystall
ine
powder
A
White
crystall
ine
powder
A
White
crystall
ine
powder
A
White
crystall
ine
powder
Identification by IR
The
infrared
absorpti
on peaks
observe
d at
1674
±5cm-1
Compli
es
Compli
es
Compli
es
Compli
es
Compli
es
37
and
2954
±5cm-1
Loss on drying at 105℃
for 3 hours(% w/w)
Not
more
than
0.50
0.11 0.06 0.08 0.12 0.08
Assay by potentiometry
(% w/w, on dried basis)
Not less
than
98.0 and
not
more
than
102.0
100.7 100.4 98.8 100.8 100.2
Chiral purity by HPLC
(% Area normalization)
R-Isomer Content
Not less
than
99.0
99.9 99.9 99.9 99.8 99.9
Related
Substance
by HPLC(%
w/w)
Any other
individual
impurity
Not
more
than
0.15
0.01 0.01
Not
detecte
d
Not
detecte
d
0.01
Total
impurity
Not
more
than
0.50
0.01 0.03
Not
detecte
d
Not
detecte
d
0.01
As shown in Table 7, a white crystalline powder form was uniformly maintained for six
months under accelerated conditions.
With respect to the loss on drying at 105°C for 3 hours, the loss rate at the initial stage
5 was 0.11% which is less than 0.5%. After 1-6 months under accelerated conditions, the
loss rate after drying at 105°C for 3 hours was on a similar level as observed at the initial
stage.
The (R)-form ((+)-Cibenzoline) of Example 4 was not changed to (S)-form ((-)-
Cibenzoline) under long-term storage conditions and stably maintained, demonstrating
10 a remarkably excellent stability.
As confirmed from the potentiometry analysis results, it was measured between equal
to or more than 98% and 102% at the initial stage and even after storing for 1-6 months,
demonstrating that the initial level was maintained.
Impurities were nearly not detected under accelerated conditions, demonstrating that the
15 crystalline form of (+)-Cibenzoline succinate according to according to Example 4
maintained high purity with no change even under accelerated conditions and therefore
had an excellent stability.
38
We Claim:
1. (+)-Cibenzoline·chiral acid salt of formula (IV).
HN
N
Formula (IV)
. Chiral acid salt
(+)-Cibenzoline Chiral aicd salt
wherein the suitable chiral acid is one selected from the group consisting of L5 (+)-Tartaric acid, D-(−)-Tartaric acid, (R)-(−)-Mandelic acid, (S)-(+)-Mandelic
acid, Dibenzoyl-L-tartaric acid, (+)-2,3-Dibenzoyl-D-tartaric acid, (−)-O,O′-
Dibenzoyl-L-tartaric acid monohydrate, (+)-O,O-Dibenzoyl-D-tartaric acid
monohydrate, (−)-O,O′-Dibenzoyl-L-tartaric acid mono(dimethylamide), Di-ptoluoyl-D-tartaric acid monohydrate, Di-p-toluoyl-L-tartaric acid monohydrate,
10 (−)-O,O′-Di-p-toluoyl-L-tartaric acid, (+)-O,O′-Di-p-toluoyl-D-tartaric acid, (+)-
O,O′-Di-p-toluoyl-D-tartaric acid, D-Glutamic acid, L-Glutamic acid, L-(−)-
Malic acid, D-(+)-Malic acid, (−)-Menthyloxyacetic acid, (+)-Menthyloxyacetic
acid, (R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid, (S)-(−)-α-Methoxyα-trifluoromethylphenylacetic acid, (R)-(−)-5-Oxo-2-tetrahydrofurancarboxylic
15 acid, (S)-(+)-5-Oxo-2-tetrahydrofurancarboxylic acid, (R)-(+)-N-(1-
Phenylethyl)phthalamic acid, (S)-(−)-N-(1-Phenylethyl)phthalamic acid, (R)-(−)-
2-Phenylpropionic acid, (S)-(+)-2-Phenylpropionic acid, L-Pyroglutamic acid, DPyroglutamic acid, D-(−)-Quinic acid, L-(+)-Quinic acid, L-Aspartic acid, DAspartic acid, (R)-1,4-Benzodioxane-2-carboxylic acid, (S)-1,4-Benzodioxane-2-
20 carboxylic acid, N,N-Bis[(S)-(−)-1-phenylethyl]phthalamic acid, N,N-Bis[(R)-
(+)-1-phenylethyl]phthalamic acid, (1S)-(+)-3-Bromocamphor-10-sulfonic acid
hydrate, (1R)-(-)-3-Bromocamphor-10-sulfonic acid hydrate, (1S)-(−)-
Camphanic acid, (1R)-(+)-Camphanic acid, (1R,3S)-(+)-Camphoric acid,
(1S,3R)-(−)-Camphoric acid, (1R)-(−)-10-Camphorsulfonic acid, and (1S)-(+)-
25 10-Camphorsulfonic acid.
