CZ305436B6 - Solid form of ivabradine hydrochloride and (R)-mandelic acid and pharmaceutical composition thereof - Google Patents

Abstract

The present invention relates to a novel solid form of ivabradine hydrochloride and (R)-mandelic acid of the general formula II, in 1:1 molar ratio. A process for preparing the said co-crystal consists in mixing or grinding of the separate components in the presence of a solvent. The invention also relates to a polymorphic stable pharmaceutical composition and a granulation product containing the co-crystal and a pharmaceutically acceptable excipient.

Description

Technical field

The present invention relates to a novel solid form of ivabradine hydrochloride and (R) - mandelic acid, to processes for its preparation, and to a physically stable pharmaceutical composition comprising the solid form.

BACKGROUND OF THE INVENTION

Ivabradine, 3- [3 - ({[(7X) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl} (methyl) amino) propyl] -7, 8-dimethox-2,3,4,5-tetrahydro-1 H -3-benzazepin-2-one hydrochloride represented by chemical formula 1;

CH,

CH, HCl

is present in the hydrochloride form in medicinal products (genuine Procorolan 5 mg; 7.5 mg). He represents a newly constituted group, referred to as sinus node inhibitors or brads. The mechanism of action of ivabradine is to inhibit the spontaneous depolarization of sinus node cells by blocking a specific potassium channel 1f. Ivabradine effectively reduces heart rate and consequently myocardial oxygen consumption. An indication of ivabradine is symptomatic treatment of angina pectoris.

The preparation and therapeutic use of ivabradine and its salts, especially hydrochloride, are described in EP 0 534 859.

Numerous polymorphic forms are known for ivabradine hydrochloride. The server described the following polymorphs: alpha (EP 1 589 005), beta (EP 1 695 965), beta-d (EP 1 695 710), gamma (EP 1 707 562), gamma-d (EP 1 695 709), delta and delta d (WO 2007/042656 and WO 2007/042657). Later, other polymorphs of ivabradine hydrochloride were described: form I (WO 2008/065681), form IV (WO 2013/064307) and forms Z, X and K in WO 2011/098582. WO 2008/146308 describes an amorphous form.

Among the salts of ivabradine, oxalate in WO 2008/14308 and sulfate in WO 2010/081342 have been described.

Co-crystals are steehiometric multicomponent compounds composed of two or more molecular or ionic compounds that are solid at room temperature. Pharmaceutical co-crystals most often consist of an active compound molecule and a co-crystallization partner (inactive molecules). The co-crystallization partner must meet the requirement of pharmaceutical acceptability. Co-crystals are intensively studied in pharmacy as they represent another large group of solid forms in addition to polymorphs, hydrates, solvates and salts. The co-crystals exhibit different physico-chemical properties, such as solubility or dissolution rate directly related to the bioavailability of the drug substance. Co-crystals of ivabradine, resp. ivabradine hydrochloride have not been described in the literature.

-1 CZ 305436 B6

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides processes for the preparation of a co-crystal of ivabradine hydrochloride and (R-mandelic acid), its characterization, and the preparation of a pharmaceutical composition comprising the co-crystal. ,

Co-crystal of ivabradine hydrochloride with (R) -mandelic acid in a molar ratio of 1: 1 represented by chemical formula II:

(Π),

said co-crystal showing characteristic reflections in an X-ray powder record: 6.9; 11.5; 15.6; 17.0; 17.7; 20.6; 24.2 ° ± 0.2 ° 2-theta, using CuK radiation _and λ = 0.1542 nm, lattice parameters a = 0.754 nm, b = 0.863 nm, c = 5.1506 nm, α = β = γ = 90 ° and in DSC record the main onset temperature at 132 ° C.

The co-crystal is prepared by mixing ivabradine hydrochloride, (R) -mandelic acid and a solvent. Another possibility is to grind ivabradine hydrochloride and (R-mandelic acid).

