WO2020067683A1

WO2020067683A1 - Novel process for the preparation of (+)-cibenzoline succinate

Info

Publication number: WO2020067683A1
Application number: PCT/KR2019/012267
Authority: WO
Inventors: Srinivas Reddy Desi Reddy; Vijayavitthal Thippannachar Mathad; Dnyandev Ragho Rane; Vikas Shivaji Patil
Original assignee: Celltrion Inc.
Priority date: 2018-09-28
Filing date: 2019-09-20
Publication date: 2020-04-02

Abstract

The present invention relates to a crystalline form of (+)-Cibenzoline succinate. The present invention is also related to a process for the preparation of (+)-Cibenzoline succinate with chiral purity greater than 99.9%. The present invention also provides a process for the preparation of (+)-Cibenzoline succinate and a crystalline form thereof.

Description

NOVEL PROCESS FOR THE PREPARATION OF (+)-CIBENZOLINE SUCCINATE

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%.

The present invention also provides a process for the preparation of (+)-Cibenzoline succinate and a crystalline form thereof.

Cibenzoline succinate (Racemic) is chemically known as (±)-2-(2,2-diphenylcyclopropyl)-2-imidazoline succinate with its structure (formula II). It was developed and marketed as Cipralan ^® by Bristol-Myers Squibb (BMS) and Exacor ^® 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 May;70(5):588-92).

Enantiomerically, each (-)-Cibenzoline salt and (+)-Cibenzoline salt, for example the crystalline forms thereof are not known anywhere. For example, the crystalline forms 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; 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 (NaClO ₂), hydrogen peroxide (H ₂O ₂), and sodium dihydrogen phosphate (NaH ₂PO ₄) in acetonitrile-water (MeCN-H ₂O) to give acid compound of formula (VIII), further it was condensed with ethylenediamine (H ₂NCH ₂CH ₂NH ₂) in the presence of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and triethylamine (Et ₃N) in dichloromethane (CH ₂Cl ₂) to give the corresponding amide compound of formula (IX). Finally, the amide of formula (IX) was converted under reduced pressure (2 mmHg) at 160℃ for 37 hours to obtain (+)-Cibenzoline.

The said synthetic process is illustrated in the following Scheme-I.

Scheme-I

Tetrahedron: Asymmetry (2009), 20(17), 2065-2071 discloses a process for the preparation of (+)-Cibenzoline and it was synthesized from (+)-2,2-diphenylcyclopropylmethanol formula (VI) as follows; compound of formula (VI) with 76% enantiomeric excess (ee) was reacted with compound of formula (X) in triethylamine (Et ₃N), 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 (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 (I ₂), potassium carbonate (K ₂CO ₃) in tert-butyl alcohol (tBuOH) to obtain (+)-Cibenzoline.

The said synthetic process is illustrated in the following Scheme-II.

Scheme-II

The advantages of enantiomerically pure drugs use can potentially lead to simpler and more selective pharmacologic profiles, improved therapeutic indices, simpler 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.

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 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 some cases. These demands of pure enantiomers Cibenzoline succinate for the clinical studies are followed by commercial supply. Thus, we felt a need to develop industrially 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 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 (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 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. 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.

The present disclosure provides a novel (+)-Cibenzoline·chiral acid salt of formula (IV).

The present disclosure provides a novel process for the preparation of (+)-Cibenzoline succinate of formula (I) with high yield and purity.

The present disclosure provides a crystalline form of (+)-Cibenzoline succinate of formula (I).

The present disclosure provides a process for the preparation of a crystalline form of (+)-Cibenzoline succinate of formula (I).

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).

The present disclosure relates to a crystalline form of (+)-Cibenzoline succinate and a process for the preparation thereof

The one embodiment of the present invention provides a novel of (+)-Cibenzoline·chiral acid salt of formula (IV).

