Technical Field

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

Background Art

Ivabradine, S-tS-tittV^-S^-dimethox bicyclo^^.Ojocta-l^^-trien-T-yymethylXmethyl)- amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro- lH-3-benzazepin-2-one hydrochloride, represented by chemical formula I,

(I) is present in its hydrochloride form in medicinal products (original product Procorolan 5 mg; 7.5 mg). 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. Ivabradine is used for 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 1 589 005), 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 (WO2007042656 and WO2007042657). Later, further polymorphs of ivabradine hydrochloride were described: form I (WO2008065681), form IV ( O2013064307) and forms Z, X and K in WO2011098582. Patent application WO2008146308 describes an amorphous form.

As regards salts of ivabradine, the oxalate was described in WO2008/146308 and the sulphate was described in WO2010/0813142.

Cocrystals are stoichiometric multi-component compounds composed of two or more molecular or ionic compounds that are in the solid state at the room temperature. Pharmaceutical cocrystals most frequently consist of a molecule of the active compound and a molecule of the cocrystallization partner (inactive molecule). The cocrystallization partner 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 substances. Cocrystals of ivabradine, or 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 (S)-mandelic acid (IC1SM), its characterization and preparation of a pharmaceutical composition containing said cocrystal. The prepared cocrystal manifests a high physical stability and thus it appears to be a suitable form of ivabradine hydrochloride useful in a pharmaceutical composition.

A cocrystal of ivabradine hydrochloride with (5)-mandelic acid in the molar ratio of 1 :1, represented by chemical formula II:

wherein said cocrystal shows the following characteristic reflections in the X-ray powder pattern: 11.0; 17.2; 17.9; 20.9; 24.5; 25.9° ± 0,2° 2-theta, using the radiation Cu o, λ = 0.1542 run, grid parameters a = 7.44 A, b = 8.50 A, c = 52.16 A, a = β = γ = 90° and a main temperature onset at 160.2°C in the DSC record. The high physical stability of the crystalline form exhibited a conversion rate of less than 3% molar after three months at 40°C and 75% RH.

The cocrystal is prepared by mixing of ivabradine hydrochloride, (S)-mandelic acid and a solvent, the solvent being selected from the group of C1-C4 alcohols, esters, ketones, ethers and dimethyl sulfoxide. A convenient solvent is methanol, ethanol, ethyl acetate, acetone, dioxan. Another possible preparation method is grinding of ivabradine hydrochloride and (S)- mandelic acid.

Another embodiment of the invention comprises a polymorphically stable pharmaceutical composition, comprising a cocrystal of ivabradine hydrochloride and (5)-mandelic acid. Still another embodiment of the invention comprises a granulate, composed of a cocrystal of ivabradine hydrochloride and (S -mandelic acid and at least one pharmaceutically acceptable excipient, said components being in an intimate contact with each other.

Description of Figures

Fig. 1. X-ray powder pattern of a cocrystal.

Fig. 2. X-ray powder pattern of an ICISM cocrystal (top pattern). Diffraction patterns of the starting form of ivabradine hydrochloride (delta-d form; middle) and (S)- mandelic acid (bottom) are also given. Fig. 3. ssNMR spectrum of am ICISM cocrystal (bottom) and comparison to the spectra of both the input components: (5)-mandelic acid at the top, delta d form of ivabradine hydrochloride in the middle.

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

Fig. 5. DSC record of an ICISM cocrystal.

Fig. 6. Raman spectrum of an ICISM cocrystal.

Fig. 7. Raman spectrum of an ICISM cocrystal, comparison to the spectra of both the input components. Dashed line - spectrum of the delta d form of ivabradine hydrochloride, dotted line - spectrum of (S)-mandelic acid.

Fig. 8. Infrared spectrum of an ICISM cocrystal.

Fig. 9. Infrared spectrum of an ICISM cocrystal, comparison to the spectra of both the input components. Dashed line - spectrum of the delta d form of ivabradine hydrochloride, dotted line - spectrum of (5)-mandelic acid.

Fig. 10. DVS curve of an ICISM cocrystal.

