The present invention relates to novel salts and physical forms of ivabradine, methods for their formation, and uses thereof, such as in the treatment of myocardial ischemia and the like.

Ivabradine (Formula I), and in particular pharmaceutically acceptable acid salts thereof, have highly valuable pharmacological and therapeutic properties, especially for the treatment of bradycardia. These compounds are also useful in the treatment or prevention of myocardial ischemia, such as angina pectoris, myocardial infarct and associated rhythm disturbances, and in various pathologies relating to rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.

(I)

Ivabradine acts on the \f ion current, which is highly expressed in the sinoatrial node. I _f , also known as the "funny current", is an electric current in the heart that flows through the funny channel. \f is a mixed Na ⁺ - K ⁺ inward current activated by hyperpolarisation and modulated by the autonomic nervous system. \f is understood to be one of the most important ionic currents for regulating pacemaker activity in the sinoatrial node. Ivabradine selectively inhibits the pacemaker \f current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, selectively slowing the heart rate and allowing more time for blood to flow to the myocardium. Other commonly used rate-reducing medications, such as beta-blockers and calcium channel blockers, not only reduce heart rate, but also the cardiac contractility. Given the selective decrease in rate without loss of contractility, ivabradine may prove efficacious for treatment of congestive heart failure without decreases in ejection fraction. Ivabradine hydrochloride (i.e. a compound of Formula I as a hydrochloric acid salt) has been approved by the European Medicines Agency (EMEA) in 27 Europe countries for use in the treatment of chronic stable angina pectoris of normal sinus rhythm which has contraindication or intolerance to the beta- receptor blocking agent. Ivabradine hydrochloride can be isolated in many crystalline polymorphic forms, the most well-known being the a-form, β-form, 3d- form, γ-form, yd-form, δ-form and 5d-form. Many other polymorphic forms are known, including form-ω, form-l, form-ll, form-Ill, form-IV, form-ζ, form-K, form-X, form-Z and an amorphous form. There is extensive interest in ivabradine hydrochloride as an active pharmaceutical ingredient (API) and the possibility and occurrence of additional stable polymorphic forms.

The particular polymorph of ivabradine hydrochloride formed may be dependent upon a number of factors, such as

i. the solvent (or solvent mixture) that is used to crystallise ivabradine hydrochloride;

ii. the temperature at which the ivabradine hydrochloride is dried; and/or iii. the degree of hydration of ivabradine hydrochloride. Some polymorphs may be characterized as "pseudopolymorphs" due to their high sensitivity to humidity, which may be crystallised as a hemihydrate, monohydrate, tetrahydrate or mixtures thereof having different total hydration degrees. Some polymorphic forms are characterised as "metastable" due to their ease of transformation from one polymorphic form to another, i.e. from 5- form to 5d-form and vice versa. The δ-form of ivabradine hydrochloride is a solvated form and may exist as either 51 or 52 dependent upon the solvent that co-exists in the crystal lattice. Form-51 is acetonitrile solvated, whereas form-52 is acetone solvated. A further hydrated δ-form is known, however, the form-51 , form-52, and 5-form may have identical X-ray powder diffraction (XRPD) patterns.

Drying 5-polymorphs of ivabradine hydrochloride can form an anhydrous 5d- form. This transformation is dependent upon the volatility of the solvated crystallised solvent. Conversely, an anhydrous 5d-form of ivabradine hydrochloride will readily convert to a δ-hydrated form upon exposure to environmental humidity, δ, 51 , or δ2 may form form-β of ivabradine hydrochloride upon exposure to an environment saturated with humidity. Form-β is ivabradine hydrochloride tetrahydrate and is generally understood to be the most stable polymorphic form of ivabradine hydrochloride. Drying forms- δ1 and δ2 of ivabradine hydrochloride at low temperature in vacuo may afford an anhydrous 5d-form, however, excessive drying at higher temperature may leads to anhydrous form-a. Form-IV is referred as hemihydrate of ivabradine hydrochloride.