The second embodiment of the present invention provides a novel process for the preparation of enantiomerically pure (+)-Cibenzoline succinate of formula (I),

which comprises the steps of:

a)treating the racemic Cibenzoline succinate of formula (II) with a base to produce the racemic Cibenzoline free base of formula (III);

b)treating the racemic Cibenzoline free base of formula (III) with a chiral acid in the presence of solvent to obtain racemic Cibenzoline·chiral acid salt of formula (IIIA);

c)isolating the (+)-Cibenzoline·chiral acid salt of formula (IV);

d)neutralizing the (+)-Cibenzoline·chiral acid salt of formula (IV) with a base to produce the (+)-Cibenzoline free base of formula (V); and

e)treating the (+)-Cibenzoline free base of formula (V) with succinic acid in presence of solvent to produce the (+)-Cibenzoline succinate of formula (I)

The third embodiment of the present invention provides a crystalline form of the (+)-Cibenzoline succinate of formula (I).

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.

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 (+)-Cibenzoline succinate; and

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 succinate of formula (I).

(+)-Cibenzoline succinate according to the present invention can be prepared with high chiral purity though a simple process, is affordable, and is highly advantageous in mass production.

In addition, a crystalline form of (+)-Cibenzoline succinate of the present invention has low hygroscopicity, is remarkably stable according to accelerated condition and long-term storage condition, and can be stably maintained with no change in the amount for long term. Accordingly, the crystalline form of (+)-Cibenzoline succinate of the present invention can be obtained as a raw material having high purity and can maintain its high purity and crystalline form for long term even when stored for long periods of time. Furthermore, the crystalline form of (+)-Cibenzoline succinate can be obtained with high purity and yield through a simple, affordable and industrially applicable process without requiring additional purification process.

Fig. 1 illustrates the X-ray powder diffraction pattern of a crystalline form of (+)-Cibenzoline succinate according to Example 4.

Fig. 2 illustrates high-performance liquid chromatography (HPLC) of (+)-Cibenzoline succinate according to Example 4.

A process for the preparation of (+)-Cibenzoline succinate of formula (I) by employing novel chiral acid salt of formula (IV).

The present disclosure relates to a crystalline form of (+)-Cibenzoline succinate and a process for the preparation thereof.

The one embodiment of the present invention provides a novel (+)-Cibenzoline·chiral acid salt of formula (IV),

wherein the 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-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-L-tartaric acid monohydrate, (-)-O,O'-Di-p-toluoyl-L-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-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-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 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.

which comprises the steps of:

c)isolating the (+)-Cibenzoline·chiral acid salt of formula (IV);

e)treating the (+)-Cibenzoline free base of formula (V) with succinic acid in presence of solvent to produce the (+)-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 for mass production and economical.

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) may be racemic Cibenzoline-L-tartrate salt, wherein the racemic Cibenzoline-L-tartrate 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 0-30℃ 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 chiral acid at suitable temperature in the presence of solvent to obtain the racemic Cibenzoline·chiral acid salts of formula (IIIA), wherein the temperature for the reaction is about 20- 65℃ and the reaction is carried out for 30 minutes to 6 hours.

The (+)-Cibenzoline·chiral acid salt of formula (IV) may be isolated by techniques such as filtration or centrifugation and the like.

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, centrifugation and the like.

According to the embodiment, the present invention comprises neutralizing the (+)-Cibenzoline·chiral acid salt of formula (IV) with a base to produce the (+)-Cibenzoline free base of formula (V), wherein the reaction is carried out at a temperature of 10-50℃, for 30 minutes to 5 hours.

According to the embodiment, the present invention comprises treating the (+)-Cibenzoline free base of formula (V) with succinic acid at 0-65℃ 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 solvents to get optically pure (+)-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 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-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-L-tartaric acid monohydrate, (-)-O,O'-Di-p-toluoyl-L-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-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-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 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.

According to the embodiment of the present invention, wherein the 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 potassium bicarbonate and the like or mixtures thereof.

According to the embodiment of the present invention, wherein the 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, 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 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 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

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 may be prepared in the presence of a solvent.

In embodiments of the present invention, preparing racemic Cibenzoline-L-tartrate 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

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 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.

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.

