CZ2015758A3

CZ2015758A3 - Solid forms of the calcium salt of the ethyl ester of (2R, 4S)-5-(biphenyl-4-yl)-4-[(3-carboxy-propionyl)amino]-2-methylpentanoic acid, their preparation and use

Info

Publication number: CZ2015758A3
Application number: CZ2015-758A
Authority: CZ
Inventors: Pavel Žvátora; Ondřej Dammer; Lukáš Krejčík; Michal Voslař
Original assignee: Zentiva, K.S.
Priority date: 2015-10-27
Filing date: 2015-10-27
Publication date: 2017-05-10

Abstract

Řešení se týká pevných krystalických forem vápenaté soli ethyl esteru (2R, 4S)-5-(bifenyl-4-yl)-4-[(3-karboxypropionyl)amino]-2-methylpentanové kyseliny vzorce I, známého jako AHU 377 nebo sacubitril, způsobu jejich přípravy a použití v lékové formě pro léčbu hypertenze a srdečního selhání.The present invention relates to solid crystalline forms of the calcium salt of (2R, 4S) -5- (biphenyl-4-yl) -4 - [(3-carboxypropionyl) amino] -2-methylpentanoic acid ethyl ester of formula I, known as AHU 377 or sacubitrile , a method for their preparation and use in dosage form for the treatment of hypertension and heart failure.

Description

Solid Forms of Calcium Salt of (2R, 4S) -5- (Biphenyl-4-yl) -4 - [(3-carboxonionyl) aminol-2-methylenetanoic acid ethyl ester, Preparation Method and Use

Technical field

The invention relates to solid forms of calcium salt of (2R, 4S) -5- (biphenyl-4-yl) -4 - [(3-carboxypropionyl) amino] -2-methylpentanoic acid ethyl ester of formula 1, known as AHU 377 or also a sacubitril, a process for their preparation and use in dosage form for the treatment of hypertension and heart failure.

Sacubitril sodium is a component of the drug for the treatment of hypertension and heart failure. Patent applications (WO03059345 and WO2007056546) disclose the synthesis and therapeutic use of a crystalline supramolecular sacubitrile sodium salt of valsartan disodium salt of formula 2 in a 1: 1 ratio, which crystallizes as hemipentahemihydrate. This supramolecular complex has been approved by the Food and Drug Administration (FDA) for the treatment of hypertension and heart failure.

BACKGROUND OF THE INVENTION The preparation of sacubitrile was first described in patent application EP555175 and subsequently also in a professional publication (J. Med. Chem. 1995, 38, 1689-1700). Further possibilities for synthesizing sacubitril and its advanced intermediates are described in the following patent applications: WO2008031567, WO2008083967, WO2009090251, WO2011088797A, WO2012025501, WO2012025502 and WO 2014032627.

In addition to the pharmaceutically preferred sodium salt of sacubitrile, three other pharmaceutically useful forms have been described in patent applications so far (WO2008031567, WO2008083967 and WO2003059345); namely, calcium salt, triethanolamine salt, and tris (hydroxymethyl) aminomethane. Data on the chemical purity of these salts, their crystal structure and the yields of their preparation have not been published.

SUMMARY OF THE INVENTION The present invention provides pharmaceutically acceptable semicrystalline and crystalline forms of the calcium salt of sacubitrile and processes for their preparation. These solid forms of sacubitrile calcium are prepared by crystallization, precipitation or evaporation from a solution of the calcium salt of sacubitrile in a suitable solvent or solvent mixture. The subject of the invention is a crystalline form I of calcium sacubitrile showing characteristic reflections in X-ray powder recording using CuKα radiation: 3.6; 6.4; 14.5 and 19.6 ° ± 0.2 ° 2-theta. In some embodiments, the crystalline form I is calcium sacubitrile characterized by the following additional reflections in X-ray powder recording: 8.4; 10.8; 17.7; 20.6 and 22.5 ° ± 0.2 ° 2-theta. In some embodiments, the crystalline form I of calcium sacubitrile is further characterized by a differential scanning calorimetric curve with a melting point of 86 ° C.