Another embodiment of the invention is a polymorphically stable pharmaceutical composition comprising a co-crystal of ivabradine hydrochloride and (Weekan) acid.

A further embodiment of the invention is also a granulate consisting of a co-crystal of ivabradine hydrochloride 25 and (1 H -nandlic acid) and at least one pharmaceutically acceptable excipient, being intimate contact with each other.

Clarification of drawings

Figure 1. ICIRM co-crystal X-ray powder record.

Figure 2. ICIRM cocrystal X-ray powder record (top record). Diffractograms of the starting form of ivabradine hydrochloride (Form II, center) and (A) -mandelic acid (below) are also shown.

Figure 3. SsNMR spectrum of ICIRM co-crystal (DOLE. Comparison with spectra of both input components: top (R) mandelic acid, middle form ivabradine hydrochloride.

Figure 4. Comparison of theoretical (bottom) and experimental (upper) X-ray powder record.

Figure 5. ICIRM co-crystal DSC recording.

Figure 6. Raman spectrum of ICIRM co-crystal.

Figure 7. Infrared spectrum of ICIRM co-crystal.

Figure 8. ICIRM co-crystal DVS curve.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a new solid form of ivabradine hydrochloride, its co-crystal with (R)-mandelic acid, with physicochemical properties suitable for use in pharmacy.

The invention describes methods for preparing a co-crystal of ivabradine hydrochloride with (R)-mandelic acid: (i) suspending a mixture of ivabradine hydrochloride and T-mandelic acid in a small amount of solvent and subsequently stirring the suspension in a shaker; (iii) slow cooling in a hot saturated solution containing ivabradine hydrochloride and (R) -mandelic acid. Alternatively, (iv) spray drying a solution of ivabradine hydrochloride and (R) - mandelic acid in ethanol.

The thus prepared ivabradine hydrochloride / γ-mandelic acid co-crystal, which has not been described in the literature, was characterized by the following analytical methods: X-ray powder diffraction (XRPD), single crystal diffraction (SXRD), Differential Scanning Calorimetry (DSC), Raman spectroscopy, IR spectroscopy, NMR spectroscopy and dynamic vapor sorption (DVS).

The crystal form of the ICIRM co-crystal of the present invention is characterized by the reflections listed in Table 1. Table 1 includes reflections whose relative intensity values are greater than 2 percent. Characteristic ICIRM co-crystal diffraction peaks of the present invention are: 6.9; 11.5; 15.6; 17.0; 17.7; 20.6; 24.2 ° ± 0.2 ° 2-theta. The X-ray powder pattern is shown in Figure 1. Figure 2 shows the X-ray powder pattern of the ICIRM co-crystal and the powder record of the components from which the co-crystal was prepared: ivabradine hydrochloride Form II (middle diffractogram) and (R) mandelic acid (lower diffractogram). It can be seen that the diffractogram of the co-crystal differs from that of the starting components. The upper diffractogram thus corresponds to a completely new phase of the co-crystal. Solid-state NMR spectra confirmed observations from X-ray powder diffraction: the co-crystal spectrum differs from that of the starting components (Figure 3).

Table 1

Position (° 2) Mezirovinná distance d (λ) = 0.1 nm Rel. Intensity (%) 3.46 25,530 4.6 6.87 12,873 9.9 11.46 7,721 17.8 11.78 7,510 15.3 12.72 6,957 2.9 13.51 6,555 2.2 14.45 6,131 2.3 15.58 5,681 22.2 16.36 5,417 5.1