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 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 temperature of 40-60℃ after the reaction at room temperature to accelerate reaction, more particularly approximately equal to or higher than 45℃, or more particularly approximately equal to or higher than 50℃, or even more particularly approximately 50-55℃.

In embodiments of the present invention, the additional organic solvent may be 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, and 4 hours.

In embodiments of the present invention, the step of isolating (+)-Cibenzoline-L-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.

In embodiments of the present invention, the step of isolating (+)-Cibenzoline-L-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.

In embodiments of the present invention, the heating may be carried out at a temperature of approximately equal to or higher than 45℃, or more particularly approximately equal to or higher than 50℃, or even more particularly approximately 50-55℃.

In embodiments of the present invention, the isolating (+)-Cibenzoline-L-tartrate 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.

In embodiments of the present invention, the cooling may be carried out at a temperature of approximately 20-30℃, particularly approximately 25-30℃.

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 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.

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 (+)-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.

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.

The embodiment of the present invention provides a novel pharmaceutical composition comprising (+)-Cibenzoline·chiral acid salt of formula (IV) and a pharmaceutically acceptable carrier, diluent, or excipient.

Preparation of salts other than (+)-Cibenzoline succinate and (+)-Cibenzoline·chiral acid salt

A pharmaceutically acceptable salt of (+)-Cibenzoline can be prepared through a novel process for the preparation of enantiomerically pure (+)-Cibenzoline succinate of the present invention or a process regarded as identical thereto.

The above (+)-Cibenzoline · chiral acid salt comprising (+)-Cibenzoline free base, (+)-Cibenzoline succinate, and (+)-Cibenzoline-L-tartrate salt obtained by a method according to the embodiment of the present invention can prepare a pharmaceutically acceptable salt of (+)-Cibenzoline through an additional reaction.

The above "pharmaceutically acceptable salt" comprises both inorganic acid salt and organic acid salt including, for example, but not limited to, hydrochloride, sulfate, nitrate, phosphate, acetate, trifluoroacetate, benzenesulfonate, and citrate.

A crystalline form of (+)-Cibenzoline succinate and a process for the preparation thereof

The third embodiment of the present invention provides a novel crystalline form of (+)-Cibenzoline succinate of formula (I).

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°)

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 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 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 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°, 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.

(+)-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°, 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 (sp3 stretching vibration).

According to the embodiment of the present invention, the crystalline form of (+)-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-K _α or Cu-K _β radiation, more particularly, Cu-K _αradiation, even more particularly, Cu-K _α1, Cu-K _α2, Cu-K _β, or Cu-K _α1and Cu-K _α2radiation. For example, the XRPD pattern might have been be measured by using Cu-K _αradiation.

According to the embodiment of the present invention, identification by FT-IR 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.

In addition, the crystalline form of (+)-Cibenzoline succinate of the present invention may be defined in terms of additional physical properties such as solid C-NMR, a specific diffraction peak at crystal lattice plane spacing, the shape of solid crystalline form in microscopic image, or particle size of solid crystalline form in microscopic image or particle size distribution (D-value).

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 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 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 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 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).

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 (+)-Cibenzoline free base of formula (V) to prepare a mixture; and

b)cooling the mixture to prepare the crystalline form of (+)-Cibenzoline succinate of formula (I).

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).

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.

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.

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 1-5:1, more particularly 1-3:1, even more 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 20-60℃, particularly 20-50℃, more particularly 20-35℃.

According to the embodiment of the present invention, the cooling of the step b) may be carried out at a temperature of 0-10℃.

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 crystalline form of (+)-Cibenzoline succinate.

According to the embodiment of the present invention, the mixing of step a) 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) 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 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 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 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 1-5:1, more particularly 1-3:1 even more 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 20-60℃, more particularly 20-50℃, even more particularly 20-35℃ at room temperature.

According to the embodiment of the present invention, the cooling of the step b') may be carried out at a temperature of 0-10℃ 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.

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.

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 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 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.

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 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.

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.

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, 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 the scope of the invention.

EXPERIMENTAL PROCEDURE :

<Instrumental analysis and measurement condition>

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.

