(-)-Cibenzoline succinate Polymorphs

Abstract

The present invention relates to a crystal form of (-)-cibenzoline succinate. The present invention also provides a method for preparing (-)-cibenzoline succinate and its crystal form. The crystal form of (-)-cibenzoline succinate according to the present invention has low water absorption, excellent stability under accelerated conditions and long-term storage conditions, and can be stably maintained with its content unchanged for a long time.

Description

Technical Field

[0001] The present invention relates to a polymorph of (-)-cibenzoline succinate.

[0002] In addition, the present invention also provides a method for preparing a polymorph of (-)-cibenzoline succinate. Background Art

[0003] Cibenzoline succinate (racemic) is chemically known as (±)-2-(2,2-diphenylcyclophenyl)-2-succinimidazoline, and its structure is represented by formula (II). It was developed and sold by Bristol-Myers Squibb (BMS) and Laboratory XO respectively under and Cibenzoline succinate (racemic) is an antiarrhythmic drug sold under the trade names Cipralan and Exacor. On October 21, 1983, France approved racemic cibenzoline succinate for the treatment of patients with arrhythmic heart disease. Cibenzoline is effective in the treatment of arrhythmic heart disease (Eur J Clin Pharmacol., 1984; 26(3): 297-302) and heart failure (CircJ. May 2006; 70(5): 588-92).

[0004]

[0005] Only the polymorphs of cibenzoline succinate (racemic) have been studied (Japanese Patent Application Publication No.: JP2010132561).

[0006] The use of enantiopure drugs can lead to simpler and more selective pharmacological profiles, improved therapeutic indices, simpler pharmacokinetics, and reduced drug interactions due to different metabolic rates of different enantiomers, and pharmaceutical companies are increasingly using chiral switching as a marketing strategy. In addition, due to different pharmacological activities, the toxicity of the enantiomers of chiral drugs may be different from that of racemic drugs.

[0007] Compounds known to have polymorphs exhibit different physical properties for each crystal form. Especially in drugs, there are differences in solubility, dissolution rate, stability, absorption, etc. between crystal forms. Even when using the same compound, due to different crystal forms of the same compound, there are also differences in its formulation process, storage stability, bioavailability, and the rate or intensity of drug action.

[0008] Therefore, when a compound having polymorphs is used as a drug, in order to ensure a constant bioavailability, it is necessary to stably provide a uniform crystal form of the compound. Accordingly, the present inventors have developed a novel and stable crystal form by studying the polymorphs of (-)-cibenzoline and its salts. SUMMARY OF THE INVENTION

[0009] TECHNICAL PROBLEM

[0010] The present invention provides a crystal form of (-)-cibenzoline succinate having any one selected from the group consisting of the following X-ray powder diffraction patterns (XRPD):

[0011] i) A crystal form having an X-ray powder diffraction spectrum including diffraction peaks at 9.7°, 14.9°, 21.5°, 23.4° and 24.1° (2θ ± 0.2°) (hereinafter referred to as "crystal form 1");

[0012] ii) A crystal form having an X-ray powder diffraction spectrum including diffraction peaks at 20.6°, 21.1°, 22.9°, 25.2° and 37.4° (2θ ± 0.2°) (hereinafter referred to as "crystal form 2"); and

[0013] iii) A crystal form having an X-ray powder diffraction spectrum including diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5° and 26.1° (2θ ± 0.2°) (hereinafter referred to as "crystal form 3").

[0014] The present invention provides a crystal form of (-)-cibenzoline succinate which is a triclinic system and has a space group of P1.

[0015] The present invention provides a method for preparing crystal form 3 of (-)-cibenzoline succinate, comprising the following steps:

[0016] a) Dissolving (-)-cibenzoline succinate represented by formula (IA) in a polar solvent; and

[0017] b) Precipitating crystal form 3 of (-)-cibenzoline succinate by adding a hydrocarbon solvent having 6 or more carbon atoms to the solution of step a):

[0018]

[0019] The present invention provides a pharmaceutical composition comprising a crystal form of (-)-cibenzoline succinate and a pharmaceutically acceptable carrier, diluent or excipient.

[0020] TECHNICAL SOLUTION

[0021] A first embodiment of the present invention provides a crystal form of (-)-cibenzoline succinate, which has any one selected from the group consisting of the following X-ray powder diffraction patterns (XRPD):

[0022] i) A crystal form having an X-ray powder diffraction spectrum with diffraction peaks at 9.7°, 14.9°, 21.5°, 23.4° and 24.1° (2θ±0.2°) (hereinafter referred to as "crystal form 1");

[0023] ii) A crystal form having an X-ray powder diffraction spectrum with diffraction peaks at 20.6°, 21.1°, 22.9°, 25.2° and 37.4° (2θ±0.2°) (hereinafter referred to as "crystal form 2"); and

[0024] iii) A crystal form having an X-ray powder diffraction spectrum with diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5° and 26.1° (2θ±0.2°) (hereinafter referred to as "crystal form 3").

[0025] According to one embodiment of the present invention, the crystal form of (-)-cibenzoline succinate can be anhydrous and can have an XRPD pattern with diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5° and 26.1° (2θ±0.2°).

[0026] According to one embodiment of the present invention, the crystal form of (-)-cibenzoline succinate can be anhydrous and can have an XRPD pattern further including at least one diffraction peak selected from the group consisting of diffraction peaks at 9.7°, 12.8°, 14.6°, 16.1°, 16.3°, 17.5°, 19.4°, 22.4°, 22.7°, 23.5° and 25.4° (2θ±0.2°).

[0027] According to one embodiment of the present invention, the crystal form of (-)-cibenzoline succinate can be anhydrous and can have a differential scanning calorimetry (DSC) endothermic peak at a heating rate of 10°C / min at a temperature of 190 to 193°C.

[0028] According to one embodiment of the present invention, in the crystal form of (-)-cibenzoline succinate, 50% of the particles [D 50 have a particle size of 10 μm to 50 μm.

[0029] According to one embodiment of the present invention, the crystal form of (-)-cibenzoline succinate can be characterized by having the following dynamic vapor sorption (DVS) pattern:

[0030] i) showing a water absorption rate of 0.3% in the adsorption cycle;

[0031] ii) shows a water absorption rate of 0.2% at 80% relative humidity; and

[0032] iii) completely releases 0.3% of the absorbed water during the desorption cycle.

[0033] A second embodiment of the present invention provides a crystal form of (-)-cibenzoline succinate, which is a triclinic system and has a space group of P1.