The ability of polymorphic forms of ivabradine hydrochloride to interconvert cannot easily be controlled, and may have a negative effect on the physical properties of ivabradine hydrochloride. Dissolution, melting point, hygroscopicity, stability and degradation of ivabradine hydrochloride may differ from one polymorphic form to another, with certain polymorphic forms of ivabradine hydrochloride requiring storage at low temperature to avoid degradation. The ease with which one form of ivabradine hydrochloride can transform to another has led to a lack of confidence in projected expiration and storage limits, particularly when formulated as an API. In view of this, ivabradine hydrochloride may not be the most suitable choice of an ivabradine addition salt for use as a medicament.

WO 2011/104723 relates to acid addition salts of ivabradine and their use in pharmaceutical compositions and as medicines.

In view of the above, there is a need for alternative forms of ivabradine that do not suffer the same issues as ivabradine hydrochloride. In particular, there is a need to provide a new form of ivabradine that addresses

(a) the existence of metastable polymorphic forms of ivabradine hydrochloride;

(b) the stability issues associated with ivabradine hydrochloride; and/or (c) the need for low temperature storage of the API, which may place a demanding requirement on its transportation.

In a first aspect of the present invention there is provided a composition comprising a compound of Formula I as a p-toluenesulfonic acid salt, wherein the compound is in the form of an amorphous solid.

(I)

The p-toluenesulfonic acid salt of the compound of Formula I may be stable at room temperature, which can be an advantage over various polymorphic forms of ivabradine HCI. Further, the p-toluenesulfonic acid salt of the compound of Formula I may be characterised as having one solid form, with no polymorphic forms other than the amorphous form.

As used herein, the compound of Formula I is the free base of ivabradine unless otherwise stated, such as when referred to the p-toluenesulfonic acid salt thereof. The compound of Formula I as a p-toluenesulfonic acid salt may be referred to as ivabradine tosylate. As the skilled person would be aware, p- toluenesulfonic acid is para-toluenesulfonic acid, which may also be referred to as PTSA, pTsOH, or tosylic acid (TsOH).

It will be appreciated by those skilled in the art that compounds of Formula I may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism when in crystalline form. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of Formula I, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallisation techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

The composition may comprise the compound of Formula I in a variety of additional pharmaceutically acceptable acid salts in addition to the p- toluenesulfonic acid salt. Those additional pharmaceutically acceptable acids include, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, benzoic acid, methansulfonic acid, isethionic acid, or benzenesulfonic acid.

As used herein, an "amorphous solid" is a material that does not have a periodical three-dimensional pattern, i.e. the material has no long-range intermolecular order. An amorphous solid, such as amorphous ivabradine tosylate, lacks crystallinity and can be identified as amorphous by XRPD as described herein.

An amorphous solid may be "X-ray amorphous" when the XRPD spectra contains no crystalline diffraction peaks. As is known in the art, a crystalline material comprises diffraction peaks that are relatively sharp in an XRPD spectra compared to peaks in an XRPD spectra of an amorphous solid, which are relatively broad peaks.

In a particular feature of the first aspect of the invention, the composition comprises at least about 70 wt%, such as at least about 80 wt%, for instance at least about 90 wt%, preferably about 95 wt%, of the compound of Formula I in the form of an amorphous solid, based upon the total amount of the compound of Formula I in the composition. It may be advantageous that the composition comprises at least about 99 wt%, even more preferably at least about 99.9 wt%, of the compound of Formula I in the form of an amorphous solid, based upon the total amount of the compound of Formula I in the composition.

In a feature of the invention, substantially all of the compound of Formula I is in the form of an amorphous solid, preferably all of the compound of Formula I is in the form of an amorphous solid. In this case, the XRDP of the composition will comprise no sharp peaks, such as those that relate to crystalline forms of the compound of Formula I. As used herein, "substantially all" means all except for impurity levels of other compounds. Substantially all may therefore mean at least 95 wt%, such as at least 99 wt%, preferably 99.9 wt%, more preferably 99.99 wt% of the compound of Formula I is in the form of an amorphous solid. As mentioned above, the composition may comprise salts of ivabradine other than the p-toluenesulfonic acid salt. Examples of such salts are those formed from hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid; acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, oxalic acid, benzoic acid, methansulfonic acid, isethionic acid, benzenesulfonic acid, or combinations thereof.

