AND ITS PHARMACEUTICAL COMPOSITION

Technical Field

The invention relates to a new solid form of ivabradinc hydrochloride and (R)- mandelic acid, methods of its preparation and a physically stable pharmaceutical composition containing this solid form.

Background Art

Ivabradine, 3-[3-({[ (75)-3,4-dimethoxybicyclo[4.2.0]octa-1 ,3,5-trien-7-yi]methyl }(methyl)- amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazep in-2-one hydrochloride, represented by chemical formula I,

is found in medical products (original product Procorolan 5 mg; 7.5 mg) in the hydrochloride form. It is a representative of a newly constituted group, referred to as the sinus node inhibitors, or bradines. The mechanism of action of ivabradine consists in inhibition of spontaneous depolarization of the sinus node cells by blocking the specific potassium channel If. Ivabradine efficiently reduces the heart rate and consequently the oxygen consumption by the myocardium. The indication of ivabradine is symptomatic treatment of angina pectoris. The preparation and therapeutic use of ivabradine and its salts, especially hydrochloride, are described in the patent EP 0 534 859.

A number of polymorphic forms of ivabradine hydrochloride are known. Servier have described the following polymorphs: alpha (EP 1 589005), 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 (WO2007042656 and WO2007042657). Recently, further polymorphs of ivabradine hydrochloride have been described: Form 1 (WO2008065681), Form IV (WO2013064307) and Forms Z, X and K in WO2011098582. The patent application WO2008146308 describes an amorphous form.

As regards salts of ivabradine, the oxalate has been described in WO2008/346308 and the sulphate in WO2010081342.

Cocrystals are stoichiometric multi-component compounds consisting of two or more molecular or ionic compounds, which are in the solid state at the room temperature. Pharmaceutical cocrystals most frequently consist of a molecule of the active ingredient and a cocrystal former (inactive molecule). The cocrystal former must meet the condition of pharmaceutical acceptability. Cocrystals are subject to intensive studying in pharmacology as they represent another numerous group of solid forms besides polymorphs, hydrates, solvates and salts. Cocrystals exhibit different physical-chemical properties, e.g. solubility or dissolution rate, which are directly related to the bioavailability of the active ingredient. Cocrystals of ivabradine, or of ivabradine hydrochloride, have not been described in the literature yet.

Disclosure of Invention

The invention provides methods for the preparation of a cocrystal of ivabradine hydrochloride and (R)-mandelic acid (ICIRM), its characterization and preparation of a pharmaceutical composition containing this cocrystal. The prepared cocrystal manifests a high physical stability and thus it appears to be a suitable form of ivabradine hydrochloride applicable in a pharmaceutical composition.

The cocrystal of ivabradine hydrochloride with (R)-mandelic acid in the molar ratio of 1:1 is represented by the chemical formula II:

this cocrystal showing the following characteristic reflections in the X-ray powder pattern: K

lattice parameters and the main temperature onset at 132°C in the DSC pattern.

The cocrystal is prepared by mixing of ivabradine hydrochloride, (R)-mandelic acid and a solvent. Another possible preparation method is grinding of ivabradine hydrochloride and (R)- mandelic acid. In another aspect, the invention provides a polymorphically stable pharmaceutical composition, containing the cocrystal of ivabradine hydrochloride and (R)-mandelic acid.

In still aspect, the invention provides a granulate, consisting of the cocrystal of ivabradine hydrochloride and (R)-mandelic acid and at least one pharmaceutically acceptable excipient, both being in an intimate contact with each other.

Brief Description of Drawings

Fig. 1. X-ray powder pattern of the IC1RM cocrystal.

Fig. 2. X-ray powder pattern of the IC1RM cocrystal (top pattern). Diffractograms of the initial form of ivabradine hydrochloride (form II, in the middle) and (R)-mandelic acid (at the bottom) are also shown.

Fig. 3. ssNMR spectrum of the 1C1RM cocrystal (BOTTOM. Comparison to the spectra of both the input components: (R)-mandelic acid at the top, form II of ivabradine hydrochloride in the middle.

Fig. 4. Comparison of the theoretical (at the bottom) and experimental (top pattern) X-ray powder patterns.

Fig. 5. DSC record of the ICIRM cocrystal.

Fig.6. Raman spectrum of the ICIRM cocrystal.

Fig. 7. Infrared spectrum of the ICIRM cocrystal.

Fig. 8. DVS curve of the ICIRM cocrystal. Detailed description of the invention.

The invention provides a new solid form of ivabradinc hydrochloride, its cocrystal with (R)-mandelic acid with physical-chemical properties suitable for pharmaceutical use.

The invention describes the following preparation methods of the cocrystal of ivabradine hydrochloride with (R)-mandelic acid: (i) suspending of a mixture of ivabradine hydrochloride and R -mandelic acid in a small amount of a solvent and subsequent agitation of the suspension in a shaker, (ii) kneading of a mixture of ivabradine hydrochloride and (R)- mandelic acid in a ball mil) in the presence of a few drops of a solvent, (tit) slow cooling of a solution containing ivabradine hydrochloride and (R)-mandelic acid saturated when hot. Another possible preparation method may include fiv) spray drying of a solution of ivabradine hydrochloride and (R)-mandelic acid in ethanol.