Detailed description of the invention

The invention provides a new solid form of ivabradine hydrochloride, its cocrystal with (5 -mandelic acid with physical-chemical properties suitable for pharmaceutical use. It is especially the high physical stability of this solid form that makes it possible to obtain a stable pharmaceutical composition. The invention describes preparation methods of a cocrystal of ivabradine hydrochloride with (5)-mandelic acid: (i) slow evaporation of the solvent (ethanol) from a solution containing ivabradine hydrochloride and ( _< S)-mandelic acid; (ii) suspending the mixture of ivabradine hydrochloride and (S)-mandelic acid in a small amount of a solvent and subsequent agitation of the suspension in a shaker, (iii) kneading the mixture of ivabradine hydrochloride and (S)- mandelic acid in a ball grinder in the presence of a few drops of a solvent, (iv) slow and (v) abrupt cooling of the hot saturated solution containing ivabradine hydrochloride and (5)- mandelic acid. Another possible preparation method may comprise (vi) spray drying of a solution of ivabradine hydrochloride and (5}-mandelic acid in ethanol.

The thus prepared cocrystal of ivabradine hydrochloride with (S)-mandelic acid, which has not been described in the literature, has been characterized by 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 ICISM cocrystal in accordance with this invention is characterized by the reflections presented in Table 1. Table 1 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of the ICISM cocrystal in accordance with this invention are: 11.0; 17.2; 17.9; 20.9; 24.5; 25.9° ± 0.2° 2-theta. The X- ray powder pattern is shown in Fig. 1. Figure 2 shows the X-ray powder patterns of the ICISM cocrystal and those of the components from which the cocrystal has been prepared: the delta-d form of ivabradine hydrochloride (middle diffraction pattern) and (S)-mandelic acid (bottom diffraction pattern). It is obvious that the diffraction pattern of the cocrystal differs from that of the input components. Thus, the top diffraction pattern corresponds to an entirely new phase - cocrystal. The solid-phase NMR spectra have confirmed observations of the X-ray powder diffraction: the spectrum of the cocrystal differs from the spectra of the input components (Figure 3). Table 1

Interplanar el.

Position spacing Intensity (°2 Theta) d (A) {%)

6.83 12.943 3.5

10.60 8.343 3.2

11.00 8.042 10.9

11.65 7.598 11.8

11.99 7.384 9.4

12.36 7.163 1.8

12.90 6.865 4.2

13.63 6.495 1.9

15.64 5.667 8.7

15.85 5.590 19.2

16.15 5.489 12.2

16.59 5.345 25.2

17.19 5.160 87.1

17.93 4.947 100.0

18.80 4.720 7.6

20.40 4.354 6.5

20.94 4.243 28.6

21.46 4.142 4.7

21.93 4.052 7.3

22.13 4.018 8.5

22.92 3.880 12.4

23.59 3.772 16.6

24.05 3.701 6.1

24.58 3.622 43.9

25.27 3.525 2.2

25.51 3.493 5.6

25.94 3.435 17.8

26.42 3.373 1.7

26.86 3.319 10.9 Interplanar Rel.

Position spacing Intensity

("2 Theta) rf (A) (%)

27.34 3.262 6.6

27.89 3.199 4.3

28.12 3.173 4.8

28.62 3.119 6.2

30.19 2.960 4.8

30.54 2.927 2.3

31.91 2.805 4.4

33.09 2.708 6.7

33.74 2.656 1.4

34.37 2.609 1.7

35.33 2.541 1.7

36.06 2.491 1.2

37.93 2.372 1.8

38.87 2.317 1.3

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

The crystalline structure of the ICISM cocrystal was determined using the single crystal X-ray diffraction. The clear colourless crystal used was obtained by crystallization by cooling from a solution of ivabradine hydrochloride and (S)-mandelic acid in ethanol. The structure was evaluated 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 cry stallo graphic data of the ICISM cocrystal. Table 2

A theoretical powder pattern was obtained from the single crystal diffraction, which was compared to the measured X-ray powder pattern. Conformity of both the patterns was achieved, see Figure 4.

