Polymorphic Form of (-)-Cibenzoline Succinate

Abstract

The present invention relates to a crystalline form of (−)-cibenzoline succinate. The present invention also provides a process for preparing (−)-cibenzoline succinate and a crystalline form thereof. The crystalline form of (−)-cibenzoline succinate according to the present invention has low hygroscopicity, and excellent stability under accelerated conditions and long-term storage conditions, and may be stably maintained without a change in content thereof for a long period of time.

Claims

1: A crystalline form of (−)-cibenzoline succinate, which has any one selected from the group consisting of the following X-ray powder diffraction patterns (XRPDs): i) a crystalline form having an X-ray powder diffraction spectrum comprising diffraction peaks at 9.7°, 14.9°, 21.5°, 23.4° and 24.1° (2θ±0.2°) (hereinafter referred to as “crystalline form 1”); ii) a crystalline form having an X-ray powder diffraction spectrum comprising diffraction peaks at 20.6°, 21.1°, 22.9°, 25.2° and 37.4° (2θ±0.2°) (hereinafter referred to as “crystalline form 2”); and iii) a crystalline form having an X-ray powder diffraction spectrum comprising diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5° and 26.1° (2θ±0.2°) (hereinafter referred to as “crystalline form 3”).

2: The crystalline form of (−)-cibenzoline succinate of claim 1, which is anhydrous and has an XRPD pattern comprising diffraction peaks at 13.0°, 14.8°, 23.3°, 25.5° and 26.1° (2θ±0.2°).

3: The crystalline form of (−)-cibenzoline succinate of claim 2, which is anhydrous and has 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°).

4: The crystalline form of (−)-cibenzoline succinate of claim 1, which has a differential scanning calorimetry (DSC) endothermic peak at a temperature of 190 to 193° C.: at a temperature rise rate of 10° C./min.

5: The crystalline form of (−)-cibenzoline succinate of claim 1, wherein 50% of the particles[D.sub.50] have a particle size of 10 μm to 50 μm.

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

7: A crystalline form of (−)-cibenzoline succinate, which is a triclinic crystal system and has a space group of P1.

8: The crystalline form of (−)-cibenzoline succinate of claim 7, wherein the triclinic crystal system has the following lattice constant parameters: α=7.87(6)Å b=8.00(9)Å c=9.36(12)Å α=96.71(5)° β=95.47(7)° γ=118.51(6)° V=507.06(10)Å.sup.3 Z=1(1)

9: A process for preparing crystalline form 3 of (−)-cibenzoline succinate comprising steps of: a) dissolving (−)-cibenzoline succinate represented by Formula (IA) in a polar solvent; and b) precipitating crystalline form 3 of (−)-cibenzoline succinate by adding a hydrocarbon solvent having 6 or more carbon atoms to the solution of step a): ##STR00010##

10: The process of claim 9, wherein the polar solvent in step a) is water, an alcohol-based solvent, an aldehyde-based solvent, an ester-based solvent, an amide-based solvent, or a mixture thereof.

11: The process of claim 10, wherein the alcohol-based solvent is methanol, ethanol, linear or branched propanol, linear or branched butanol, linear or branched pentanol, or a mixture thereof.

12: The process of claim 9, wherein the hydrocarbon solvent having 6 or more carbon atoms in step b) is cyclohexane, cycloheptane, n-hexane, n-heptane, or a mixture thereof.

13: A pharmaceutical composition containing the crystalline form of (−)-cibenzoline succinate of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

14: The pharmaceutical composition of claim 13, which is in the form of a capsule or tablet for oral administration.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0142] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of an amorphous form of (−)-cibenzoline succinate prepared according to Example 1.

[0143] FIG. 2 shows the X-ray powder diffraction (XRPD) patterns of crystalline forms 1 to 3 of (−)-cibenzoline succinate prepared according to Examples 2 to 4.