Thus prepared cocrystal of ivabradine hydrochloride with (R)-mandelic acid, which has not been described in the literature yet, has been characterized with the following analytic methods: X-ray Powder Diffraction (XRPD), Single Crystal X-ray Diffraction (SXRD), Differential Scanning Calorimetry (DSC), Raman Spectroscopy. IR spectroscopy, NMR spectroscopy and Dynamic Vapour Sorption (DVS).

The crystalline form of the ICIRM cocrystal in accordance with this invention is characterized by the reflections presented in Table 1. Table 1 includes reflections whose relative intensity values are higher than 2 percent. The characteristic diffraction peaks of the ICIRM cocrystal in accordance with this invention are: 6.9; 11.5; 15.6; 17.0; 17.7; 20.6; 24.2° ± 0.2° 2-thcta. The X-ray powder pattern is shown in Fig. 1. Figure 2 shows the X-ray powder patterns of the ICIRM cocrystal and powder patterns of the components the cocrystal was prepared from: Form II of ivabradine hydrochloride (the middle diffractogram) and (R)-mandelic acid (the bottom diffractogram). It can be seen mat the diffractogram of the cocrystal differs from those of the input components. The top diffractogram thus corresponds to an entirely new phase - a cocrystal. The solid-phase NMR spectra confirmed observations of the X-ray powder diffraction: the spectrum of the cocrystal differs from those of the input components (Figure 3).

The stoichiometry of the cocrystal was determined using the NMR spectroscopy. It has been determined that the stoichiometric ratio in the cocrystal is 1 :1, there is one molecule of (R)- mandelic acid per one molecule of ivabradine hydrochloride.

The crystalline structure of the 1C1RM cocrystal was determined using the single crystal X- ray diffraction. The used clear colourless crystal was obtained by crystallization by cooling from a solution of ivabradine hydrochloride and (R)-mandelic acid in ethanol.

The structure was determined by direct methods (SIR92 program) and specified in the CRYSTALS 14.40b program. All non-hydrogen atoms were specified with thermal oscillations. The structure did not contain any traces of disorder or solvent presence.

Table 2 summarizes the crystallographic data of the 1C1RM cocrystal.

The monocrystal diffraction provided a theoretical powder pattern, which was compared to the experimentally obtained X-ray powder pattern. Conformity of both the patterns was achieved, see Figure 4.

The DSC pattern of the ICIRM cocrystal (Figure 5) shows the majority endotherm with peak). The melting points of the input components are different from the melting point of the cocrystal: (R)-mandelic acid Form II of ivabradine hydrochloride

The Raman spectrum of the ICIRM cocrystal is shown in Figure 6. The measured spectrum of the cocrystal is not a mere sum of the spectra of the input components and thus it is not a plain physical mixture. The observed changes in the cocrystal spectrum can be ascribed to the newly created interactions between ivabradine hydrochloride and (R)-mandelic acid. Shifts of vibrations of the (R)-mandelic acid carbonyl towards higher wave number values, and of ivabradin hydrochloride carbonyl towards lower wave number values and changes of C-H deformation vibrations of ivabradine around 1450 cm ^-1 are the most significant. The observed changes are related to the occurrence of a new phase.

The infrared spectrum of the ICIRM cocrystal is shown in Figure 7. Like in the Raman spectrum, the IR spectrum of the cocrystal is not a mere sum of spectra of the input components. Changes of (R)-mandelic acid are observed: (i) changes in the range of valence vibrations of the -OH groups around 3000 cm ^-1 (it) changes of deformation vibrations of the hydroxy groups in the area of 1400 cm ^-1 (Hi) a shift of the vibration band of the carbonyi of the carboxy!ic group of mandelic acid towards higher wave numbers and that of the ivabradine hydrochloride carbonyi towards lower wave numbers.

Further, the vibration intensity of the N-H ⁺ functional group of the hydrochloride at 2500 cm ^-1 changes, which corresponds to the newly formed interaction between ivabradine hydrochloride and (R)-mandelic acid.

ICIRM was further characterized with the dynamic vapour sorption. The sample was loaded with two cycles of 0 - 90 - 0% of relative humidity (RH). At 90% RV the sample increased its weight by 1.1 % due to water sorption. During the subsequent desorption all the absorbed water was lost. The whole cycle appears to be reversible. The first cycle is identical to the other cycle. The ICIRM cocrystal is weakly hygroscopic.

The invention also provides a pharmaceutical composition, containing the above mentioned cocrystal and at least one pharmaceutically acceptable substance. The composition may be prepared either with the use of the prepared cocrystal by means of common pharmaceutical processes (dry granulation, wet granulation, direct tabletting), or the cocrystal may be produced in situ in the course of the preparation process of the composition by one of the above mentioned processes. In the case of the in situ preparation of the cocrystal the resulting product has the form of granulate consisting of the cocrystal and at least one pharmaceutically acceptable substance, being in an intimate contact.