Compounds of Formula I, other than the p-toluenesulfonic acid salt of Formula I, may be present in the composition in any amount. However, it is preferred that compounds of Formula I other than the p-toluenesulfonic acid salt are present in only trace amounts.

As used herein, "trace amounts" means that those compounds are present in an amount of less than about 1 wt%, such as less than about 0.5 wt%, preferably less than about 0.1 wt%, more preferably less than about 0.05 wt%, most preferably less than about 0.001 wt%, based upon the total weight of the composition.

The composition may consist essentially of, preferably consists of, the compound of Formula I as a p-toluenesulfonic acid salt. That is, the composition may contain only trace amounts of compounds other than the compound of Formula I as a p-toluenesulfonic acid salt. The amount of impurities and compounds of Formula I other than the p- toluenesulfonic acid salt may be determined by any suitable method, such as by HPLC. The amorphous solid, such as amorphous ivabradine tosylate, may be free flowing which may be particularly advantageous when processing, formulating and transporting the compound.

The composition may be a pharmaceutical composition comprising a compound of Formula I as a p-toluenesulfonic acid salt and a pharmaceutically-acceptable excipient. The compound of Formula I as a p-toluenesulfonic acid salt should therefore be present in the composition in a therapeutically effective amount.

Suitable pharmaceutically-acceptable excipients are known to the skilled person, and include diluents (fillers), disintegrants, binders, lubricants, and glidants amongst others.

In a second aspect of the invention, the composition of the invention is provided for use as a medicament. Such use may be in the treatment of myocardial ischemia, such as angina pectoris.

In a feature of the second aspect of the invention there is provided a method of treating myocardial ischemia, such as angina pectoris, comprising administering a composition of the invention comprising a therapeutically effective amount of a compound of Formula I as a p-toluenesulfonic acid salt to a subject in need thereof.

In a third aspect of the invention there is provided a process for the formation of a composition of the invention, wherein the process comprises the step of reacting a compound of Formula I (which may be referred to as the free base of ivabradine) with p-toluenesulfonic acid, in a first solvent, to form a compound of Formula I as a p-toluenesulfonic acid salt in the form of an amorphous solid.

The first solvent may be selected from the group consisting of saturated or unsaturated, cyclic or acyclic, C ₅ to d ₂ hydrocarbons, such as n-pentane, n- hexane, n-heptane, cyclohexane, and toluene; cyclic or acyclic C ₂ to Ci ₂ ethers, such as tetrahydrofuran, diethyl ether, diisopropyl ether, and dioxane; C ₂ to Ci ₂ esters, such as methyl acetate, and ethyl acetate; Ci to C ₆ alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol; C ₂ to C ₈ sulfoxides, such as dimethyl sulfoxide; C ₂ to Ci ₂ amides, such as dimethylformamide, and dimethyl acetamide; acetonitrile; C3 to Ci ₂ ketones, such as acetone; and a combination thereof. It is preferred that the first solvent is a combination of ethyl acetate, acetone and diethyl ether, for example in a volume ratio of from about 15:1 :15 to about 25:1 :25, such as about 20:1 :20, respectively.

As the skilled person will be aware, "hydrocarbons" are compounds formed from carbon and hydrogen atoms, such as those defined above.

The reaction may be carried out at temperatures typically from about 0 °C to about 80 °C. It is preferably that the reaction is carried out at a temperature from about 18 °C to about 30 °C.

The reaction may be performed for a period of from about 15 minutes to about 24 hours. Preferably the reaction is performed for about 3 to about 5 hours, more preferable about 4 hours.

A suitable amount of p-toluenesulfonic acid should be used to ensure that all of the compound of Formula I is converted into a compound of Formula I as a p- toluenesulfonic acid salt, preferably an excess of p-toluenesulfonic acid being present in the composition. It is preferred that the amount of p-toluenesulfonic acid used is from about 1 to about 1.3, preferably about 1.2, molar equivalents based upon the amount of compound of Formula I.