.
39
2. A process for the preparation of enantiomerically pure (+)-Cibenzoline succinate of
formula (I),
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
which comprises the steps of:
5 a) treating the racemic Cibenzoline succinate of formula (II) with a suitable base to
produce the racemic Cibenzoline free base of formula (III);
HN
N
Formula (III)
HN
N
O
HO
OH
O
Formula (II)
b) treating the racemic Cibenzoline free base of formula (III) with a suitable chiral
acid in the presence of suitable solvent to obtain the racemic Cibenzoline·chiral
10 acid salt of formula (IIIA);
c) isolating (+)-Cibenzoline·chiral acid salt of formula (IV);
40
HN
N
Formula (IV)
. Chiral acid salt
(+)-Cibenzoline Chiral aicd salt
d) neutralizing the (+)-Cibenzoline·chiral acid salt of formula (IV) with a suitable
base to produce the (+)-Cibenzoline free base of formula (V); and
HN
N
Formula (V)
(+)-Cibenzoline
5 e) treating the (+)-Cibenzoline free base of formula (V) with succinic acid in
presence of suitable solvent to produce (+)-Cibenzoline succinate of formula (I).
3. The process as claimed in claim 2, wherein the suitable chiral acid is one selected
from the group consisting of L-(+)-Tartaric acid, D-(−)-Tartaric acid, (R)-(−)-
10 Mandelic acid, (S)-(+)-Mandelic acid, Dibenzoyl-L-tartaric acid, (+)-2,3-
Dibenzoyl-D-tartaric acid, (−)-O,O′-Dibenzoyl-L-tartaric acid monohydrate, (+)-
O,O-Dibenzoyl-D-tartaric acid monohydrate, (−)-O,O′-Dibenzoyl-L-tartaric acid
mono(dimethylamide), Di-p-toluoyl-D-tartaric acid monohydrate, Di-p-toluoyl-Ltartaric acid monohydrate, (−)-O,O′-Di-p-toluoyl-L-tartaric acid, (+)-O,O′-Di-p15 toluoyl-D-tartaric acid, (+)-O,O′-Di-p-toluoyl-D-tartaric acid, D-Glutamic acid, LGlutamic acid, L-(−)-Malic acid, D-(+)-Malic acid, (−)-Menthyloxyacetic acid, (+)-
Menthyloxyacetic acid, (R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid,
(S)-(−)-α-Methoxy-α-trifluoromethylphenylacetic acid, (R)-(−)-5-Oxo-2-
tetrahydrofurancarboxylic acid, (S)-(+)-5-Oxo-2-tetrahydrofurancarboxylic acid,
20 (R)-(+)-N-(1-Phenylethyl)phthalamic acid, (S)-(−)-N-(1-Phenylethyl)phthalamic
41
acid, (R)-(−)-2-Phenylpropionic acid, (S)-(+)-2-Phenylpropionic acid, LPyroglutamic acid, D-Pyroglutamic acid, D-(−)-Quinic acid, L-(+)-Quinic acid, LAspartic acid, D-Aspartic acid, (R)-1,4-Benzodioxane-2-carboxylic acid, (S)-1,4-
Benzodioxane-2-carboxylic acid, N,N-Bis[(S)-(−)-1-phenylethyl]phthalamic acid,
5 N,N-Bis[(R)-(+)-1-phenylethyl]phthalamic acid, (1S)-(+)-3-Bromocamphor-10-
sulfonic acid hydrate, (1R)-(-)-3-Bromocamphor-10-sulfonic acid hydrate, (1S)-(−)-
Camphanic acid, (1R)-(+)-Camphanic acid, (1R,3S)-(+)-Camphoric acid, (1S,3R)-
(−)-Camphoric acid, (1R)-(−)-10-Camphorsulfonic acid, and (1S)-(+)-10-
Camphorsulfonic acid.