[0144] FIG. 3 shows the single-crystal high-resolution X-ray powder diffraction (XRPD) pattern of crystalline form 3 of (−)-cibenzoline succinate prepared according to Example 4.

[0145] FIG. 4 schematically shows the particle morphology and lattice structure of crystalline form 3 of (−)-cibenzoline succinate on an optical micrograph thereof.

[0146] FIG. 5 show the results of dynamic vapor sorption (DVS) analysis of crystalline form 3 of (−)-cibenzoline succinate.

MODE FOR INVENTION

[0147] The process details of the present invention are provided in the examples given below, but these examples are provided by way of illustration only, and thus the scope of the present invention is not limited by these examples.

[0148] <Instrumental Analysis and Measurement Conditions>

[0149] 1. Chiral Purity (HPLC) Analysis

[0150] 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.

TABLE-US-00004 TABLE 4 HPLC conditions Column Chiralpak IC, 250 × 4.6 mm, 5 μm, column temperature: 35° C. Mobile phase A mixture of n-hexane, isopropyl alcohol, ethanol and diethyl amine at a ratio of 80:10:10:0.1 (v/v/v/v) Flow rate 0.8 mL/min. Detection 220 nm. Instrument System manufacturer: Shimadzu. LC-2030C, i-services. details

[0151] 2. .sup.1H-NMR and .sup.13C-NMR Analysis

[0152] The nuclear magnetic resonance spectrum of (−)-cibenzoline succinate was obtained using Bruker advance-III FT-NMR. .sup.1H NMR was measured at 400 MHz (in DMSO-D.sub.6) and .sup.13C NMR was measured at 400 MHz (in CD.sub.3OD).

[0153] 3. Infrared Spectroscopy (IR)Analysis

[0154] IR analysis of (−)-cibenzoline succinate was performed using a PerkinElmer spectrum FT-IR spectrophotometer. IR spectrum was recorded by using a KBr disc.

[0155] 4. Mass Spectral Analysis

[0156] Mass spectral analysis of (−)-cibenzoline succinate was performed using an Agilent LCQ Fleet Thermo-ion trap mass spectrometer equipped with Electro Spray Ionization (ESI).

[0157] 5. UV-Visible Spectroscopy Analysis

[0158] UV-visible spectroscopy analysis of (−)-cibenzoline succinate was performed 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 200 nm to 400 nm.

[0159] 6. Specific Optical Rotation Analysis

[0160] Specific optical rotation analysis of a (−)-cibenzoline succinate solution whose concentration is 1.401 g/100 ml (in methanol) was performed on Agilent Autopol V, Serial #81225 at room temperature.

[0161] 7. Single-Crystal X-Ray Diffraction (XRD) Analysis

[0162] The single crystal XRD of crystalline form 3 was analyzed using the following modeling method under the following conditions. [0163] Manufacturer: Bruker, USA [0164] Model: Nonius Kappa-CCD [0165] Measurement temperature: 296K [0166] Full sphere data: Reflected light measurement at up to 0=32.6° [0167] Modeling method for single-crystal structure identification

[0168] 1) Data reduction: HKL Scalepack (Otwinowski & Minor 1997)

[0169] 2) Cell parameter: Denzo and Scalepak (Otwinowski & Minor, 1997)

[0170] 3) Structure solving method: SHELXT-2014/7 (Sheldrick, G. M., 2015a)

[0171] 4) Square full matrix refinement: SHELXL-2014/7 (Sheldrick, G. M., 2015b)

[0172] 8. High-Throughput X-Ray Diffraction (XRD) Analysis

[0173] The high-throughput XRD of the crystalline form was analyzed under the following conditions. [0174] Manufacturer: Bruker, USA [0175] Model: General Area Detector Diffraction System (GADDS) [0176] Measurement temperature: 25° C. (RT) [0177] 20 measurement range: 1.5 to 41.5° [0178] Exposure time: 90 seconds [0179] Others: Measurement of intensity and geometric parameters with a V A NTEC-500 gas area detector (Bruker, USA)