In particular feature of the third aspect of the invention, a compound of Formula I (i.e. the free base of ivabradine) may be dissolved in a solvent mixture of ethyl acetate and acetone (such as in a volume ratio of 10:1 , respectively) with stirring at a temperature of from about 18 °C to about 30 °C. 1.2 equivalents of p- toluenesulfonic acid (as the monohydrate), dissolved in ethyl acetate (for instance 10 volumes), may be added slowly to the mixture to form a reaction mixture. The reaction mixture may be stirred for three hours at a temperature of from about 18 °C to about 30 °C. During this time a precipitate may be formed. Diethyl ether (preferably a volume equal to that of ethyl acetate used to form the reaction mixture, for instance 20 volumes) may be added to the reaction mixture, and the reaction mixture may be stirred for one additional hour at a temperature of from about 18 °C to about 30 °C. The precipitate may be collected by filtration and dried for a period of from about 10 to about 20 hours, preferably about 14 to about 16 hours, at a temperature of from about 35 °C to about 45 °C, preferably about 40 °C.

It may be advantageous conduct the process at a low concentration and/or include in the reaction mixture acetone in an amount of from about 2.5 vol% to about 5 vol% as a co-solvent. It may be preferable to use about 2.5 vol% of acetone as a co-solvent. This may delay precipitation and/or afford the compound of Formula I as a p-toluenesulfonic acid salt in higher purity.

Without being bound by theory, the use of diethyl ether may increase precipitation and/or assist in the recovery of the compound of Formula I as a p-toluenesulfonic acid salt.

The compound of Formula I as a p-toluenesulfonic acid salt as an amorphous solid may be washed with a second solvent. This purification process may increase the purity of the solid by, for instance, removing impurities (such as those soluble in the second solvent) including other solvents.

The second solvent may be selected from the group consisting of saturated or unsaturated, cyclic or acyclic, C ₅ to d ₂ hydrocarbons, such as n-pentane, n- hexane, n-heptane, cyclohexane, and toluene; cyclic or acyclic C ₂ to Ci ₂ ethers, such as tetrahydrofuran, diethyl ether, diisopropyl ether, and dioxane; C ₂ to Ci ₂ esters, such as methyl acetate, and ethyl acetate; Ci to C ₆ alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol; C ₂ to C ₈ sulfoxides, such as dimethyl sulfoxide; C ₂ to Ci ₂ amides, such as dimethylformamide, and dimethyl acetamide; acetonitrile; C3 to Ci ₂ ketones, such as acetone; and a combination thereof. Preferably the second solvent is selected from the group consisting of n-heptane, ethyl acetate, diethyl ether and a combination thereof. It is particularly preferred that the second solvent is diethyl ether.

The amorphous solid may be stirred in the second solvent for a period of from about 15 minutes to about 24 hours, such as from about 3 hours to about 5 hours, and preferably about 4 hours, at a temperature of from about 0 °C to about 80 °C. It is particularly preferred that the purification process is carried out by trituration at a temperature from about 18 °C to about 30 °C. When the second solvent comprises diethyl ether it is preferred that the temperature is below about 35 °C. Dependent on the second solvent used during the purification process the compound of Formula I as a p-toluenesulfonic acid salt may be partially or fully dissolved. This may occur in particular if purification is conducted at a higher temperature, such as at a temperature of from about 40 °C to about 80 °C. For instance, when the second solvent comprises ethyl acetate, the amorphous solid may be partially or fully dissolved in the solvent, in particular at a temperature above about 65 °C. The compound of Formula I as a p-toluenesulfonic acid salt which is dissolved in the second solvent may be recovered by methods known to the skilled person, such as by precipitation and filtration. As the skilled person will understand the compound of Formula I as a p-toluenesulfonic acid salt in the form of an amorphous solid, once treated with the second solvent, may be filtered, such as under suction or gravity, to remove the second solvent. The compound of Formula I (i.e. the free base of ivabradine) may be formed from a hydrochloric acid salt of a compound of Formula I. Therefore, a particular feature of the third aspect of the invention comprises the step of reacting a compound of Formula I as a hydrochloric acid salt with a suitable base in a suitable third solvent to form the compound of Formula I.