HPLC condition
Column	Chiralpak IC, 250 X 4.6mm, 5㎛, column temperature: 35℃.
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.

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-D ₆) and ¹³C NMR was measured at 400 MHz (in CD ₃OD).

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.

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. 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.

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.

<Example>

Example 01:

* Preparation of (±)-Cibenzoline free base:

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 25-30℃ 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 mmHg) at below 45℃ to afford a white solid as (±)-Cibenzoline free base (30 g).

[ Chiral purity measured by chiral HPLC: mixture of (-)-Cibenzoline 48.76% and (+)-Cibenzoline 51.24%]

Example 02:

Preparation of (+)-Cibenzoline-L- tartrate:

(±)-Cibenzoline free base (15.0 g, Example 1) was dissolved in acetonitrile (250 ml), stirred at 25-30℃ 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℃. The resultant mixture was stirred for 30 min, followed by addition of methyl tert butyl ether (MTBE, 250 ml) over a period of 20 min and then stirred for 2.5 hours at room temperature. The reaction mixture was heated to 50-55℃ and stir for 1 hour and then allowed to cool at 25-30℃ 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 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.

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 25-30℃ and extracted with dichloromethane (220 ml). The extracted dichloromethane layer was dried over anhydrous sodium sulphate and followed by distillation under reduced pressure (500- 20 mmHg) at below 40℃ 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:

Preparation of (+) Cibenzoline Succinate:

(+)-Cibezoline base (10 g, example 3) was dissolved in isopropanol (100 ml) and stirred at 50-55℃, 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℃ for 30 min, allowed to cool at 0-5℃ for 1.5 hours. The resultant white solid was filtered, washed with isopropanol (15 ml) and then dried at 40-45℃ under vacuum to afford pure (+)-Cibezoline Succinate (11 g) with 99.9% chiral purity measured by chiral HPLC (Fig. 2).

¹H-NMR (400 MHz, CD ₃OD): 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.

¹³C-NMR (100 MHz, CD ₃OD): 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)

UV absorption: 0.9171 absorption at 202.7 nm

Specific Optical Rotation: [α] _D +132.17; Rotation +VE.

Example 05:

Preparation of (±) Cibenzoline-D-Tartrate salt:

(±)-Cibenzoline free base (17.0 g, Example 1) was dissolved in acetonitrile (280 ml), stirred at 25-30℃ 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℃ 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℃ for 1.5 hours and allow to cool at 25-30℃ stir for 1 hour at same temperature. The resultant solid was 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]

Example 06:

Preparation of (±)-Cibenzoline free base:

(±)-Cibenzoline-D-Tartrate salt (70g, Example 5) was added in water (250 ml) and 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 mmHg) at below 40℃ to get the semisolid of (±)-Cibenzoline free base (43.0 g).

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℃ for 15 min, followed by addition of one molar equivalent aqueous L-(+)-tartaric acid (80 ml) over a period of 15 min at 25-30℃. 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℃, stir for 1 hour and then allowed to cool at 25-30℃. The resultant solid was filtered and 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:

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℃, followed by addition of methyl tert-butyl ether (55 ml) and stir for 30 minutes. The resultant suspension was allowed to cool at 25-30℃. The obtained solid was filtered, washed with mixture of (1:1) acetonitrile : methyl tert-butyl ether (12.2 ml), water (0.8 ml) and dried at 45-50℃ to afford the pure (+)-Cibenzoline-L-tartrate Salt (9.3 g) with ≥99% chiral purity measured by chiral HPLC.

Example 09:

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 (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 stirred at 50-55℃, 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℃ for 30 min, allowed to cool at 0-5℃ for 1 hours. The resultant white solid was filtered and dried at 40-45℃ under vacuum to afford pure (+)-Cibenzoline Succinate (13.9g) with ≥99% chiral purity measured by chiral HPLC.

<Experimental example>

Experimental example 1: X-ray powder diffraction (XRPD) analysis

The X-ray powder diffraction (XRPD) pattern of (+)-Cibenzoline succinate of Example 4 was measured under below conditions and the results are presented in Figure 1.