It is a further object of the invention to provide a process for the preparation of crystalline Form I of calcium sacubitrile comprising: a) dissolving the calcium salt of sacubitrile in one of a solvent selected from: ethanol, methanol, dimethylsulfoxide, butyl acetate, acetonitrile, isopropyl alcohol, butanol, acetone or mixtures thereof at a temperature in a range of from 25 ° C to the boiling point of the solvent; b) precipitating the solid by crystallization or precipitation at temperatures of -30 ° C to the boiling point of the solvent or evaporation from the solution; d isolating the precipitated solid.

Another object of the invention is the crystalline form II of the sacubitrile calcium salt, exhibiting characteristic reflections in X-ray powder recording using CuKα radiation. 3.2, 7.4, 12.9, 18.7 and 22.5 ± 0.2 ° 2-theta. In some embodiments, the crystalline form II of the sacubitrile calcium salt is characterized by the following additional reflections in X-ray powder recording: 11.4; 16.2; 23.7 and 27.1 ± 0.2 ° 2-theta. In some embodiments, crystalline Form II of the sacubitrile calcium salt is further characterized by a differential scanning calorimetric curve with a melting point of 68 ° C.

It is a further object of the invention to provide a process for the preparation of crystalline Form II calcium salt of sacubitrile comprising: a) dissolving the calcium salt of sacubitrile in a mixture of dioxam water (1: 1) at a temperature ranging from 25 ° C to the boiling point of the solvent; b) precipitating the solid by crystallization or precipitation at temperatures of -30 ° C to the boiling point of the solvent or evaporation from the solution; c / isolating the precipitated solid.

A further object of the invention is the semicrystalline form III of calcium sacubitrile, exhibiting reflections in X-ray powder recording using CuKα radiation: 4.0 and 4.7 ± 0.2 ° 2-theta. In some embodiments, the semi-crystalline form III of the sacubitrile calcium salt is further characterized by a differential scanning calorimetric curve with a melting point of 124 ° C.

It is a further object of the present invention to provide a process for preparing a semicrystalline form III of a calcium salt of sacubitrile comprising: a) dissolving a calcium salt of a sacubitrile in one of a solvent selected from tetrahydrofuran, toluene, xylene, dichloromethane, or mixtures thereof at a temperature between 25 ° C and boiling point solvents; b) precipitating the solid by crystallization or precipitation at temperatures of -30 ° C to the boiling point of the solvent or evaporation from the solution; cl isolation of the precipitated solid.

It is a further object of the invention to provide a semi-crystalline solid form IV of calcium sacubitrile exhibiting characteristic reflections in X-ray powder recording using CuKα radiation: 4.6; 6.4 and 14.3 ± 0.2 ° 2-theta. In some embodiments, the semicrystalline solid form IY of the sacubitril calcium salt is further characterized by a differential scanning calorimetric curve with a melting point of 173 ° C.

Another object of the invention is to provide a process for preparing semicrystalline sacubitrile calcium form IV comprising: a) dissolving the sacubitrile calcium salt in chloroform at a temperature ranging from 25 ° C to the boiling point of the solvent; b) precipitating the solid by crystallization or precipitation at temperatures of -30 ° C to the boiling point of the solvent; c / isolating the precipitated solid.

Description of the picture

Figure 1: X-ray powder recording of crystalline Form I of calcium sacubitrile Figure 2: X-ray powder recording of crystalline Form II of calcium sacubitrile Figure 3: X-ray powder recording of semi-crystalline Form III calcium salt of sacubitrile Figure 4: X-ray powder recording of semi-crystalline Form IV calcium salt of sacubitril

DETAILED DESCRIPTION OF THE INVENTION

Generally, the salts of the pharmaceutically active substances have a higher solubility and bioavailability than their corresponding free acid or base forms. Although the preparation of the salt by the reaction of the acid and the base is known, it is always a problem to obtain said salts in the solid state and purity according to the requirements for their pharmaceutical use. The bioavailability is highly dependent on whether the product obtained is crystalline or amorphous. The amorphous product is usually more readily soluble, often not of adequate quality, and is also unstable. In contrast, the crystalline product is often stable with more easily obtainable purity compared to the amorphous form and dissolves more slowly. The solution may be mixtures of amorphous and crystalline solids (semi-crystalline forms). The present invention provides several solid forms of sacubitrile calcium in crystalline form or in a mixture of crystal and amorphous. In the solution, crystalline calcium salt forms of sacubitrile are preferred. SUMMARY OF THE INVENTION The present invention provides solid forms of sacubitrile calcium at varying molar ratios. In the solution, molar ratios of 2: 1 are preferred.