[0034] According to one embodiment of the present invention, the crystal form of (-)-cibenzoline succinate can be a triclinic system and can have the following lattice constant parameters:

[0035]

[0036]

[0037]

[0038] α = 96.71(5)°

[0039] β = 95.47(7)°

[0040] γ = 118.51(6)°

[0041]

[0042] Z = 1(1)

[0043] A third embodiment of the present invention provides a method for preparing crystal form 3 of (-)-cibenzoline succinate, comprising the following steps:

[0044] a) dissolving (-)-cibenzoline succinate represented by formula (IA) in a polar solvent; and

[0045] b) precipitating crystal form 3 of cibenzoline succinate by adding a hydrocarbon solvent having 6 or more carbon atoms to the solution of step a):

[0046]

[0047] According to one embodiment of the present invention, the polar solvent in step a) can be water, an alcohol-based solvent, an aldehyde-based solvent, an ester-based solvent, an amide-based solvent, or a mixture thereof.

[0048] According to one embodiment of the present invention, the alcohol-based solvent can be methanol, ethanol, linear or branched propanol, linear or branched butanol, linear or branched pentanol, or a mixture thereof.

[0049] According to one embodiment of the present invention, the hydrocarbon solvent having 6 or more carbon atoms may be cyclohexane, cycloheptane, n-hexane, n-heptane, or a mixture thereof.

[0050] A fourth embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of a crystalline form of (-)-cibenzoline succinate.

[0051] According to one embodiment of the present invention, the composition may be in the form of a capsule or tablet for oral administration.

[0052] (-)-Cibenzoline succinate Preparation

[0053] (-)-Cibenzoline succinate is an enantiopure isomer represented by formula (IA) according to the present invention and can be prepared by the following process comprising the following steps:

[0054]

[0055] a) Prepare the racemic cibenzoline free base represented by formula (III) by reacting the racemic cibenzoline succinate represented by formula (II) with a base;

[0056]

[0057] b) React the racemic cibenzoline free base represented by formula (III) with a chiral acid in the presence of a solvent to obtain the racemic cibenzoline · chiral acid salt represented by formula (IIIA);

[0058]

[0059] c) Isolate the (-)-cibenzoline · chiral acid salt represented by formula (IVA);

[0060]

[0061] d) Prepare the (-)-cibenzoline free base represented by formula (VA) by neutralizing the (-)-cibenzoline · chiral acid salt represented by formula (IVA) with a base; and

[0062]

[0063] e) Prepare (-)-cibenzoline succinate represented by formula (IA) by reacting the (-)-cibenzoline free base represented by formula (VA) with succinic acid in the presence of a solvent.

[0064] In step b) of the preparation process, the racemic cibenzoline chiralate represented by formula (IIIA) may include (+)-cibenzoline chiralate and (−)-cibenzoline chiralate, where the (+)-cibenzoline chiralate and the (−)-cibenzoline chiralate may be diastereomers of each other. For example, when the chiral acid is D-tartaric acid, the racemic cibenzoline chiralate represented by formula (IIIA) may be racemic cibenzoline D-tartrate, and the racemic cibenzoline D-tartrate may include (+)-cibenzoline D-tartrate and (−)-cibenzoline D-tartrate, which are diastereomers of each other.

[0065] Step b) of the preparation process includes the step of preparing the racemic cibenzoline free base represented by formula (III) by reacting the racemic cibenzoline succinate represented by formula (II) with a base at a temperature of 0 to 30 °C for 0 to 30 minutes.

[0066] Step b) of the preparation process may include the step of reacting the racemic cibenzoline free base represented by formula (III) with a chiral acid in the presence of a solvent at an appropriate temperature to obtain the racemic cibenzoline chiralate represented by formula (IIIA), where the temperature in the reaction is about 20 to 65 °C, and the reaction may be carried out for 30 minutes to 6 hours.

[0067] In step c) of the preparation process, the (−)-cibenzoline chiralate represented by formula (IVA) may be separated by techniques such as filtration or centrifugation, and the (−)-cibenzoline chiralate represented by formula (IVA) may be further dried by using a tray dryer, a vacuum oven, a fluidized bed dryer, and a rotary flash dryer.

[0068] Step d) of the preparation process includes the step of preparing the (−)-cibenzoline free base represented by formula (VA) by neutralizing the (−)-cibenzoline chiralate represented by formula (IVA) with a base, where the reaction may be carried out at a temperature of 10 to 50 °C for 30 minutes to 5 hours.

[0069] Step e) of the preparation process includes the step of preparing (−)-cibenzoline succinate represented by formula (IA) by reacting the (−)-cibenzoline free base represented by formula (VA) with succinic acid at a temperature of 0 to 65 °C and stirring for 10 minutes to 5 hours.

[0070] (-)-Cibenzoline succinate Crystal Forms

[0071] The first embodiment of the present invention provides a crystal form of (−)-cibenzoline succinate, which has any one selected from the group consisting of the following X-ray powder diffraction patterns (XRPD):

[0072] 1) A crystal form having an X-ray powder diffraction spectrum with diffraction peaks at 9.7°, 14.9°, 21.5°, 23.4°, and 24.1° (2θ ± 0.2°) (hereinafter referred to as "crystal form 1");

[0073] 2) A crystal form having an X-ray powder diffraction spectrum with diffraction peaks at 20.6°, 21.1°, 22.9°, 25.2°, and 37.4° (2θ ± 0.2°) (hereinafter referred to as "crystal form 2"); and

[0074] 3) A crystal form having an X-ray powder diffraction spectrum with diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5°, and 26.1° (2θ ± 0.2°) (hereinafter referred to as "crystal form 3").

[0075] According to one embodiment of the present invention, crystal form 1 of (-)-cibenzoline succinate has an X-ray powder diffraction pattern (XRPD) with diffraction peaks at 9.7°, 14.9°, 21.5°, 23.4°, and 24.1° (2θ ± 0.2°).

[0076] According to one embodiment of the present invention, in addition to the XRPD diffraction peaks at 9.7°, 14.9°, 21.5°, 23.4°, and 24.1° (2θ ± 0.2°), crystal form 1 of (-)-cibenzoline succinate may further have an XRPD pattern including at least one diffraction peak selected from the group consisting of diffraction peaks at 16.5°, 17.2°, and 26.1° (2θ ± 0.2°).

[0077] According to one embodiment of the present invention, as shown in Table 1 below, crystal form 1 of (-)-cibenzoline succinate may have an XRPD pattern with diffraction peaks at 8.98°, 9.67°, 13.35°, 14.12°, 14.90°, 16.53°, 17.18°, 18.36°, 19.05°, 20.07°, 21.50°, 23.40°, 24.06°, 24.78°, 25.38°, 26.08°, 27.44°, 28.24°, 29.41°, 30.20°, 31.20°, 32.52°, 33.80°, 35.29°, and 38.33° (2θ ± 0.2°).