In this feature the suitable base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. It is preferred that the suitable base is sodium hydroxide. The third solvent may be water, and in particular purified water.

The compound of Formula I (i.e. the free base of ivabradine) may be separated from the third solvent by any conventional means known to the skilled person, such as by extraction with an extraction solvent. The extraction solvent may be ethyl acetate, which may be removed from the compound of Formula I by a suitable method, such as evaporation.

Whilst the compound of Formula I as the hydrochloric acid salt may be converted into the compound of Formula I (i.e. the free base of ivabradine) in the process of the invention as described above, the free base of ivabradine may be converted into the compound of Formula I as a hydrochloric acid salt as part of that process. The conversion of ivabradine between the compound of Formula I (i.e. the free base) and the compound of Formula I as the hydrochloric acid salt may increase purity of the composition. For instance, it may be easier to remove impurities from the compound of Formula I as the hydrochloric acid salt when in a solid form, such as a crystalline form, (i.e. by washing and/or recrystallisation) compared to the removal of impurities from a compound of Formula I as the free base.

In particular, a solid compound of Formula I as the hydrochloric acid salt may be treated with an organic solvent, which is preferably acetonitrile, at a temperature from about 0 °C to 80 °C, preferably at about 70 °C to about 80 °C, for a period of from about 0.5 hours to about 24 hours, preferably about 2 hours, and subsequently and optional at a temperature of about 0 °C to about 5 °C, preferably at about 0 °C, for about 1 hour to about 24 hours, preferably about 18 hours. The solid may be filtered at 0 °C to afford the compound of Formula I as the hydrochloric acid salt. This may produce a composition at a higher purity. Therefore, in a feature of the third aspect of the invention the process comprises the step of reacting a compound of Formula I (i.e. the free base of ivabradine) and hydrochloric acid in a suitable fourth solvent to form the compound of Formula I as the hydrochloric acid salt. In this feature the fourth solvent may be selected from the group consisting of Ci to C ₆ alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol; cyclic or acyclic C ₂ to d ₂ ethers, such as tetrahydrofuran, diethyl ether, diisopropyl ether, and dioxane; C ₂ to C ₈ sulfoxides, such as dimethyl sulfoxide; C ₂ to Ci ₂ amides, such as dimethylformamide, and dimethyl acetamide; acetonitrile; C3 to Ci ₂ ketones, such as acetone; and a combination thereof. It is preferred that the fourth solvent is a combination of acetonitrile and isopropanol. The hydrochloric acid may be provided in isopropanol, preferably from about 5 to about 6 N HCI in isopropanol, which may be added to the compound of Formula I (i.e. the free base of ivabradine).

Ivabradine (i.e. a compound of Formula I) may be purchased as its hydrochloric acid salt. However, the compound of Formula I may be formed according to the following process.

(V)

(1 S)-4,5-Dimethoxy-1 -[(methylamino)methyl]benzocyclobutane hydrochloride (Formula II) may be reacted with 1 -bromo-3-chloropropane (Formula III) in the presence of a base (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, preferably potassium carbonate) in a solvent (e.g. water, a Ci to C ₆ alcohol, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert- butanol; an ether, such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; a sulfoxide, such as dimethyl sulfoxide; or an amide, such as dimethylformamide, dimethyl acetamide; acetonitrile or the like or mixtures thereof or under neat conditions, i.e. where no solvent is added, preferably water, such as deionized water) at a temperature of from about 0 °C to about the reflux temperature of the reaction mixture, for instance at 40 °C. This forms (S)- 3-chloro-N-((3,4-dimethoxybicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)methyl)-N- methylpropan-1 -amine (Formula IV).