[0180] 9. High-Resolution X-Ray Diffraction (XRD) Analysis

[0181] The high-resolution XRD of the crystalline form was analyzed using the following modeling method under the following conditions. [0182] Manufacturer: Bruker, USA [0183] Model: D8 Advance diffractometer [0184] Measurement radiation: Cu Kα1 radiation (1.54056 Å) [0185] Measurement temperature: 25° C. (RT) [0186] 20 measurement range: 2 to 41.5° [0187] Detector: LynxEye detector (Bruker, USA) [0188] Detection rate: 5 sec/step (1 step=0.016°) [0189] Sample measurement: 8-mm long glass capillary with 0.5 mm outer diameter [0190] Exposure time: 90 seconds

[0191] 10. Thermogravimetric Analysis Coupled with Mass Spectroscopy (TGMS)

[0192] Thermogravimetric analysis coupled with mass spectroscopy for the crystalline form was performed under the following conditions. [0193] Manufacturer: Mettler-Toledo GmbH, Switzerland [0194] Model: TGA/DSC 3+ STARe system [0195] Temperature range: 25 to 300° C. [0196] Temperature rise rate: 10° C./min [0197] Mass spectrometer: mass spectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany)

[0198] 11. Differential Scanning Calorimetry (DSC) Analysis

[0199] The calorimetric analysis of the crystalline form was performed by differential scanning calorimetry (DSC) under the following conditions. [0200] Manufacturer: Metter Toredo GmbH, Switzerland [0201] Model: heat flux DSC3+ STARe system [0202] Temperature rise rate: 10° C./min [0203] Temperature range: 25 to 300° C. [0204] N.sub.2 flow rate: 50 ml/min.

[0205] 12. Karl Fischer Titration Analysis

[0206] The hydrate and water contents of the crystalline form were measured by Karl

[0207] Fischer titration under the following conditions. [0208] Manufacturer: SI Analytics, Germany [0209] Model: Titroline 7500 KF trace titrator [0210] Solvent: methanol

[0211] 13. Polarized Light Microscopy Analysis

[0212] The morphology of the crystalline form was measured with a polarizing microscope under the following conditions. [0213] Manufacturer: Leica Microsystems GmbH, Germany [0214] Model: Leica DM 2500M optical microscope

[0215] 14. Ultra-Performance Liquid Chromatography-Mass Spectrometer (UPLC-MS) Analysis

[0216] The mass of the crystalline form was measured by ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) under the following conditions. [0217] Manufacturer: Agilent, USA [0218] Model: Agilent 1290 [0219] Detector 1: UV detector set at 224 nm [0220] Detector 2: MSD XT in Positive Scan Mode [0221] Measurement temperature: 25° C. (RT) [0222] Column: Agilent Eclipse Plus C18 HD (50×2.1 mm; 1.8 μm) [0223] Column temperature: 35° C. [0224] Flow cell: 10 mm path [0225] Gradient: Mobile phase A: 10 mM Ammonium acetate/Mobile phase B: Acetonitrile [0226] Flow: 0.8 ml/min [0227] Sample concentration: 0.8 mg/ml [0228] Solvent: Water: Acetonitrile (50:50 v/v) [0229] Injection: 1 μl [0230] Retention time: 1.54 min

[0231] 15. Analysis of Particle Size Distribution (PSD)

[0232] The particle size of the crystalline form was measured with a laser diffraction particle size analyzer under the following conditions. [0233] Manufacturer: Malvern Instruments Limited, UK [0234] Model: Mastersizer 2000 [0235] Sampler: Hydro 2000 G/S

[0236] Instrumental conditions: [0237] Particle reflection index (RI)): 1.52 [0238] Dispersant: heptane [0239] Absorbance: 0.1 [0240] Refractive index of dispersant: 1.39 [0241] Analysis model: general purpose [0242] Sensitivity: enhanced [0243] Absorption limit: 10-15% [0244] Measurement time: 30 seconds (repeated three times per sample) [0245] Agitation speed: 3500 RPM

[0246] Sample preparation:

[0247] About 150 mg of CT-G20 was dissolved in 20 mL of 0.2% Span 85-containing heptane in a 50 mL beaker. The solution was sonicated for about 10 seconds and placed in a sampler, and when the absorption limit reached 10 to 15%, measurement was performed.