[0078] [Table 1]

[0079]

[0080]

[0081] According to one embodiment of the present invention, polymorph 2 of (-)-cibenzoline succinate has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks at 20.6°, 21.1°, 22.9°, 25.2° and 37.4° (2θ±0.2°).

[0082] According to one embodiment of the present invention, as shown in Table 2 below, polymorph 2 of (-)-cibenzoline succinate may have an XRPD pattern comprising diffraction peaks at 16.72°, 19.06°, 20.58°, 21.14°, 22.87°, 24.13°, 25.16°, 27.07°, 28.64°, 32.68°, 34.54°, 37.35°, 39.44° and 40.95° (2θ±0.2°).

[0083] [Table 2]

[0084]

[0085] According to one embodiment of the present invention, polymorph 3 of (-)-cibenzoline succinate is anhydrous and has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5° and 26.1° (2θ±0.2°).

[0086] According to one embodiment of the present invention, polymorph 3 of (-)-cibenzoline succinate is anhydrous and, in addition to the XRPD diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5° and 26.1° (2θ±0.2°), may have an XRPD pattern further comprising at least one diffraction peak selected from the group consisting of diffraction peaks at 9.7°, 12.8°, 14.6°, 16.1°, 16.3°, 17.5°, 19.4°, 22.4°, 22.7°, 23.5° and 25.4° (2θ±0.2°).

[0087] According to one embodiment of the present invention, as shown in Table 3 below, polymorph 3 of (-)-cibenzoline succinate is anhydrous and may have an XRPD pattern comprising diffraction peaks at 9.68°, 12.84°, 13.00°, 14.57°, 14.81°, 16.14°, 16.29°, 17.47°, 19.38°, 21.19°, 21.41°, 22.38°, 22.50°, 22.68°, 23.29°, 23.50°, 25.42°, 25.53°, 25.80°, 26.11°, 26.26°, 27.80°, 28.00°, 28.53°, 29.27°, 31.38°, 34.38° and 34.91° (2θ±0.2°).

[0088] [Table 3]

[0089]

[0090]

[0091] According to one embodiment of the present invention, the polymorphic form 3 of (-)-cibenzoline succinate can be anhydrous and can have a differential scanning calorimetry (DSC) endothermic peak at a temperature of about 190 to 193 °C with a heating rate of 10 °C / min. Generally, the measured values of the melting point and the endothermic transition temperature are within a tolerance of ±2 °C, or generally within a tolerance of ±1 °C.

[0092] According to one embodiment of the present invention, the particle size distribution of the polymorphic form 3 of (-)-cibenzoline succinate can have such a particle size distribution that: 10% of the particles [D 10 are less than 10 μm, 50% of the particles [D 50 are from 10 μm to 50 μm, and 90% of the particles [D 90 are greater than 50 μm. For example, D 10 can be 8.8 μm, D 50 can be 30.44 μm, and D 90 can be 60.72 μm. In addition, D 50 can have a particle size of 10 μm to 50 μm, 15 μm to 45 μm, 20 μm to 40 μm, or 25 μm to 35 μm. It can be seen that the particle size of the polymorphic form 3 of (-)-cibenzoline succinate is very fine. The polymorphic form 3 can be formulated without additional processes such as grinding.

[0093] According to one embodiment of the present invention, the polymorphic form of (-)-cibenzoline succinate can be characterized by having the following dynamic vapor sorption (DVS) pattern:

[0094] i) shows a water absorption rate of 0.3% in the adsorption cycle;

[0095] ii) shows a water absorption rate of 0.2% at 80% relative humidity; and

[0096] iii) completely releases 0.3% of the absorbed water in the desorption cycle.

[0097] It can be seen that the water absorption rate of the polymorphic form 3 of (-)-cibenzoline succinate at room temperature and 80% relative humidity is 0.2%. It has been confirmed that the polymorphic form 3 does not absorb water (see the CHARACTERS SECTION in the European Pharmacopoeia 5.0, 5.11. Monographs, Hygroscopicity classification).

[0098] According to one embodiment of the present invention, as Figure 4 shown, the polymorph 3 of (-)-cibenzoline succinate can be triclinic and can have a space group of P1.

[0099] According to one embodiment of the present invention, the polymorph 3 of (-)-cibenzoline succinate can be triclinic and can have the following lattice constant parameters:

[0100]

[0101]

[0102]

[0103] α = 96.71(5)°

[0104] β = 95.47(7)°

[0105] γ = 118.51(6)°

[0106]

[0107] Z = 1(1)

[0108] In addition, the polymorph 3 of (-)-cibenzoline succinate according to the present invention has excellent stability under accelerated conditions and thus remains stable when its content remains unchanged for a long time. Therefore, the polymorph 3 of (-)-cibenzoline succinate according to the present invention can be obtained as a high-purity raw material and can maintain the high purity of the crystal form even during long-term storage.

[0109] The polymorphs 1 to 3 of (-)-cibenzoline succinate according to the present invention can be defined by additional physical properties, such as solid C-NMR peaks, specific diffraction peaks at lattice plane spacings, morphology on electron or optical micrographs of the solid crystal form, particle size on electron or optical micrographs of the solid crystal form, Brunauer-Emmett-Teller (BET) specific surface area (SSA), inverse gas chromatography (IGC) surface energy, or particle size distribution (D-value), etc.

[0110] The second embodiment of the present invention provides a polymorph of (-)-cibenzoline succinate, which is triclinic and has a space group of P1.

[0111] According to one embodiment of the present invention, the triclinic system can have the following lattice constant parameters:

[0112]

[0113]

[0114]

[0115] α = 96.71(5)°

[0116] β = 95.47(7)°

[0117] γ = 118.51(6)°

[0118]

[0119] Z = 1(1)

[0120] The triclinic system is one of the seven crystal systems described by three vectors in crystallography. In the triclinic system, the three vectors have different lengths, and the angles formed by the vectors are different and not orthogonal.

[0121] The space group is a mathematical description of the inherent symmetry in a crystal structure. P1 corresponds to a simple parallelogram lattice with only simple translational transformations and no rotational, reflection, or glide reflection transformations. The two translational transformations that make up the space region can have different lengths, and the angle formed between them can be any angle.