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Position (° 2) Mezirovinná distance λ (λ) = 0.1 nm Rel. Intensity (%) 16.98 5,222 84.4 17.72 5,006 100.0 18.63 4,763 20.6 19.34 4,590 5.5 19.63 4,523 5.5 20.58 4,315 35.1 20.81 4,268 10.7 21.18 4,195 4.7 21.48 4,137 5.5 22.20 4,005 15.7 22.98 3,870 18.2 23.40 3,802 15.2 23.63 3,765 17.9 24.21 3,677 48.3 24.63 3,615 11.3 25.78 3,456 14.9 26.04 3,422 7.3 26.56 3,356 11.4 26.96 3,307 5.7 27.38 3,257 5.4 28.29 3,155 4.6 28.68 3,112 3.4 29.95 2,984 4.4 30.39 2,941 2.6 31.28 2,860 4.9 32.42 2,761 2.6 33.31 2,690 5.6 33.88 2,646 2.5 34.83 2,577 2.7 35.37 2,538 2.7

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Stoichiometry of the co-crystal was determined by NMR spectroscopy. The stoichiometric ratio in the co-crystal was determined to be 1: 1, with one molecule of (R)-mandelic acid per molecule of ivabradine hydrochloride.

The crystal structure of IC1RM co-crystal was determined by single crystal X-ray diffraction. The clear colorless crystal used was obtained by crystallization by cooling from a solution of ivabradine hydrochloride and (R) - mandelic acid in ethanol.

io The structure was solved by direct methods (SIR92 program) and specified in CRYSTALS 14.40b. All non-hydrogen atoms were refined with thermal oscillations. The structure contained no traces of disorder or solvent presence.

Table 2 summarizes the crystallographic data of co-crystal IC1RM.

Table 2

System Ortorombic Grupa symmetie P2,2,2, and (A) 7.5398 (2) b (A) 8.6296 (2) c (Á) 51.5013 <x (°) 90 β (°) 90 r (°) 90 Volume (Á ³ ) 3350,96 (14) OF 4 D Off (g / ml) 1,303 Number of reflections 11567 Number of reflections with I> 2 σ (AND) 5472 R (I> 2 σ (I)) 0,0449

-5GB 305436 B6

From the single crystal diffraction, a theoretical powder record was obtained, which was compared with an experimentally obtained X-ray powder record. Both records were consistent, see Figure 4.

The DSC record of the IC1RM co-crystal (Figure 5) shows the majority endotherm with T _onset = 131.5 ° C (135.4 ° C at maximum). The melting points of the input components differ from the melting point of the co-crystal: (A) mandelic acid T _onset = 131.8 ° C (134.3 ° C at maximum), ivabradine hydrochloride Form T _onset = 151.6 ° C (157.1 ° C maximum).

The Raman spectrum of the ICIRM co-crystal is shown in Figure 6. The measured co-crystal spectrum is not a mere sum of the spectra of the input components and is not a simple physical mixture. The observed changes in the co-crystal spectrum are attributable to the newly formed interactions between ivabradine hydrochloride and (γ-mandelic acid). in the neighborhood of 1450 cm ^1. The observed changes are related to the formation of a new phase.

The infrared spectrum of the ICIRM co-crystal is shown in Figure 7. Changes in (A) -mandelic acid are observed: (i) changes in the region of valence vibration of -OH groups of about 3000 cm ¹ (ii) changes in deformation vibration of hydroxy groups in the region of 1400 cm ^-1 (iii) to higher wave numbers and carbonyl ivabradine hydrochloride to lower wave numbers.

Furthermore, the vibration intensity of the NH ⁺ hydrochloride functional group varies at 2500 cm ^-1 , corresponding to the newly formed interaction between ivabradine hydrochloride and (A) -mandelic acid. ICIRM was further characterized by dynamic vapor sorption. The sample was loaded with two cycles of 0 to 90 to 0% RH. At 90% RH the sample increased weight by 1.1% due to water sorption. On subsequent desorption, all the absorbed water was lost. The whole process proves to be reversible. The first cycle is identical to the second cycle. ICIRM co-crystal is slightly hygroscopic.