The solid forms of sacubitrile calcium may be prepared in appropriate proportions and yields with high chemical purity in crystalline or amorphous form, optionally in a mixture of amorphous and crystalline solids.

These solid forms may be both anhydrous or unsolvated as well as the hydrates / solvates of the respective solvents.

These new solid forms are suitable for the preparation of sacubitrile of high chemical and optical purity. The preparation of a new solid form of sacubitrile is carried out by reacting the cyclohexylammonium salt of the sacubitrile with calcium chloride in water or a mixture of water with a suitable organic solvent. The resulting product of this reaction is recrystallized in a suitable solvent such as ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or mixtures thereof. Aliphatic C 1 -C 4 alcohols, ethers, chlorinated solvents, water or mixtures thereof are preferred. The most widely used solvents are ethanol, tetrahydrofuran, dioxane, chloroform, water or mixtures thereof. The resulting product is precipitated or crystallized typically at temperatures from -30 ° C to the boiling point of the solvent. In the solution, crystalline calcium salt forms of sacubitrile (Form I and Form II) are preferred, which due to their crystalline form excel in their high physical and chemical stability. The prepared solid forms of the calcium salts of sacubitrile exhibit a sufficiently high melting point, physical and chemical stability for use in a dosage form. The main advantage of the calcium salts of sacubitrile over the sodium salt of sacubitrile is their higher physical and chemical stability during storage.

The sacubitrile calcium salt sample (Form I) was exposed to 80 ° C for 3 days with 0% RH and 75% RH. During this time there was no change in the crystalline state of the calcium salt of sacubitrile. The same experiment was also carried out with the sodium salt of sacubitrile, which showed a high degree of polymorphic instability and at 75% RV there was complete amortization of the sample (see Table 1).

Table 1; Stability of the solid salt forms of sacubitrile

It has been found that in the case of the test conditions, the saccharitrile calcium salt does not undergo a change in chemical purity. Of the described processes for the preparation of solid forms of sacubitrile calcium, a process of preparation from ethanol is preferred, wherein the crystalline product prepared exhibits suitable stability for use in a dosage form. The crystalline forms of sacubitrile calcium can be prepared and isolated in high yield and high chemical purity.

The sacubitrile cyclohexylammonium salt was prepared according to the procedure described in Example 1. The sacubitrile calcium salt was prepared according to the procedure of Example 2.

The crystalline form I of calcium sacubitrile is characterized by the reflections shown in Table 2. Table 2 includes reflections whose relative intensity value is greater than 1%. The characteristic diffraction peaks of the crystalline form I of the calcium salt of the sacubitrile of the present invention using CuKα radiation are: 3.6; 6.4; 14.5 and 19.6 ° ± 0.2 ° 2-theta. An X-ray powder record is shown in Figure 1.

Table 2

Using differential scanning calorimetry (DSC), the melting point of crystalline Form I of calcium sacubitrile was measured to be 86 ° C.

The saccharitrile calcium salt form II is characterized by the reflections shown in Table 3. Table 3 includes reflections whose relative intensity value is greater than 1%. The characteristic diffraction peaks of the crystalline form II of the sacubitrile calcium salt of the present invention using CuKα radiation are: 3.2; 7.4; 12.9; 18.7 and 22.5 ± 0.2 ° 2-theta. An X-ray powder record is shown in Figure 2.

Table 3

Using differential scanning calorimetry (DSC), the melting point of crystalline Form II of sacubitrile calcium salt was measured to be 68 ° C.

The semicrystalline form III of the sacubitrile calcium salt is characterized by the reflections shown in Table 4. Table 4 includes reflections whose relative intensity value is greater than 1%. The characteristic diffraction peaks of the semicrystalline form III of the sacubitrile calcium salt of the present invention using CuKα radiation are: 4.0 and 4.7 ± 0.2 ° 2-theta. An X-ray powder record is shown in Figure 3.

Table 4

Using differential scanning calorimetry (DSC), the melting point of semicrystalline form III of calcium sacubitrile was measured to be 124 ° C.

The semicrystalline form IV of the calcium salt of sacubitrile is characterized by the reflections shown in Table 5. Table 5 includes reflections whose relative intensity value is greater than 1%. The characteristic diffraction peaks of the semi-crystalline form IV of the sacubitrile calcium salt of the present invention using CuKα radiation are: 4.6, 6.4 and 14.3 ± 0.2 ° 2-theta. An X-ray powder record is shown in Figure 4.