Examples

Example 1

Preparation of the cocrystal of ivabradine hydrochloride and (R)-mandelic acid hydrochloride) was always weighed in the amount of 50 mg (0.1 mmol) to a HPLC vial and was mixed with an equimolar amount of (R)-mandelic acid. The mixture was suspended in 0.5 ml of the solvent. The solvents were selected from the group of C1-C4 alcohols (preferably ethanoi and methanol), esters (preferably ethyl acetate), ketones (preferably acetone), ethers (preferably dioxane) and dimethyl sulfoxide. The vials were placed in an HLC shaker and shaken at 500 rpm at the room temperature for 3 days. The resulting crystalline product was isolated by filtration, dried at the room temperature and then described as a cocrystal of ivabradine hydrochloride and (R)-mandelic acid. An admixture of the starting Form H of ivabradine hydrochloride was detected in the crystalline product.

Example 2,

Preparation of the cocrystal of ivabradine hydrochloride and (R)-mandelic acid

M

hydrochloride) in the amount of 100 mg (0.2 mmo!) was mixed with 30 mg (0.2 mtnol) of (R)-mandelic acid. The mixture was put in a ball mill with added two drops of the solvent and finely ground for 30 minutes. The solvents were selected from the group of C1-C4 alcohols (preferably ethanoi and methanol), esters (preferably ethyl acetate), ketones (preferably acetone), ethers (preferably dioxane) and dimethyl sulfoxide. The final product was identified as a cocrystal of ivabradine hydrochloride and (R)-mandelic acid. Admixtures of the starting components were detected in the crystalline product: Form H of ivabradine hydrochloride and (R)-mandelic acid.

Example 3

Preparation of the cocrystal of ivabradine hydrochloride and (R)-mandelic acid

3

p

hydrochloride) in the amount of 100 mg (0.2 mmol) was mixed with 30 mg (0.2 mmol) of (R)-mandelic acid and dissolved in a hot state in 2 ml of ethanoi. During slow cooling of the solution to the room temperature the crystalline product, cocrystal of ivabradine hydrochloride and (R)-mandelic acid, was separated during 72 h. Experimental part

X-ray powder diffraction

The diffractograms were obtained using an X PERT PRO MPD PANalytical powder diffractometer, radiation used CuKα (λ=1.542 Å), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40' 20, increment: 0.01° 20 at the dwell time at a reflection of 0.5 s» the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a l/4° fixed anti-dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.

LiquidNMR

For determination of stoichiometry of the cocrystal

Instrumentation: Broker Avance 250 or 500 MHZ; solvent: DMSO; method: 1H NMR spectrum (repetition delay 10s).

Solid-phase ssNMR

For studying the polymorphism

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

Differential Scanning Calorimetry (DSC)

The records were measured with a DSC Pyris 1 device made by the company Perkin Elmer. The sample charge in a standard Al pot was 2.7 - 3.9 rag and the heating rate was 10°C/min. The temperature program that was used consists of Imin stabilization of the sample at 20°C and then of heating up to 220°C at the rate of 10 ^e C/min. As the carrier gas 4.0 N2 was used at the flow of 20 ml/min.

Raman spectroscopy

The samples were measured in glass HPLC vials with a FT- Raman RFS100/S spectrometer with a germanium detector (Bruker Optics, Germany), at the wavelength Nd: YAO laser 1064 nm, in the measurement range from 4000 to -2000 cm ^-1 , with the spectral resolution of 4.0 cm-1. The data were obtained at 64 spectrum accumulations. The OMNIC software was used to process the spectra.

Infrared spectroscopy

ATR (ZnSe - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTOS KBr detector, in the measurement range of 600-4000 cm-1 and the spectral resolution of 2.0 cm-1. The data were obtained at 12 spectrum accumulations. The OMNIC 6.2 software was used to process the spectra.

Dynamic vapour sorption (DVS)

The dynamic vapour sorption (DVS) patterns were measures with a DVS Advantage 1 device made by the company Surface Measurement Systems. The sample charge in a quartz pot was 19-22 mg and the temperature in the device was 25.6 °C. Measurement program used: the sample was loaded with two cycles with the course from the relative humidity of 0% to 90% (sorption) and then from 90% to 0% RH (desorption). This procedure was repeated in the second cycle. As the carrier gas 4.0 N2 was used at the flow of 200 seem.

Single crystal diffraction

The analysis was conducted at the temperature of 120 K using the Xcalibur, Atlas, Gemini ultra diffractometer with a mirror monochromator and CCD detector, CuKα radiation with the wavelength of 1.5418 Å. The data were collected and reduced by the CrysAlisPro program by Agilent Technologies, version 1.171.36.28. The SCALE3 ABSPACK scaling algorithm was used for empirical correction to absorption.