[0122] (-)-Cibenzoline succinate Crystal Form Preparation Method

[0123] The third embodiment of the present invention provides a method for preparing (-)-cibenzoline succinate crystal form 3, comprising the following steps:

[0124] a) Dissolving (-)-cibenzoline succinate represented by formula (IA) in a polar solvent; and

[0125] b) Precipitating crystal form 3 of (-)-cibenzoline succinate by adding a hydrocarbon solvent having 6 or more carbon atoms to the solution of step a):

[0126]

[0127] According to one embodiment of the present invention, crystal form 3 of (-)-cibenzoline succinate is anhydrous and may have an XRPD pattern further comprising at least one diffraction peak selected from the group consisting of diffraction peaks at 9.7°, 12.8°, 14.6°, 16.1°, 16.3°, 17.5°, 19.4°, 22.4°, 22.7°, 23.5°, and 25.4° (2θ ± 0.2°) in addition to the XRPD diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5°, and 26.1° (2θ ± 0.2°).

[0128] According to an embodiment of the present invention, as shown in Table 3 above, the polymorph 3 of (-)-cibenzoline succinate is anhydrous and may have an XRPD pattern including diffraction peaks at 9.68°, 12.84°, 13.00°, 14.57°, 14.81°, 16.14°, 16.29°, 17.47°, 19.38°, 21.19°, 21.41°, 22.38°, 22.50°, 22.68°, 23.29°, 23.50°, 25.42°, 25.53°, 25.80°, 26.11°, 26.26°, 27.80°, 28.00°, 28.53°, 29.27°, 31.38°, 34.38° and 34.91° (2θ±0.2°).

[0129] According to an embodiment of the present invention, the polymorph 3 of (-)-cibenzoline succinate may be anhydrous and may have a differential scanning calorimetry (DSC) endothermic peak at a heating rate of 10 °C / min at a temperature of about 190 to 193 °C. Generally, the measured values of the melting point and the endothermic transition temperature are values within a tolerance range of ±2 °C, or generally within a tolerance range of ±1 °C.

[0130] According to an embodiment of the present invention, as Figure 4 shown, the polymorph 3 of (-)-cibenzoline succinate may be triclinic and may have a space group of P1.

[0131] According to an embodiment of the present invention, the polymorph 3 of (-)-cibenzoline succinate may be triclinic and may have the following lattice constant parameters:

[0132]

[0133]

[0134]

[0135] α = 96.71(5)°

[0136] β = 95.47(7)°

[0137] γ = 118.51(6)°

[0138]

[0139] Z = 1(1)

[0140] According to an embodiment of the present invention, the preparation process of the polymorph 3 of (-)-cibenzoline succinate may further include a separation or drying process.

[0141] According to an embodiment of the present invention, filtration or centrifugation can be used for the separation process.

[0142] According to an embodiment of the present invention, a disk dryer, a vacuum oven, a fluidized bed dryer, and a rotary flash dryer can be used for the drying process.

[0143] According to an embodiment of the present invention, the method for preparing crystalline form 3 of (-)-cibenzoline succinate may further include a cooling process.

[0144] According to an embodiment of the present invention, the cooling can be carried out at room temperature (about 20 to 30 °C) for 1 week or 2 weeks, or can be carried out at 5 °C for as short as a few minutes to as long as two weeks for equilibration.

[0145] According to an embodiment of the present invention, step a) is a process of adding (-)-cibenzoline succinate represented by formula (IA) to a solvent and then dissolving it by heating. Examples of solvents that can be used in this method include, but are not limited to, water, alcohol-based solvents, aldehyde-based solvents, ester-based solvents, amide-based solvents, and mixtures thereof.

[0146] According to an embodiment of the present invention, the alcohol solvent can be a straight-chain or branched-chain C 1 to C 5 alcohol. For example, it can be methanol, ethanol, straight-chain or branched-chain propanol, straight-chain or branched-chain butanol, straight-chain or branched-chain pentanol, or a mixture thereof. More specifically, it can be methanol, ethanol, straight-chain or branched-chain propanol, or a mixture thereof. More specifically, it can be methanol, straight-chain or branched-chain propanol, or a mixture thereof.

[0147] According to an embodiment of the present invention, step a) can be carried out at 20 to 80 °C, and the reaction time can be as short as a few minutes to as long as 2 weeks or longer for equilibration.

[0148] According to an embodiment of the present invention, adding a hydrocarbon solvent having 6 or more carbon atoms in step b) may include adding a hydrocarbon solvent that has 6 or more carbon atoms and has low solubility in (-)-cibenzoline succinate in an amount of 25% to 400% of the solvent amount in the dissolution process to form a precipitate.

[0149] According to an embodiment of the present invention, the hydrocarbon solvent having 6 or more carbon atoms in step b) can be cyclohexane, cycloheptane, n-hexane, n-heptane, or a mixture thereof.

[0150] Drug Composition Containing (-)-Cibenzoline succinate Crystal Form

[0151] The third embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of crystalline form of (-)-cibenzoline succinate as an active ingredient, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0152] The composition can be formulated into a dosage form selected from the group consisting of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, ointments, creams, suppositories, eye drops, and injections according to conventional formulation methods known to those skilled in the art.

[0153] The composition can exhibit a prophylactic or therapeutic effect on at least one disease selected from the group consisting of heart diseases, arrhythmogenic heart diseases, and heart failure.

[0154] According to one embodiment of the present invention, the pharmaceutical composition can be prepared in unit dosage form or provided in a multi-dose container by using a pharmaceutically acceptable carrier according to a method easily implemented by those of ordinary skill in the art to which the present invention pertains.

[0155] According to one embodiment of the present invention, the content of the additive in the pharmaceutical composition is not particularly limited and can be appropriately adjusted within the range used in conventional preparations.

[0156] According to one embodiment of the present invention, an effective amount of the pharmaceutical composition can be administered to a patient by various routes (e.g., oral or parenteral routes). Preferably, the composition of the present invention can be formulated into an oral dosage form, such as capsules, tablets, dispersants, and suspensions.

[0157] The preferred dosage and administration frequency of the pharmaceutical composition according to the embodiments of the present invention can vary depending on the patient's body weight, age, gender, health status, diet, administration time, administration method, administration duration or interval, excretion rate, individual constitution, nature of the formulation, and severity of the disease, and can be appropriately selected by those skilled in the art.

[0158] Beneficial effects

[0159] The crystal form of (-)-cibenzoline succinate according to the present invention has low hygroscopicity, excellent stability under accelerated conditions and long-term storage conditions, and can stably maintain its content unchanged for a long time. Therefore, the crystal form of (-)-cibenzoline succinate according to the present invention can be obtained as a high-purity raw material, and the high purity of the crystal form can be maintained for a long time even during long-term storage. Description of the drawings

[0160] Figure 1 Shows the X-ray powder diffraction (XRPD) pattern of the amorphous form of (-)-cibenzoline succinate prepared according to Example 1.