The present invention also provides a pharmaceutical composition comprising said co-crystal and at least one pharmaceutically acceptable agent. The composition may be prepared using either the prepared co-crystal by conventional pharmaceutical processes (dry granulation, wet granulation, direct tabletting), or the co-crystal may be formed in-situ during the process of preparing the composition by any of the processes described above. In the case of in-situ co-crystal preparation, the resulting product is in the form of a granulate consisting of a co-crystal and at least one intimate contact pharmaceutically acceptable substance.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of co-crystal of ivabradine hydrochloride (A) -Mandelic acid

3- [3 - ({[(75) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl} (methyl) amino) propyl] -7,8- Dimethoxy-2,3,4,5-tetrahydro-1 H -3-benzazepin-2-one hydrochloride (ivabradine hydrochloride) was always weighed in an amount of 50 mg (0.1 mmol) into an HPLC vial and mixed with an equimolar amount (A) -mandelic acid. The mixture was suspended in 0.5 mL of solvent. The solvents were selected from the group of C1-C4 alcohols (preferably ethanol and methanol), esters (preferably ethyl acetate), ketones (preferably acetone), ethers (preferably dioxane) and dimethylsulfoxide. The vials were placed in an HLC shaker and shaken at 500 rpm. at room temperature for 3 days. The resulting crystalline product was isolated by filtration, dried at room temperature

And further described as (7R)-mandelic acid as the co-crystal of ivabradine hydrochloride. The admixture of starting form II of ivabradine hydrochloride was detected in the crystalline product.

Example 2

Preparation of co-crystal of ivabradine hydrochloride (N-mandelic acid)

3- [3 - ({[(75) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl} (methyl) amino) propyl] -7,8- Dimethoxy-2,3,4,5-tetrahydro-1 H -3-benzazepin-2-one hydrochloride (ivabradine hydrochloride) in an amount of 100 mg (0.2 mmol) was mixed with 30 mg (0.2 mmol) of the acid (/?) almond. The mixture was placed in a ball mill, dripped with two drops of solvent and finely ground for 30 minutes. The solvents were selected from the group of C1-C4 alcohols (preferably ethanol and methanol), esters (preferably ethyl acetate), ketones (preferably acetone), ethers (preferably dioxane) and dimethylsulfoxide. The resulting product was identified as (7R) -mandelic acid ivabradine hydrochloride co-crystal. Additives of starting components: ivabradine hydrochloride Form II and (R) - mandelic acid were detected in the crystalline product.

Example 3

Preparation of co-crystal of ivabradine hydrochloride (7 R) - mandelic acid

3- [3 - ({[(75) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl} (methyl) amino) propyl] -7,8- Dimethoxy-2,3,4,5-tetrahydro-17,7-benzazepin-2-one hydrochloride (ivabradine hydrochloride) in an amount of 100 mg (0.2 mmol) was mixed with 30 mg (0.2 mmol) of acid (R). almond and hot dissolved in 2 ml of ethanol. With gradual cooling of the solution to room temperature, a crystalline product precipitated over 72 h, ivabradine hydrochloride (7α-mandelic acid) co-crystal.

Experimental part

X-ray powder diffraction

Diffractograms were obtained on X'PERT PRO MPD PANalytical powder diffractogram, using CuKα radiation (λ = 0.1542 nm (1.542 Å)), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 to 40 ° 20 at residence time for reflection of 0.5 s, the measurement was performed on a flat sample with an area / thickness of 10 / 0.5 mm. For the primary beam correction, 0.02 rows of the Soller orifice plate, a 10 mm mask and a 1/4 ° fixed anti-scattering lens were used. The irradiated area of the sample is 10 mm, programmable divergence screens were used. For the correction of the secondary beam, 0.02 rows of Soller or 5.0 mm anti-scattering were used.

Liquid NMR

To determine the co-crystal stoichiometry

Instrumentation: Bruker Avance 250 or 500 MHz; solvent: DMSO; method: 1HNMR spectrum (repetition delay of 1 Os).