[0248] 16. Dynamic Vapor Sorption (DVS) Analysis

[0249] Dynamic vapor sorption was measured using a vapor sorption analyzer under the following conditions. [0250] Manufacturer: Surface Measurement Systems Ltd, UK [0251] Model: DVS Adventure-I system [0252] Analysis of crystalline form of obtained solid: HT-XRPD

[0253] Relative humidity cycle:

[0254] Relative humidity was cycled from 40% to 95% (sorption), from 95% to 0% (desorption) and back to 40% (sorption 2). In each step, the relative humidity was changed to 10% at a constant temperature of 25° C. The weight equilibrium was set to a dm/dt of 0.002%/min.

PREPARATION EXAMPLES

Preparation Example 1: Preparation of (−)-Cibenzoline Succinate

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

[0255] 50 g of a suspension of (±)-cibenzoline succinate was stirred in 200 ml of water and basified with 10% sodium hydroxide solution to a pH of 10.5 to 10.8 over 30 minutes at a temperature of 25 to 30° C. and extracted with 400 ml of ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, followed by concentration under reduced pressure (400-20 mmHg) at 45° C. or lower to afford 30 g of (±)-cibenzoline free base as a white solid.

[0256] [Chiral purity measured by chiral HPLC: mixture of (−)-cibenzoline 48.76% and (+)-cibenzoline 51.24%]

Preparation Example 1-2: Preparation of (−)-Cibenzoline-D-Tartrate

[0257] 15 g of the (±)-cibenzoline free base prepared according to Preparation Example 1-1 was dissolved in 250 ml of acetonitrile and then stirred at a temperature of 25 to 30° C. for 15 min, and D-(−)-tartaric acid (1.0 m. eq.) solution in water (30 ml) was added thereto 20 min at a temperature of 25 to 30° C. to obtain a mixture. The mixture was stirred for 30 min, and 250 ml of methyl tert butyl ether (MTBE) was added to the mixture over 20 min, followed by stirring for 2.5 hours at room temperature, thereby preparing a mixture. The mixture was heated to a temperature of 50 to 55° C., stirred for 1 hour, and then allowed to cool at 25 to 30° C. and stirred for 1 hour. The obtained solid was filtered and washed with 23 ml of acetonitrile to afford (−)-cibenzoline-D-tartrate (6.4 g) having 99.0% chiral purity measured by chiral HPLC (yield: 41 (w/w) %).

[0258] .sup.1H-NMR (400 MHz, CD.sub.3OD): 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.

[0259] .sup.13C-NMR (100 MHz, CD.sub.3OD): 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.

[0260] IR (cm.sup.−1): 1731.23, 3531.63.

Preparation Example 1-3: Preparation of (−)-Cibenzoline Free Base

[0261] 5 g of the (−)-cibenzoline-D-tartrate prepared according to Preparation Example 1-2 was added to 25 ml of water and basified 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 40° C. or below to afford a (−)-cibenzoline free base (3.0 g) as a semisolid having [α].sub.D−153.82 and 99.09% chiral purity measured by chiral HPLC.

Preparation Example 1-4: Preparation of (−)-Cibenzoline Succinate

[0262] 2.5 g of the (−)-cibenzoline base prepared according to Preparation Example 1-3 was dissolved in 25 ml of isopropanol and then stirred at a temperature of 50 to 55° C., and a solution of succinic acid (1.0 m. eq.) in 12.5 ml of methanol was added thereto over 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 and 30 minutes. The resulting white solid was filtered, washed with 3.75 ml of isopropanol and then dried at a temperature of 40 to 45° C. under vacuum to afford pure (−)-cibenzoline succinate (3.2 g) having 99.9% chiral purity measured by chiral HPLC (FIG. 4).