[0161] Figure 2 Shows the X-ray powder diffraction (XRPD) patterns of crystal forms 1 to 3 of (-)-cibenzoline succinate prepared according to Examples 2 to 4.

[0162] Figure 3 The single crystal high-resolution X-ray powder diffraction (XRPD) pattern of crystalline form 3 of (-)-cibenzoline succinate prepared according to Example 4 is shown.

[0163] Figure 4 The particle morphology and lattice structure of crystalline form 3 of (-)-cibenzoline succinate are schematically shown in its optical micrograph.

[0164] Figure 5 The results of dynamic vapor sorption (DVS) analysis of crystalline form 3 of (-)-cibenzoline succinate are shown. Detailed Description of the Invention

[0165] The process details of the present invention are provided in the examples given below, but these examples are provided for illustration only, and thus the scope of the present invention is not limited by these examples.

[0166] <Instrumental Analysis and Measurement Conditions>

[0167] 1. Chiral Purity (HPLC) Analysis

[0168] The chiral purity (e.e) of the prepared compound was measured by high performance liquid chromatography (HPLC) under the measurement conditions shown in Table 4 below.

[0169] [Table 4]

[0170]

[0171] 2. 1 1H-NMR and 13 13C-NMR Analysis

[0172] The nuclear magnetic resonance spectra of (-)-cibenzoline succinate were obtained using a Bruker advance III FT-NMR. 1H NMR was measured at 400 MHz (in DMSO-d 6 6) and 13C NMR was measured at 400 MHz (in CD 1 3OD). 3 13

[0173] 3. Infrared Spectroscopy (IR) Analysis

[0174] (-)-Cibenzoline succinate was analyzed by infrared using a Perkinlemer spectrum FT-IR spectrophotometer. The infrared spectrum was recorded using a KBr disk.

[0175] 4. Mass Spectrometry Analysis

[0176] The mass spectrometry analysis of (-)-cibenzoline succinate was carried out using an Agilent LCQ Fleet thermoionic trap mass spectrometer equipped with electrospray ionization (ESI).

[0177] 5. Ultraviolet-visible spectroscopy analysis

[0178] The ultraviolet-visible spectroscopy analysis of (-)-cibenzoline succinate was performed using a Perkin Elmer ultraviolet-visible spectrophotometer (model Lambda 25). A 10 μg / mL solution was prepared by dissolving (-)-cibenzoline succinate in methanol as the solvent and scanned from 200 nm to 400 nm.

[0179] 6. Specific rotation analysis

[0180] At room temperature, the specific rotation analysis of a (-)-cibenzoline succinate solution with a concentration of 1.401 g / 100 mL (in methanol) was carried out on an Agilent Autopol V series #81225.

[0181] 7. Single crystal X-ray diffraction (XRD) analysis

[0182] The single crystal XRD of polymorph 3 was analyzed using the following modeling methods under the following conditions.

[0183] - Manufacturer: Bruker, USA

[0184] - Model: Nonius Kappa-CCD

[0185] - Measurement temperature: 296 K

[0186] - Complete sphere data: Reflection light measurement up to θ = 32.6°

[0187] - Modeling method for single crystal structure identification

[0188] 1) Data reduction: HKL Scalepack (Otwinowski & Minor 1997)

[0189] 2) Unit cell parameters: Denzo and Scalepak (Otwinowski & Minor, 1997)

[0190] 3) Structure solution method: SHELXT-2014 / 7 (Sheldrick, G.M., 2015a)

[0191] 4) Square full matrix refinement: SHELXL-2014 / 7 (Sheldrick, G.M., 2015b)

[0192] 8. High-throughput X-ray diffraction (XRD) analysis

[0193] Analyze the high-throughput XRD of the crystal form under the following conditions.

[0194] - Manufacturer: Bruker, USA

[0195] - Model: General Area Detector Diffraction System (GADDS)

[0196] - Measurement temperature: 25 °C (room temperature)

[0197] - 2θ measurement range: 1.5 to 41.5°

[0198] - Exposure time: 90 seconds

[0199] - Others: Use - Measurement of the intensity and geometric parameters of the 500 gas area detector (Bruker, USA)

[0200] 9. High-resolution X-ray diffraction (XRD) analysis

[0201] Under the following conditions, analyze the high-resolution XRD of the crystal form using the following modeling method.

[0202] - Manufacturer: Bruker, USA

[0203] - Model: D8 Advance diffractometer

[0204] - Measurement radiation: Cu Kα1 radiation

[0205] - Measurement temperature: 25 °C (room temperature)

[0206] - 2θ measurement range: 2 to 41.5°

[0207] - Detector: LynxEye detector (Bruker, USA)

[0208] - Detection rate: 5 seconds / step (1 step = 0.016°)

[0209] - Sample measurement: 8 mm long glass capillary with an outer diameter of 0.5 mm

[0210] - Exposure time: 90 seconds

[0211] 10. Thermogravimetric analysis coupled with mass spectrometry (TGMS)

[0212] Perform thermogravimetric analysis coupled with mass spectrometry on the crystal form under the following conditions.

[0213] - Manufacturer: Mettler-Toledo GmbH, Switzerland

[0214] - Model: TGA / DSC 3+STARe system

[0215] - Temperature range: 25 to 300 °C

[0216] - Heating rate: 10 °C / min

[0217] - Mass spectrometer: Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany)

[0218] 11. Differential scanning calorimetry (DSC) analysis

[0219] Under the following conditions, calorimetric analysis of the crystal form was carried out by differential scanning calorimetry (DSC).

[0220] - Manufacturer: Metter Toredo GmbH, Switzerland

[0221] - Model: Heat flux DSC3+STARe system

[0222] - Heating rate: 10 °C / min

[0223] - Temperature range: 25 to 300 °C

[0224] - N 2 Flow rate: 50 mL / min.

[0225] 12. Karl Fischer titration analysis

[0226] Under the following conditions, the hydrate and water content of the crystal form were measured by Karl Fischer titration.

[0227] - Manufacturer: SI Analytics, Germany

[0228] - Model: Titroline 7500KF microtitrator

[0229] - Solvent: Methanol

[0230] 13. Polarizing light microscopy analysis

[0231] Under the following conditions, the morphology of the crystal form was measured using a polarizing light microscope.

[0232] - Manufacturer: Leica Microsystems GmbH, Germany

[0233] - Model: Leica DM 2500M optical microscope

[0234] 14. Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) Analysis

[0235] Under the following conditions, the quality of the crystal form was measured by an Ultra Performance Liquid Chromatography-Mass Spectrometer (UPLC-MS).