The DSC pattern of the ICISM cocrystal (Figure 5) shows a major endotherm with T _onse t = 160.2°C (162.9°C peak). The melting points of the input components are considerably different from those of the cocrystal: (5)-mandelic acid T _onS et ⁼ 131.8°C (134.3°C peak), delta d form of ivabradine hydrochloride T _onset = 194.7°C (196.7°C peak).

The Raman spectrum of the ICISM cocrystal is shown in Figure 6. The measured spectrum of the cocrystal is not a mere sum of the input components and thus this is not a mere physical mixture, as shown in Figure 7. The observed changes in the cocrystal spectrum can be ascribed to the newly created interactions between ivabradine hydrochloride and (S)-mandelic acid. The most significant is a shift of the vibration of the (>S)-mandelic acid carbonyl by 30 cm ^"1 towards higher values of the wave number and changes of C-H vibrations in the vicinity of quaternary nitrogen. The observed changes are related to the occurrence of a new phase.

The infrared spectrum of the ICISM cocrystal is shown in Figure 8. Fig. 9 shows the IR spectrum of the ICISM cocrystal and the spectra of the starting components. Neither the IR spectrum of the cocrystal is a mere sum of the input components, similarly to the Raman spectrum. Changes of (S^mandelic acid are observed: shift of the carbonyl band of the carboxylic group by 30 cm ^"1 to higher wave numbers and (ii) a drop of vibration intensity at 3500 cm ^"1 pertinent to the secondary alcohol. 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 (S)-mandelic acid.

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

The physical stability of the ICISM cocrystal was tested under two different conditions: 25°C/60% RH and 40°C/75% RH. The samples were collected after 2 weeks, 1 and 3 months and analyzed using the X-ray diffraction method. The X-ray patterns of the samples for both the stability conditions (25/60 and 40/75) at all the three time points of sampling were identical and were equal to the pattern measured before the stability testing. The crystalline form of the ICISM cocrystal has not changed. Table 3 contains the results of the stability testing of the crystalline form of the cocrystal and the starting crystalline form of ivabradine hydrochloride - delta-d form. While the cocrystal form has not changed, the delta-d form manifested transformation after one month of stability testing at the conditions of 25°C/60% RH already. Table 3

The invention further provides a pharmaceutical composition, comprising 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 compression), 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 a granulate consisting of the cocrystal and at least one pharmaceutically acceptable substance, which are in an intimate contact.

Examples Example 1

Preparation of a cocrystal of ivabradine hydrochloride and (5)-mandelic acid

3-[3-({[(7S)-3,4-dimemoxybicyclo[4.2.0]oc^

propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-3-berizazepin-2- one hydrochloride (ivabradine hydrochloride) in the amount of 100 mg (0.2 mmol) was mixed with 30 mg (0.2 mmol) of (S raandelic acid and dissolved in 3 ml of ethanol. During slow evaporation of the solvent at the room temperature a crystalline product, cocrystal of ivabradine hydrochloride and (5)- mandelic acid, precipitated. Example 2

Preparation of a cocrystal of ivabradine hydrochloride and (S)-mandelic acid

3-[3 {[(7≤)-3,4-dimetto^

propyl]-7,8-dimethoxy-2 ₅ 3,4,5-tetrahydro-lH-3-benzazepin-2-one hydrochloride (ivabradine hydrochloride) was weighed into HPLC vials 50 mg (0.1 mmol) each and mixed with an equimolar amount of (5)-mandelic acid. The mixture was suspended in 0.5 ml of a 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 dioxan) 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 further described as a cocrystal of ivabradine hydrochloride and (S -mandelic acid. Example 3

Preparation of a cocrystal of ivabradine hydrochloride and (^-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 the amount of 100 mg (0.2 mmol) was mixed with 30 mg (0.2 mmol) of (5)- mandelic acid. The mixture was put in a ball grinder, added with two drops of a 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 dioxan) and dimethyl sulfoxide. The final product was identified as a cocrystal of ivabradine hydrochloride and (^-mandelic acid.