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.

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.

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 λabsorbance 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 ㎛
Flow rate	1.0 mL / min
UV Detector	230 nm
Buffer
	10 mL Potassium dihydrogen orthophosphate (KH ₂PO ₄) 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.

- 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.

Specifically, the crystalline form of Example 4 was packed in three levels and subjected to the test at a temperature of 25±2℃ and a relative humidity of 60±5%. The results are provided in Table 5.

Parameter		Specification	Initial	1-month	2-month	3-month	6-month
Description		A White to off-white crystalline powder	A Whitecrystalline powder	A Whitecrystalline powder	A Whitecrystalline powder	A Whitecrystalline powder	A White crystalline powder
Identification by IR		The infrared absorption peaks observed at 1674 ±5cm ^-1 and 2954 ±5cm ^-1	Complies	Complies	Complies	Complies	Complies
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 detected	Not detected	Not detected	0.01
Related Substance by HPLC(% w/w)	Total impurity	Not more than 0.50	0.01	Not detected	Not detected	Not detected	0.01

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℃ 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 conditions, the loss rate after drying at 105℃ 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.

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 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 was tested under accelerated test conditions. And related substances was measured by HPLC under below conditions.

< Packing details>

- 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 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 40±2℃ and a relative humidity of 75±5%. The results are provided in Table 7.

Parameter		Specification	Initial	1-month	2-month	3-month	6-month
Description		A White to off-white crystalline powder	A Whitecrystalline powder	A Whitecrystalline powder	A Whitecrystalline powder	A Whitecrystalline powder	A White crystalline powder
Identification by IR		The infrared absorption peaks observed at 1674 ±5cm ^-1 and 2954 ±5cm ^-1	Complies	Complies	Complies	Complies	Complies
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 detected	Not detected	0.01
Related Substance by HPLC(% w/w)	Total impurity	Not more than 0.50	0.01	0.03	Not detected	Not detected	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 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.

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 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.

Claims

(+)-Cibenzoline·chiral·acid salt of formula (IV):

wherein the 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-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-L-tartaric acid monohydrate, (-)-O,O'-Di-p-toluoyl-L-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-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-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 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.
A pharmaceutical composition comprising (+)-Cibenzoline·chiral acid salt of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.
A process for the preparation of enantiomerically pure (+)-Cibenzoline succinate of formula (I),

which comprises the steps of:

a)treating the racemic Cibenzoline succinate of formula (II) with a base to produce the racemic Cibenzoline free base of formula (III);

b)treating the racemic Cibenzoline free base of formula (III) with a chiral acid in the presence of solvent to obtain the racemic Cibenzoline·chiral·acid salt of formula (IIIA);

c)isolating (+)-Cibenzoline·chiral acid salt of formula (IV);

d)neutralizing the (+)-Cibenzoline·chiral acid salt of formula (IV) with a base to produce the (+)-Cibenzoline free base of formula (V); and

e)treating the (+)-Cibenzoline free base of formula (V) with succinic acid in presence of solvent to produce (+)-Cibenzoline succinate of formula (I)
The process as claimed in claim 2, wherein the 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-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-L-tartaric acid monohydrate, (-)-O,O'-Di-p-toluoyl-L-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-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-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 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 process as claimed in claim 2, wherein the 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 potassium bicarbonate and the like or mixtures thereof
The process as claimed in claim 2, wherein the 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, 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 polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile or water and or mixtures thereof.
Crystalline form of the (+)-Cibenzoline succinate of formula (I).
The crystalline form of (+)-Cibenzoline succinate as claimed in claim 6, wherein the crystalline form 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°).
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°).
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).
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 mixture; and

b') cooling the resultant mixture to obtain solid (+)-Cibenzoline succinate of Formula (I).
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.
The process as claimed in claim 10, wherein the reaction is carried out at a temperature of 20-60ºC in the step a').
The process as claimed in claim 10, wherein the cooling is carried out at a temperature of 0-10ºC in the step b').
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.
The composition of claim 14, which is of the form of a capsule or a tablet for oral administration.