[0236] - Manufacturer: Agilent, USA

[0237] - Model: Agilent 1290

[0238] - Detector 1: UV detector set at 224 nm

[0239] - Detector 2: MSD XT in positive scan mode

[0240] - Measurement temperature: 25 °C (room temperature)

[0241] - Column: Agilent Eclipse Plus C18 HD (50ⅹ2.1 mm; 1.8 μm)

[0242] - Column temperature: 35 °C

[0243] - Flow cell: 10 mm path

[0244] - Gradient: Mobile phase A: 10 mM ammonium acetate / Mobile phase B: acetonitrile

[0245] - Flow rate: 0.8 mL / min

[0246] - Sample concentration: 0.8 mg / mL

[0247] - Solvent: Water: acetonitrile (50:50 v / v)

[0248] - Injection: 1 μl

[0249] - Retention time: 1.54 min

[0250] 15. Particle Size Distribution (PSD) Analysis

[0251] Under the following conditions, the particle size of the crystal form was measured using a laser diffraction particle size analyzer.

[0252] - Manufacturer: Malvern Instruments Limited, UK

[0253] - Model: Mastersizer 2000

[0254] - Sampler: Hydro 2000G / S

[0255] Instrument conditions:

[0256] - Particle reflection index (RI): 1.52

[0257] - Dispersant: heptane

[0258] - Absorbance: 0.1

[0259] - Refractive index of the dispersant: 1.39

[0260] - Analysis model: general purpose

[0261] - Sensitivity: enhanced

[0262] - Absorption limit: 10 - 15%

[0263] - Measurement time: 30 seconds (repeated three times for each sample)

[0264] - Stirring speed: 3500 RPM

[0265] Sample preparation:

[0266] In a 50 mL beaker, dissolve approximately 150 mg of the sample in 20 mL of heptane containing 0.2% Span 85. Ultrasonically treat the solution for approximately 10 seconds and place it in a sampler. When the absorption limit reaches 10% to 15%, perform the measurement.

[0267] 16. Dynamic vapor sorption (DVS) analysis

[0268] Under the following conditions, measure the dynamic vapor sorption using a vapor sorption analyzer.

[0269] - Manufacturer: Surface Measurement Systems Ltd, UK

[0270] - Model: DVS Adventure-I system

[0271] - Crystal form analysis of the resulting solid: HT-XRPD

[0272] Relative humidity cycle:

[0273] The relative humidity is cycled from 40% to 95% (adsorption), from 95% to 0% (desorption), and then back to 40% (adsorption 2). In each step, at a constant temperature of 25 °C, the relative humidity is changed by 10%. Set the weight balance to dm / dt of 0.002% / min.

[0274] <Preparation Example>

[0275] Preparation Example 1: Preparation of (-)-cibenzoline succinate

[0276] Preparation Example 1-1: Preparation of (±)-Cibenzoline Free Base

[0277] 50 g of a (±)-cibenzoline succinate suspension was stirred in 200 mL of water and alkalized to pH 10.5 to 10.8 with 10% sodium hydroxide solution within 30 minutes at a temperature of 25 to 30 °C, and then extracted with 400 mL of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure (400 - 20 mmHg) at a temperature of 45 °C or lower to obtain 30 g of white solid (±)-cibenzoline free base.

[0278] [Chiral purity determined by chiral HPLC: a mixture of 48.76% (-)-cibenzoline and 51.24% (+)-cibenzoline]

[0279] Preparation Example 1-2: Preparation of (-)-Cibenzoline D-tartrate

[0280] 15 g of the (±)-cibenzoline free base prepared according to Preparation Example 1-1 was dissolved in 250 mL of acetonitrile, then stirred for 15 min at a temperature of 25 to 30 °C, and an aqueous solution (30 mL) of D-(-)-tartaric acid (1.0 m.eq.) was added thereto within 20 min at a temperature of 25 to 30 °C to obtain a mixture. The mixture was stirred for 30 minutes, and 250 mL of methyl tert-butyl ether (MTBE) was added to the mixture within 20 minutes, and then stirred at room temperature for 2.5 hours to prepare a mixture. The mixture was heated to 50 to 55 °C, stirred for 1 hour, then cooled and stirred at 25 to 30 °C for 1 hour. The resulting solid was filtered and washed with 23 mL of acetonitrile to obtain (-)-cibenzoline-D-tartrate (6.4 g), and its chiral purity was 99.0% as measured by chiral HPLC (yield: 41 (w / w)%).

[0281] 1 H-NMR (400 MHz, CD 3 OD): 7.38 (m, 6H); 7.29 (m, 3H); 7.20 (m, 1H); 4.40 (s, 2H); 3.71 (m, 2H); 3.52 (m, 2H); 2.83 (t, 1H); 2.34 (t, 1H); 1.90 (t, 1H) ppm.

[0282] 13 C-NMR (100 MHz, CD 3 OD): 177.01, 170.68, 144.71, 139.88, 130.73, 129.82, 129.72, 128.90, 128.77, 128.19, 74.21, 45.52, 42.54, 23.02, 20.11.

[0283] IR (cm -1):1731.23, 3531.63.

[0284] Preparation Example 1-3: Preparation of (-)-Cibenzoline Free Base

[0285] 5 g of (-)-cibenzoline-D-tartrate prepared according to Preparation Examples 1-2 was added to 25 mL of water, alkalized with 50 mL of saturated sodium bicarbonate solution at a temperature of 25 to 30 °C, and then extracted with 200 mL of dichloromethane. The extracted dichloromethane layer was dried over anhydrous sodium sulfate and distilled under reduced pressure (500 - 20 mmHg) at a temperature of 40 °C or lower to obtain a semi-solid (-)-cibenzoline free base (3.0 g), which had [α] D -153.82, and its chiral purity was 99.09% as measured by chiral HPLC.

[0286] Preparation Example 1-4: Preparation of (-)-Cibenzoline succinate

[0287] 2.5 g of (-)-cibenzoline base prepared according to Preparation Example 1-3 was dissolved in 25 mL of isopropanol, then stirred at a temperature of 50 to 55 °C, and a 12.5 mL methanol solution of succinic acid (1.0 m.eq) was added thereto within 10 minutes. The mixture was stirred at a temperature of 25 to 30 °C for 30 minutes, and then cooled at a temperature of 0 to 5 °C for 1 hour 30 minutes. The resulting white solid was filtered, washed with 3.75 mL of isopropanol, and then dried under vacuum at a temperature of 40 to 45 °C to obtain pure (-)-cibenzoline succinate (3.2 g), and its chiral purity was 99.9% as measured by chiral HPLC ( Figure 4 ).