The compound of Formula IV may be reacted with 7,8-dimethoxy-1 ,3,4,5- tetrahydro-2H-benzo[d]azepin-2-one (Formula V), preferably in the presence of a base (such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride or the like, preferably potassium tert-butoxide), in a suitable solvent (such as a Ci to C ₆ alcohol, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol; an ether, such as tetrahydrofuran, diethyl ether, diisopropyl ether; dioxane; a sulfoxide, such as dimethyl sulfoxide; an amide, such as dimethylformamide, dimethyl acetamide; acetonitrile or the like or mixtures thereof). This forms the compound of Formula I.

Figure 1 shows the XRPD spectra of six prepared samples of ivabradine tosylate i.e. a compound of Formula I as a p-toluenesulfonic acid salt, each being in the form of an amorphous solid. Each spectra shows only a broad peak which is indicative of an amorphous solid. The absence of sharp, defined peaks in the spectra shows that the samples lack any crystallinity. The XRPD spectra were measured using a Shimadzu 6000 diffractometer using Ka radiation (λ=0.15478 nm), with a source supply of 40kV, 30mA, receiving slits 0.30mm, Θ-2Θ scan at 2°min ^"1 , in the range 2°<2Θ<50°. The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included in the scope of the present invention.

Examples

Example 1 Preparation of (S)-3-chloro-N-((3,4-dimethoxybicyclo[4.2.0]octa-1(6

yl)methyl)-N-methylpropan-1-amine (Formula IV)

K ₂ C0 ₃ (59.54 g) was added to a stirred, clear solution of (1 S)-4,5-dimethoxy-1 - [(methylamino)methyl]benzocyclobutane hydrochloride (Formula II) (30. Og) in water (180 mL). The temperature was increased to 40 °C. The reaction mixture was stirred for about 5 to about 10 min at 40 °C. 1 -bromo-3-chloropropane (Formula III) (67.83 g) was then added and the reaction mixture was stirred for 5 hours at 40 °C. The progress of the reaction was monitored using TLC. Upon completion, the reaction was cooled to ambient temperature and a mixture of EtOAc (50 mL) and water (10ml_) was added. The organic layer was collected and the remaining aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 3M HCI (3 x 50 mL). The combined aqueous extracts were adjusted to a pH of about 13 with 4M NaOH (160 mL). The basic aqueous solution was extracted with EtOAc (1 x 200 mL & 3 x 100 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and the volatiles were removed under reduced pressure to afford 32.84 g (94%) of the compound of Formula (IV) as an oil. Example 2

Preparation of ivabradine free base, i.e. a compound of Formula (I) t-BuOK (13.05 g) was added to a stirred solution of 7,8-dimethoxy-1 ,3,4,5- tetrahydro-2H-benzo[d]azepin-2-one (Formula V) (23.39 g) in DMSO (234 mL) under nitrogen, at 25 °C. The reaction mixture was stirred for 1 hour at 25 °C. (S)-3-chloro-N-((3,4-dimethoxybicyclo[4.2.0]octa-1 (6),2,4-trien-7-yl)methyl)-N- methylpropan-1 -amine (Formula IV) (30.00 g) was added to the mixture, which was then stirred for 22 hours. The progress of the reaction was monitored by TLC and HPLC. Upon completion, a mixture of EtOAc (150 mL) and water (100 mL) was added. The two layers were separated. The pH of the aqueous layer was checked and adjusted to >10 with 4M NaOH and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with H ₂ O:brine in a ratio of 1 :1 (4 x 150 mL). The organic extract was dried (MgSO ₄ ), filtered and the volatiles were removed under reduced pressure to afford 48.41 g (98%) of the compound of Formula (I) as a viscous oil.

Example 3 Formation of ivabradine hydrochloride, i.e. a compound of Formula I as a hydrochloric acid salt

A compound of Formula I (ivabradine free base) (48.4 g) was dissolved in acetonitrile (484 mL). The solution was cooled to 0 °C and stirred for 5 to 10 min. HCI solution in isopropanol (5-6 N; 24.8 mL) was added dropwise to the stirred solution. After formation of a white solid, the reaction mixture was stirred overnight at 0° ± 5 °C. The solid was filtered and washed with acetonitrile. The solid was dried under vacuum at ambient temperature overnight affording 41.37 g (79%) of the compound of Formula (I) as a hydrochloric acid salt as white solid.