[0263] .sup.1H-NMR (400 MHz, CD.sub.3OD): 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.

[0264] .sup.13C-NMR (100 MHz, CD.sub.3OD): 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.

[0265] IR spectrum: 1674.96 cm.sup.−1 (Acid C═O stretching vibration), 2954.43 cm.sup.−1(Sp3 stretching vibration).

[0266] MW (g/mol): 380.44

[0267] m/z of (−)-Cibenzoline: 263.35 (theoretical), 263 (observed)

[0268] UV absorption: 1.155 absorption at 202.5 nm

[0269] Specific Optical Rotation: lab −124.47; Rotation—VE.

Examples

Example 1: Preparation of Amorphous Form of (−)-Cibenzoline Succinate

[0270] 2,083.4 mg of the (−)-cibenzoline succinate prepared according to Preparation Example 1 was dissolved in 30,000 μL of a t-BuOH/distilled water (50/50 v/v %) solvent, and then freeze-dried at −73° C. for 16 hours, thereby preparing an amorphous form of (−)-cibenzoline succinate.

[0271] Through high-throughput XRD analysis of the obtained amorphous form, it was confirmed that the obtained amorphous form was amorphous as shown in FIG. 1.

Example 2: Preparation of Crystalline Form 1 of (−)-Cibenzoline Succinate

[0272] 33 mg of the amorphous form of (−)-cibenzoline succinate prepared according to Example 1 was dissolved in 350 μL of distilled water to obtain a suspension which was then stored at room temperature for 2 weeks for equilibrium. Thereafter, the liquid phase was removed by a centrifuge, and the remaining material was dried under atmospheric pressure to obtain crystalline form 1 of (−)-cibenzoline succinate.

[0273] Through high-throughput XRD analysis (HT-XRD) of the obtained crystalline form 1, it was confirmed that crystalline form was a novel crystalline form as shown in FIG. 2. As shown in Table 1 above, the diffraction peaks were analyzed by high-resolution XRD analysis (HR-XRD). Through thermogravimetric analysis coupled with mass spectroscopy (TGMS), it was confirmed that crystalline form 1 was a hydrate, and through Karl Fischer titration, it was confirmed that crystalline form 1 had a water content of 10.5%. 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., and then reached a maximum at about 58.81° C., and ended at about 68.57° C., which was considered a peak for hydrate. Next, the DSC melting endothermic transition peak started at about 189.71° C. and reached a maximum at about 190.75° C., ended at 192.28° C.

Example 3: Preparation of Crystalline Form 2 of (−)-Cibenzoline Succinate

[0274] 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.

[0275] First step: temperature rise from room temperature to 50° C. at a temperature rise rate of 10° C./hour, and then temperature reduction from 50° C. to 5° C. at a temperature reduction rate of 20° C./hour.

[0276] Second step: temperature rise from 5° C. to 50° C. at a temperature rise rate of 10° C./hour, and then temperature reduction from 50° C. to 5° C. at a temperature reduction rate of 10° C./hour.

[0277] Three step: temperature rise from 5° C. to 50° C. at a temperature rise rate of 10° C./hour, and then temperature reduction from 50° C. to 5° C. at a temperature reduction rate of 5° C./hour, and then temperature rise from 5° C. to room temperature at a temperature rise rate of 10° C./hour.

[0278] After removing the liquid phase by a centrifuge, the remaining material was dried under vacuum (5 mbar) to obtain crystalline form 2 of (−)-cibenzoline succinate.