[0288] 1 H-NMR (400 MHz, CD 3 OD): 7.38 (m, 6H); 7.29 (m, 3H); 7.21 (m, 1H); 3.71 (m, 2H); 3.53 (m, 2H); 2.82 (m, 1H); 2.50 (s, 4H); 2.36 (t, 1H); 1.91 (m, 1H) ppm.

[0289] 13 C-NMR (100 MHz, CD 3 OD): 179.20, 170.55, 141.73, 139.83, 130.70, 129.78, 129.69, 128.84, 128.76, 128.16, 45.41, 42.41, 32.96, 23.00, 21.01 ppm.

[0290] IR spectrum: 1674.96 cm -1(Acid C=O stretching vibration), 2954.43 cm -1 (Sp3 stretching vibration).

[0291] MW (g / mol): 380.44

[0292] (-)-Cibenzoline m / z: 263.35 (theoretical value), 263 (observed value)

[0293] UV absorption: Absorbance value of 1.155 at 202.5 nm

[0294] Specific rotation: [α] D -124.47; Rotation - VE.

[0295] <Example>

[0296] Example 1: Preparation of (-)-Cibenzoline succinate Amorphous Form

[0297] Dissolve 2083.4 mg of (-)-cibenzoline succinate prepared according to Preparation Example 1 in 30000 μL of t-BuOH / distilled water (50 / 50 v / v%) solvent, and then lyophilize at -73°C for 16 hours to prepare the amorphous form of (-)-cibenzoline succinate.

[0298] By performing high-throughput XRD analysis on the obtained amorphous form, it was confirmed that the obtained amorphous form was amorphous, as Figure 1 shown.

[0299] Example 2: Preparation of (-)-Cibenzoline succinate Crystal Form 1

[0300] Dissolve 33 mg of the amorphous form of (-)-cibenzoline succinate prepared according to Example 1 in 350 μL of distilled water to obtain a suspension, and then store it at room temperature for 2 weeks to reach equilibrium. Thereafter, the liquid phase was removed by centrifugation, and the remaining material was dried under atmospheric pressure to obtain the crystalline form 1 of (-)-cibenzoline succinate.

[0301] By performing high-throughput XRD analysis (HT-XRD) on the obtained crystalline form 1, it was confirmed that this crystalline form was a new crystalline form, as Figure 2As shown. As shown in Table 1 above, the diffraction peaks were analyzed by high-resolution XRD analysis (HR-XRD). It was confirmed by thermogravimetric analysis and mass spectrometry (TGMS) that Polymorph 1 was a hydrate, and the water content of Polymorph 1 was confirmed to be 10.5% by Karl Fischer titration. The differential scanning calorimetry (DSC) analysis results showed that the DSC melting endothermic transition peak first started at about 47.20 °C, reached a maximum at about 47.94 °C, ended at 49.75 °C, then reached a maximum at about 58.81 °C, and ended at about 68.57 °C, which was considered to be the peak of the hydrate. Next, the DSC melting endothermic transition peak started at about 189.71 °C, reached a maximum at about 190.75 °C, and ended at 192.28 °C.

[0302] Example 3: Preparation of (-)-Cibenzoline succinate Crystal Form 2

[0303] 20 mg of the amorphous form of (-)-cibenzoline succinate prepared in Example 1 was dissolved in 200 μL of morpholine to obtain a suspension, which was then subjected to three temperature change steps and then stored at room temperature for 3 days.

[0304] First step: Raise the temperature from room temperature to 50 °C at a heating rate of 10 °C / hour, and then lower the temperature from 50 °C to 5 °C at a cooling rate of 20 °C / hour.

[0305] Second step: Raise the temperature from 5 °C to 50 °C at a heating rate of 10 °C / hour, and then lower the temperature from 50 °C to 5 °C at a cooling rate of 10 °C / hour.

[0306] Third step: Raise the temperature from 5 °C to 50 °C at a heating rate of 10 °C / hour, then lower the temperature from 50 °C to 5 °C at a cooling rate of 5 °C / hour, and then raise the temperature from 5 °C to room temperature at a heating rate of 10 °C / hour.

[0307] After removing the liquid phase by centrifuge, the remaining material was dried under vacuum (5 mbar) to obtain Polymorph 2 of (-)-cibenzoline succinate.

[0308] By performing high-throughput XRD analysis (HT-XRD) on the obtained Polymorph 2, it was confirmed that Polymorph 2 was a new polymorph, as Figure 2As shown. As shown in Table 2 above, the diffraction peaks were analyzed by high-resolution XRD (HR-XRD). By thermogravimetric analysis coupled with mass spectrometry (TGMS), it was confirmed that Polymorph 2 was a hydrate and contained morpholine solvent. The differential scanning calorimetry (DSC) analysis results showed that the DSC endothermic melting transition peak first started at about 74.09 °C, reached a maximum at about 109.76 °C, and ended at 116.45 °C, then started at about 120.42 °C, reached a maximum at about 134.98 °C, and ended at 145.93 °C, then started at about 184.90 °C, reached a maximum at about 204.69 °C, and ended at 265.85 °C.

[0309] Example 4-1. Preparation of (-)-Cibenzoline succinate Crystal Form 3

[0310] 25.2 mg of (-)-cibenzoline succinate prepared according to Preparation Example 1 was dissolved in 400 μL of methanol at 50 °C to obtain a suspension, and then 20 mL of the antisolvent cyclohexane was added thereto, followed by stirring for about 1 hour for crystallization. When precipitation occurred, the liquid phase was removed at a rotational speed of 3000 RPM for about 5 minutes by a centrifuge (Rotanta 46RSC centrifuge, Andreas Hettich GmbH&Co.KG, Germany), and the remaining material was dried under atmospheric pressure or high vacuum (5 mbar, 18 hours) to obtain Polymorph 3 of (-)-cibenzoline succinate.

[0311] By performing high-throughput XRD analysis (HT-XRD) on the obtained Polymorph 3, it was confirmed that Polymorph 3 was a new polymorph, as Figure 2 shown. As shown in Table 3 above and Figure 3 shown, the diffraction peaks were analyzed by high-resolution XRD (HR-XRD). By thermogravimetric analysis coupled with mass spectrometry (TGMS), it was confirmed that Polymorph 3 was anhydrous and contained no residual solvent. The differential scanning calorimetry (DSC) analysis results showed that the DSC endothermic melting transition peak started at about 190.26 °C, reached a maximum at about 190.86 °C, and ended at 192.70 °C.

[0312] By polarized light microscopy analysis, it was confirmed that Polymorph 3 was a single crystal, as Figure 4 shown. By single crystal X-ray diffraction (XRD) analysis, as Figure 4 shown, it was confirmed that Polymorph 3 was triclinic with a space group of P1. The crystal data and structure refinement parameters are shown in Table 5 below.