10
4. The process as claimed in claim 2, wherein the suitable base is selected from an
inorganic base like alkali metal hydroxides, such as sodium hydroxide, lithium
hydroxide or potassium hydroxide and the like, or alkali metal carbonates, such as
cesium carbonate, sodium carbonate, potassium carbonate or lithium carbonate and
15 the like, or alkali metal bicarbonates such as sodium bicarbonate or potassium
bicarbonate and the like or mixtures thereof
5. The process as claimed in claim 2, wherein the suitable solvent is selected from
alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol
20 and the like, or esters, such as ethylacetate, methylacetate, butyl acetate, isopropyl
acetate, methoxy ethyl acetate and the like, or aliphatic hydrocarbons, such as
heptane, hexane and the like, or ketones, such as acetone, methyl isobutyl ketone, 2-
pentanone, ethylmethylketone, diethylketone and the like, or aromatic hydrocarbons,
such as benzene, toluene, xylene, chlorobenzene and the like, or halogenated
25 hydrocarbons, such as chloroform, dichloromethane and the like, or ethers, such as
methyl tert-butyl ether, diethyl ether, tetrahydrofuran, dioxane and the like, or
aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile
or water and or mixtures thereof.
30
6. A crystalline form of (+)-Cibenzoline succinate of formula (I).
42
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
7. The crystalline form of (+)-Cibenzoline succinate as claimed in claim 6, wherein the
crystalline form has an X-ray powder diffraction (XRPD) pattern including
5 diffraction peaks at 11.1°, 12.9°, 14.1°, 14.6°, 23.0°, and 24.2° (2θ±0.2°).
8. The crystalline form of (+)-Cibenzoline succinate as claimed in claim 7, wherein the
crystalline form has the XRPD pattern further including one or more diffraction
peaks selected from the group consisting of 22.1°, 22.6°, 23.1°, and 26.0° (2θ±0.2°).
10
9. The crystalline form of (+)-Cibenzoline succinate as claimed in claim 8, wherein the
crystalline form has an XRPD pattern including diffraction peaks at 9.53°, 11.14°,
12.83°, 14.09°, 14.62°, 16.07°, 17.29°, 18.11°, 19.24°, 21.31°, 22.42°, 22.08°,
22.60°, 22.97°, 23.09°, 24.21°, 25.37°, 25.96°, 26.31°, and 27.59° (2θ).
15
10. A process for the preparation of a crystalline form of (+)-Cibenzoline succinate,
which comprises the steps of:
a’) reacting (+)-Cibenzoline free base of Formula (V) with succinic acid in
the presence of a straight or branched C1-C5 alcohol to prepare a resultant
20 mixture; and
HN
N
Formula (V)
(+)-Cibenzoline
43
b’) cooling the resultant mixture to obtain solid (+)-Cibenzoline succinate of
Formula (I).
HN
N
O
HO
OH
O
Formula (I)
(+)-Cibenzoline succinate
5 11. The process as claimed in claim 10, wherein the straight or branched C1-C5 alcohol
is one or more selected from the group consisting of methanol, ethanol, straight or
branched propanol, straight or branched butanol, or straight or branched pentanol.
12. The process as claimed in claim 10, wherein the reaction is carried out at a
10 temperature of 20-60ºC in the step (a’).
13. The process as claimed in claim 10, wherein the cooling is carried out at a
temperature of 0-10ºC in the step (b’).
15 14. A pharmaceutical composition comprising the crystalline form of (+)-Cibenzoline
succinate as claimed in any one of claims 6 to 9 as an active ingredient together with
a pharmaceutically acceptable carrier, diluent, or excipient.
15. The composition of claim 14, which is of the form of a capsule or a tablet for oral
20 administration.
Dated this Twelfth (12th) day of August, 2019
Sridhar Prasangi (IN/PA 2608)
25 General Manager-IPM
Optimus Drugs (P) Ltd