Example 4 Purification of ivabradine hydrochloride, i.e. a compound of Formula (I) as a hydrochloric acid salt

A compound of Formula (I) as a hydrochloric acid salt (ivabradine hydrochloride) (41.3 g) was stirred in acetonitrile (413 mL) at 80 °C for 2 hours. The mixture was cooled slowly to room temperature while stirring continued, and then stirred at ambient temperature for 1 hour and then at 0 °C for 18 hours. The solid was filtered and dried under vacuum at ambient temperature overnight affording 38.05g (92%) of the compound of Formula (I) as a hydrochloric acid salt as a colourless solid (purity: 99.6% by HPLC).

Example 5

Formation of ivabradine free base, i.e. a compound of Formula (I), from ivabradine hydrochloride, i.e. a compound of Formula (I) as a hydrochloric acid salt

To a solution of a compound of Formula (I) as a hydrochloric acid salt (ivabradine hydrochloride) (1.0 g) in deionized water (5 mL) was added NaOH (3M; 1 mL). The mixture was stirred for 10 minutes and ethyl acetate (5 mL) was added. The reaction was stirred for a further 10 minutes. The two layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 mL). The organic phases were combined, dried (MgS0 ₄ ), and volatile organics were removed under reduced pressure affording 0.88 g (95%) of the compound of Formula (I) (ivabradine free base) as a viscous oil. Example 6

Synthesis of ivabradine tosylate as an amorphous solid, i.e. a compound of Formula (I) as a p-toluenesulfonic acid salt

In a solution of a compound of Formula (I) (ivabradine free base) (1.16 g) in EtOAc (12.5 mL) and acetone (1.25 mL), was slowly added a mixture of p- toluenesulfonic acid monohydrate (0.471 g) dissolved in EtOAc (12.5 mL). The reaction mixture was stirred at ambient temperature for 3 hours after which diethyl ether (25 mL) was slowly added. The reaction mixture was then stirred for one hour at ambient temperature. The solid in the reaction mixture was filtered, washed with diethyl ether, and dried under vacuum overnight affording 1.360 g (86%) of the compound of Formula (I) as a p-toluenesulfonic acid salt (ivabradine tosylate) as a white solid.

Example 7

Purification of ivabradine tosylate, i.e. a compound of Formula (I) as a p- toluenesulfonic acid salt

A compound of Formula (I) as a p-toluenesulfonic acid salt (ivabradine tosylate) was added in a flask containing diethyl ether (20 mL). The mixture was stirred at ambient temperature for 4 hours. The solid was filtered and washed with diethyl ether affording 0.95g (95%) of pure compound of Formula (I) as a p- toluenesulfonic acid salt (ivabradine tosylate) as a white solid (more than 99.8% by HPLC).

Example 8

Stability of ivabradine hydrochloride and ivabradine tosylate Stability studies were conducted in which the stability of the 5d-form, δ-form and 51 -form of ivabradine hydrochloride was compared to the stability of amorphous ivabradine tosylate of the present invention. The amount of impurities in the test samples was established by HPLC using standard analytical techniques, such as calculating the relative area under UV peaks (expressed as a percentage in the table below). The samples were then stored for 30 days at a temperature of 40 °C ±2 °C and a relative humidity of 75% ±5%. The results are set out in the table below.

As the results show, amorphous ivabradine tosylate is more stable under an inert atmosphere that the forms of ivabradine hydrochloride. The 5d-form, 5- form and 51 -form of ivabradine hydrochloride are relatively unstable according to the data in terms of total impurities in the sample as measured by HPLC.

^* Under inert atmosphere (N ₂ )

While the present invention has been described in terms of its specific aspects and features, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included in the scope of the present invention.