Solid State Phase DC To study polymorphism

Instrumentation: Bruker Avance 400 MHz WB; method: 13C CP / MAS, 4 mm probe, 13 kHz spinning.

-7EN 305436 B6

Differential Scanning Calorimetry (DSC)

Records were measured on a DSC Pyris 1 instrument from Perkin Elmer. The sample weighed into a standard Al crucible was between 2.7-3.9 mg and a heating rate of 10 ° C / min. The temperature program that was used consists of stabilizing the sample for 1 minute at 20 ° C and then heating to 220 ° C at a rate of 10 ° C / min. 4.0 N ₂ at a flow rate of 20 ml / min was used as the carrier gas. Raman spectroscopy

Samples were measured in glass HPLC vials on an FT-Raman RFS100 / S spectrometer, with germanium detector (Bruker, Optics, Germany), at a Nd: YAG laser wavelength of 1064 nm, in a measurement range of 4000 to 2000 cm ¹ with spectral resolution of 4 , 0 cm ^'1. Data were obtained with a spectrum accumulation of 6.4. OMNIC software was used for spectra processing. Infrared spectroscopy

The ATR (ZnSe - single reflection) infrared spectra of powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a KBr DTGS detector, measuring range 600-4000 cm ¹ and with a spectral resolution of 2.0 cm ^-1 . Data were obtained with the number of spectra accumulations: 12. OMNIC 6.2 software was used for spectra processing.

Dynamic Vapor Sorption (DVS)

Dynamic Vapor Sorption (DVS) records were recorded on a DVS Advantage 1 from Surface measurement systems. The sample weighed into the quartz plate was between 19 and 22 mg and the instrument temperature was 25.6 ° C. Measurement program used: The sample was loaded with two cycles, ranging from 0 to 90% relative humidity (sorption) and then from 90 to 0% RH (desorption). This course was repeated in the second cycle. 4.0 N ₂ at a flow rate of 200 sccm was used as carrier gas.

Single crystal diffraction

Analysis was performed at 120 K using the Xcalibur diffractometer, Atlas Gemini Ultra specular monochromator and a CCD detector _and a Cu K radiation having a wavelength of 0.15418 nm. Data collection and reduction was performed by CrysAlisPro, Agilent Technologies, version 1.171.36.28. Empirical absorption correction was performed using the SCALE3 ABSPACK scaling algorithm.

Claims (7)

Cocrystal of ivabradine hydrochloride with (Rj-mandelic acid in a molar ratio of 1: 1 represented by chemical formula II): (II). A co-crystal of ivabradine hydrochloride with (R 1-mandelic acid) according to claim 1 having characteristic reflections in the X-ray powder record: 6.9; 11.5; 15.6; 17.0; 17.7; 20.6; 24.2 ° ± 0.2 ° 2-theta, using CuK radiation _and λ = 0.1542 nm. The (7R) -mandelic acid ivabradine hydrochloride cocrystal according to claim 1 having the following lattice parameters a = 0.754 nm, b = 0.863 nm, c = 51.50 nm, and = β = γ = 90 °. The (R) -mandelic acid ivabradine hydrochloride cocrystal of claim 1 having an onset temperature of 131.5 to 135.4 ° C in the DSC record. A process for preparing a co-crystal of ivabradine hydrochloride with (7 R)-mandelic acid as defined in claims 1 to 3, characterized in that it comprises mixing ivabradine hydrochloride, (7 R)-mandelic acid and a solvent or grinding ivabradine hydrochloride and (7 R)-mandelic acid. of an acid in the presence of a solvent. 6. A polymorphically stable pharmaceutical composition comprising a co-crystal of ivabradine hydrochloride and (R1-mandelic acid) as defined in claims 1 to 3. 7. A tablet granulate comprising a co-crystal of ivabradine hydrochloride with (R1-mandelic acid as defined in claims 1 to 3) and at least one pharmaceutically acceptable excipient.