[0279] Through high-throughput XRD analysis (HT-XRD) for the obtained crystalline form 2, it was confirmed that crystalline form 2 was a novel crystalline form as shown in FIG. 2. As shown in Table 2 above, the diffraction peaks were analyzed by high-resolution XRD (HR-XRD) analysis. Through thermogravimetric analysis coupled with mass spectroscopy (TGMS), it was confirmed that crystalline form 2 was a hydrate and contained the morpholine solvent. Differential scanning calorimetry (DSC) analysis results showed that the DSC melting endothermic transition peak first started at about 74.09° C. and reached a maximum at about 109.76° C., and ended at 116.45° C., and then started at about 120.42° C., reached a maximum at about 134.98° C., and ended at 145.93° C., and then started at about 184.90° C., reached a maximum at about 204.69° C., and ended at 265.85° C.

Example 4-1. Preparation of Crystalline Form 3 of (−)-Cibenzoline Succinate

[0280] 25.2 mg of the (−)-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 anti-solvent cyclohexane was added thereto, followed by stirring for about 1 hour for crystallization. When the precipitate occurred, the liquid phase was removed by a centrifuge (Rotanta 46 RSC Centrifuge, Andreas Hettich GmbH & Co. KG, Germany) at 3,000 RPM for about 5 minutes, and the remaining material was dried under atmospheric pressure or under high vacuum (5 mbar, 18 hours) to obtain crystalline form 3 of (−)-cibenzoline succinate.

[0281] Through high-throughput XRD analysis (HT-XRD) for the obtained crystalline form 3, it was confirmed that crystalline form 3 was a novel crystalline form as shown in FIG. 2. As shown in Table 3 above and FIG. 3, diffraction peaks were analyzed by high-resolution XRD (HR-XRD) analysis. Through thermogravimetric analysis coupled with mass spectroscopy (TGMS), it was confirmed that crystalline form 3 was anhydrous and did not contain the residual solvent. Differential scanning calorimetry (DSC) analysis results showed that the DSC melting endothermic transition peak started at about 190.26° C., reached a maximum at about 190.86° C., and ended at 192.70° C.

[0282] As a result of polarization microscope analysis, it was confirmed that crystalline form 3 was a single crystal as shown in FIG. 4. Through single crystal X-ray diffraction (XRD) analysis, as shown in FIG. 4, it was confirmed that crystalline form 3 was a triclinic crystal system and had a space group of P1. The crystalline data and structural refinement parameters are shown in Table 5 below.

TABLE-US-00005 TABLE 5 Crystalline data and structural refinement parameters Crystal dimensions 0.50 × 0.40 × 0.16 (mm.sup.3) Crystal system Triclinic Space group P1 space group Lattice constants a = 7.8748(6) Å b = 7.9994(9) Å c = 9.3644(12) Å α = 96.714(5)° β = 95.469(7)° γ = 118.505(6)° V = 507.06(10) Å.sup.3 Z = 1(1) Dc (density-calculated) = 1.246 (g/cm.sup.3)

Example 4-2: Preparation of Crystalline Form 3 of (−)-Cibenzoline Succinate(Scale-up)

[0283] In addition, 2247.8 mg of the (−)-cibenzoline succinate prepared according to Preparation Example 1 was dissolved in 10 mL of methanol to obtain a suspension, and the suspension was divided in aliquots of 2 mL. 20 mL of cyclohexane as an anti-solvent was added to the divided suspension, followed by stirring for 1 hour for crystallization to obtain 1 g of crystalline form 3.

Example 5: Preparation of Crystalline Form 3 Using 1-Propanol Solvent and N-Heptane Anti-Solvent

[0284] 21.8 mg of the (−)-cibenzoline succinate prepared according to Preparation Example 1 was dissolved in 2,500 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 the precipitate occurred, the liquid phase was removed by a centrifuge, and the remaining material was dried at atmospheric pressure to obtain a crystalline form of (−)-cibenzoline succinate.

[0285] Through high-throughput XRD (HT-XRD) analysis for the obtained crystalline form, it was confirmed that the crystalline form was crystalline form 3 of Example 4.