Example 4

Preparation of a cocrystal of ivabradine hydrochloride and (S)-mandelic acid

3-[3-({[(7S)-3,4-dimemoxybicyclo[4.2.0]octa-^ _^

propyl]-7,8-dimethoxy-2 _J 3 ₃ 4,5-tetrahydro-lH-3-benzazepin-2-one hydrochloride (ivabradine hydrochloride) in the amount of 100 mg (0.2 mmol) was mixed with 30 mg (0.2 mmol) of (S)- mandelic acid and dissolved while hot in 2 ml of ethanol. During slow cooling of the solution to the room temperature a crystalline product, cocrystal of ivabradine hydrochloride and (5)- mandelic acid, precipitated within 24 h. Example 5

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

3-[3-({[(7 ₁ ¾-3,4-dimethoxybicyclo[4.2 ]octa-l ,3,5- en-7-yl]methyl}(methyl)amino)- propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-2-o ne hydrochloride (ivabradine hydrochloride) in the amount of 100 mg (0.2 mmol) was mixed with 30 mg (0.2 mmol) of (5)- mandelic acid and dissolved while hot in 2 ml of ethanol. By abrupt cooling of the solution to the temperature of 0°C a crystalline product, cocrystal of ivabradine hydrochloride and (S)~ mandelic acid, precipitated during 24 h.

Example 6

The raw materials ivabradine hydrochloride (S)-mandelic acid (105 g), lactose monohydrate (100 g), maltodextrin (160 g), maize starch (67 g) and colloidal silicone dioxide (10 g), after being each separately screened through a sieve with the mesh size of 0.7 mm, were put in a homogenizer. The mixture was homogenized at 20 rpm for 15 min. Another lactose monohydrate (766 g) and maize starch (130 g) were added by sieving to the mixture and the mixture was screened through a sieve with the mesh size of 0.7 mm. The mixture was homogenized at 20 rpm for 10 min. Finally, magnesium stearate (12 g) was added and the mixture was homogenized at 20 rpm for another 3 min. The tableting blend produced in the above mentioned way was compressed in a rotary tableting machine and used for the production of tablets with the weight of 135 mg and average hardness of 60 N.

Example 7

Ivabradine hydrochloride and (5)-mandelic acid were dissolved in ethanol. The obtained solution was used for wet granulation of lactose monohydrate and maltodextrin. The obtained granulate was dried and screened to produce a granulate consisting of a cocrystal in an intimate contact with lactose monohydrate and maltodextrin. The dried granulate was mixed with colloidal silicon dioxide and maize starch. Finally, magnesium stearate was admixed. The resulting mixture was tabletted in a high-speed tableting machine with the final weight of a tablet of 135 mg and tablet strength of about 60N. Experimental part

X-ray powder diffraction

The diffraction patterns were obtained using an X ERT PRO MPD PANalytical powder diffractometer, radiation used CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40 ^° 2Θ, increment: 0.01 ⁰ 2Θ 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 1/4° 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.

Liquid NMR

For determination of stoichiometry of the cocrystal

Instrumentation: Bruker Avance 250 or 500 MHZ; solvent: DMSO; method: IH 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 from Perkin Elmer. The sample charge in a standard Al pot was 2.7 - 3.9 mg and the heating rate was 10°C/min. The temperature program that was used consists of lmin stabilization of the sample at 20°C and then of heating up to 220°C at the rate of 10°C/min. As the carrier gas 4.0 N2 was used at the flow rate 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 of a Nd:YAG laser 1064 nm, in the measurement range from 4000 to -2000 cm ^"1 , with the spectral differentiation of 4.0 cm ^" . 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 ( icolet Nexus, Thermo, USA) equipped with a DTGS 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) records were measures with a DVS Advantage 1 instrument from Surface Measurement Systems. The sample charge in a quartz pot was 19-22 mg and the temperature in the device was 25.6 °C. Used measurement program: 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 rate 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 a CCD detector, CuK^ radiation with the wavelength of 1.5418 A. The data were collected and reduced by the CrysAlisPro program by Agilent Technologies, version 1.171.36.28. The SCALE3 ABSPAC scaling algorithm was used for empirical correction to absorption.