[0313] [Table 5]

[0314]

[0315] Example 4-2: Preparation of (-)-Cibenzoline succinate Crystal Form 3 (Large Scale)

[0316] In addition, 2247.8 mg of (-)-cibenzoline succinate prepared according to Preparation Example 1 was dissolved in 10 mL of methanol to obtain a suspension, and the suspension was divided into 2-mL aliquots. 20 mL of cyclohexane was added as an anti-solvent to the divided suspension, and then the mixture was stirred for 1 hour to crystallize, to obtain 1 g of Crystal Form 3.

[0317] Example 5: Preparation of Crystal Form 3 Using 1-propanol Solvent and n-heptane Anti-solvent

[0318] 21.8 mg of (-)-cibenzoline succinate prepared according to Preparation Example 1 was dissolved in 2500 μL of 1-propanol to obtain a supersaturated solution, which was then placed in a 1.8-mL vial. The vial was placed in a 40-mL container containing 2 mL of the anti-solvent n-heptane. The container was sealed and stored at room temperature for 2 weeks. When precipitation occurred, the liquid phase was removed by centrifugation, and the remaining material was dried under atmospheric pressure to obtain the crystal form of (-)-cibenzoline succinate.

[0319] By performing high-throughput XRD (HT-XRD) analysis on the obtained crystal form, it was confirmed that the crystal form was Crystal Form 3 of Example 4.

[0320] [Experimental Example]

[0321] Experimental Example 1: Accelerated Storage Stability Test

[0322] For the crystal forms and amorphous forms of (-)-cibenzoline succinate prepared according to Examples 1 to 4 above, a storage stability test was carried out for 48 hours under accelerated aging conditions (AAC; 40 °C / 75% RH). The test results are shown in Table 6 below.

[0323] [Table 6]

[0324]

[0325] It has been confirmed that among the amorphous forms and crystal forms prepared in Examples 1 to 4, the stable crystal form of (-)-cibenzoline succinate is Crystal Form 3 of Example 4.

[0326] Experimental Example 2: Long-term Stability

[0327] The crystal form 3 of (-)-cibenzoline succinate prepared according to Example 4 was stored at 60 °C for 4 weeks, and then its long-term storage stability was evaluated by HT-XRPD, DSC, TGMS, and UPLC analysis. The test results are shown in Table 7 below.

[0328] [Table 7]

[0329]

[0330] It has been confirmed that Form 3 prepared according to Example 4 maintains its crystal form and chemical purity stable without change even during long-term storage.

[0331] Experimental Example 3: Particle Size Analysis

[0332] The particle size of Form 3 of (-)-cibenzoline succinate prepared according to Example 4 was measured by a laser diffraction particle analyzer. The test results are shown in Table 8 below.

[0333] [Table 8]

[0334] <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Crystal Form 3 Example 4 8.80 30.44 60.72 Reference Example Preparation Example 1-4 17.10 127.82 307.56

[0335] It has been confirmed that the D 50 of Form 3 prepared according to Example 4 is 30.44 μm, which is less than the USP fine particle standard of 125 μm (see Physical Tests <811> Fineness of Powder in Volume 4 of 2019 USP 42 NF 37), indicating that the particle size of Form 3 is very fine. In addition, it has been confirmed that the particle size of Form 3 is significantly smaller than that of the materials prepared in Preparation Examples 1-4, so the effective surface area of the drug increases, which indicates that the dissolution rate of the drug will increase, thus making the absorption rate and bioavailability of the drug increase.

[0336] Experimental Example 4: Dynamic Vapor Sorption Analysis

[0337] Dynamic vapor sorption data (water sorption isotherm) was measured by a vapor sorption analyzer. The experimental results are as Figure 5 shown.

[0338] As Figure 5 shown, Form 3 shows a water absorption rate of up to 0.3% in the adsorption cycle and 0.2% at 80% relative humidity. Form 3 completely releases 0.3% of the absorbed water in the desorption cycle and hardly absorbs water in Adsorption 2. It was confirmed by HT-XRPD analysis that the sample obtained after DVS remained in Form D.

[0339] It has been confirmed that Form 3 prepared according to Example 4 can be maintained even in an experimentally reversible water absorption environment, which indicates that it has stability even in a hygroscopic environment, and shows a water absorption rate of 0.2% at 80% relative humidity, indicating that Form 3 is non-hygroscopic (see the Characters Section in Monographs in European Pharmacopoeia 5.0, 5.11, Hygroscopicity Classification).

Claims

1. A crystal form of (-)-cibenzoline succinate, characterized in that: The crystal form has the following X-ray powder diffraction spectrum (XRPD), and 50% of the particles 50 have a particle size of 10 μm to 50 μm, In the X-ray powder diffraction spectrum, the crystal form includes diffraction peaks at 2θ values of 13.0° ± 0.2°, 14.8° ± 0.2°, 23.3° ± 0.2°, 25.5° ± 0.2° and 26.1° ± 0.2°, and further includes at least one diffraction peak selected from the group consisting of diffraction peaks at 2θ values of 9.7° ± 0.2°, 12.8° ± 0.2°, 14.6° ± 0.2°, 16.1° ± 0.2°, 16.3° ± 0.2°, 17.5° ± 0.2°, 19.4° ± 0.2°, 22.4° ± 0.2°, 22.7° ± 0.2°, 23.5° ± 0.2° and 25.4° ± 0.2°.

2. The crystal form of (-)-cibenzoline succinate according to claim 1, which has a differential scanning calorimetry (DSC) endothermic peak at a heating rate of 10 °C / min at a temperature of 190 to 193 °C.

3. The crystal form of (-)-cibenzoline succinate according to claim 1, which is characterized by having the following dynamic vapor sorption (DVS) pattern: i) showing a water absorption rate of 0.3% in the adsorption cycle; ii) showing a water absorption rate of 0.2% at 80% relative humidity; and iii) completely releasing 0.3% of the absorbed water in the desorption cycle.

4. The crystal form of (-)-cibenzoline succinate according to claim 1, which is triclinic and has a space group of P1.

5. The crystal form of (-)-cibenzoline succinate according to claim 4, wherein, the triclinic system has the following lattice constant parameters: α＝96.71(5)° β＝95.47(7)° γ = 118.51(6)° Z＝1(1)。 6. A pharmaceutical composition comprising the crystal form of (-)-cibenzoline succinate according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, diluent or excipient.

7. The pharmaceutical composition according to claim 6, which is in the form of a capsule or tablet for oral administration.

Images