EXPERIMENTAL EXAMPLES

Experimental Example 1: Accelerated Storage Stability Test

[0286] For the crystalline and amorphous forms of (−)-cibenzoline succinate prepared according to Examples 1 to 4 above, a 48-hour storage stability test was performed under accelerated aging conditions (AAC; 40° C./75% RH). The test results are shown in Table 6 below.

TABLE-US-00006 TABLE 6 Form Accelerated storage stability Amorphous Example 1 Unstable - presence of different crystalline forms Crystalline form 1 Example 2 Unstable - presence of different crystalline forms Crystalline form 2 Example 3 Unstable - presence of different crystalline forms Crystalline form 3 Example 4 Stable - presence of only crystalline form 3

[0287] It was confirmed that, among the amorphous and crystalline forms prepared in Examples 1 to 4, the stable crystalline form of (−)-cibenzoline succinate was crystalline form 3 of Example 4.

Experimental Example 2: Long-Term Stability

[0288] Crystalline form 3 of (−)-cibenzoline succinate prepared according to Example 4 was stored at 60° C. for 4 weeks, and then the long-term storage stability thereof was evaluated by HT-XRPD, DSC, TGMS and UPLC analysis. The experimental results are shown in Table 7 below.

TABLE-US-00007 TABLE 7 Default reference Week Week value 1 4 Crystalline Example 4 DSC (° C.) 193.2 191.2 191.1 form 3 TGA mass 0.6 0.2 0.6 loss rate (%) Chemical 100 100 100 purity (%)

[0289] It was confirmed that crystalline form 3 prepared according to Example 4 was stable without changes in the crystalline form and chemical purity thereof even when stored for a long period of time.

Experimental Example 3: Particle Size Analysis

[0290] The particle size of crystalline form 3 of (−)-cibenzoline succinate prepared according to Example 4 was measured by a laser diffraction particle analyzer. The experimental results are shown in Table 8 below.

TABLE-US-00008 TABLE 8 D.sub.10 (μm) D.sub.50 (μm) D.sub.90 (μm) Crystalline Example 4 8.80 30.44 60.72 form 3 Reference Preparation 17.10 127.82 307.56 Example Example 1-4

[0291] It was confirmed that crystalline form 3 prepared according to Example 4 has a D.sub.50 of 30.44 μm, which is smaller than a USP fine particle standard of 125 μm (see 2019 USP 42 NF 37 Volume 4 physical tests <811> powder fineness), indicating that the particle size of crystalline form 3 was very fine. Moreover, it was confirmed that the particle size of crystalline form 3 was significantly smaller than the particle size of the material prepared in Preparation Examples 1-4 so that the effective surface area of the drug increased, suggesting that the dissolution rate of the drug would increase, so that the absorption rate and bioavailability of the drug would increase.

Experimental Example 4. Dynamic Vapor Sorption Analysis

[0292] Dynamic vapor sorption data (water sorption isotherms) were measured by a vapor sorption analyzer. The experimental result is shown in FIG. 5.

[0293] As shown in FIG. 5, crystalline form 3 showed a water absorption rate of up to 0.3% in the sorption cycle, and showed a water absorption rate of 0.2% at 80% relative humidity. Crystalline form 3 completely released the 0.3% absorbed water in the desorption cycle and absorbed almost no water in sorption 2. It was confirmed through HT-XRPD analysis that the sample obtained after DVS was maintained in Form D.

[0294] It was confirmed that crystalline form 3 prepared according to Example 4 was maintained even in an experimental reversible water sorption environment, indicating its stability even in a hygroscopic environment, and showed a water absorption rate of 0.2% at 80% relative humidity, suggesting that crystalline form 3 is non-hygroscopic (see European Pharmacopeia 5.0, 5.11. CHARACTERS SECTION IN MONOGRAPHS, Hygroscopicity classification).