Table 5

Using differential scanning calorimetry (DSC), the melting point of semi-crystalline form IV of sacubitrile calcium salt was 173 ° C. The prepared solid forms of the calcium salts of the sacubitrile of the present invention can be used in the preparation of pharmaceutical compositions, in particular solid dosage forms, e.g., tablets or capsules. Such pharmaceutical compositions may contain at least one excipient from the group of fillers (e.g., lactose), binders (eg, microcrystalline cellulose), disintegrant (e.g., croscarmellose sodium), lubricants (e.g., magnesium stearate), surfactants, etc. Sacubitril calcium may be mixed with said excipients, screened through a sieve, and the resulting mixture may be packaged or filled into capsules. The tablets may further be coated with conventional coatings, e.g., polyvinyl alcohol or polyethylene glycol.

The following examples illustrate the invention. These examples, which illustrate the preparation of the novel solid forms of the sacubitrile calcium salt of the invention, are merely illustrative and are not intended to limit the scope of the invention in any way.

Experimental part X-ray powder diffraction

Diffractograms were obtained on X'PERT PRO MPD PANalytical powder diffractometer, CuKa radiation used (λ = 1.542 Å), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40 ° 20, step size: 0.01 ° 20 at a reflection of 0.5 s, the measurement was performed on a flat sample of 10 / 0.5 mm area. For the primary beam correction, 0.02 rows of Soller aperture, 10 mm mask, and 1/4 ° fixed anti-scatter diaphragm were used. The irradiated area samples 10 mm, programmable divergence apertures were used. For the secondary beam correction, 0.02 rows of Soller aperture and 5.0 mm anti-scatter aperture were used.

Differential Scanning Calorimetry (DSC) Records of new solid calcium salts of sacubitrile were measured on a Discovery DSC instrument from TA Instruments. The sample weight into a standard AI crucible (40 µL) was between 4-5 mg and a heating rate of 5 ° C / min. The temperature program used was composed of 1 stabilization minute at 0 ° C and then from heating to 250 ° C at a heating rate of 5 ° C / min (Amplitude = 0.8 ° C and Period = 60s). 5.0 N2 at a flow rate of 50 ml / min was used as carrier gas. Examples Example 1 - sacubitril salt with cyclohexylamine

To 10 g of amine hydrochloride (3) was added 100 ml of ethyl acetate and 6 ml of triethylamine. The mixture was stirred at room temperature for about 10 minutes. This was followed by the addition of 4.3 g of succinic anhydride and stirring of the mixture at room temperature for 5 hours. Then 6.5 ml of cyclohexylamine were added and the mixture was stirred at room temperature. The mixture was seeded with crystalline sacubitril salt with cyclohexylamine prepared in the previous experiments. The precipitated cyclohexylamine salt with sacubitrile was isolated by filtration, washed with mother liquor, solvent used and dried under vacuum. Example 2 - calcium salt of sacubitrile

To 21 g of the cyclohexyl-ammonium salt of sacubitrile in a 500 ml three-necked flask was added 210 ml of water. The resulting solution was brought to 30 ° C with stirring in a bath. Next, a solution of calcium chloride formed by dissolving 6.05 g of CaCl 2 - 2H 2 O in 30 ml of water was added dropwise with vigorous stirring. The resulting suspension was allowed to stir at 30 ° C for 30 min. Then the solid was collected by filtration. The filter cake was washed with 80 mL of water in two portions and further fritted for about 1 h. The moist filter cake was dried in a vacuum oven at 15 kPa for 12 h at room temperature and further at 45 ° C. 24 hours Example 3 - Preparation of crystalline Form I of calcium sacubitrile

The 104.0 mg sacubitrile calcium salt was dissolved in 0.3 ml ethanol (98%) at 78 ° C under magnetic stirring in a glass vial. The resulting solution was allowed to cool freely and evaporated in a fume cupboard for 48 hours. X-ray powder recording in FIG. 1. DSC melting point 86 ° C. Example 4 - Preparation of crystalline Form II calcium salt of sacubitrile

The 99.4 mg sacubitrile calcium salt was dissolved in 0.4 mL of a 1: 1 V: V dioxam water mixture at 100 ° C with a magnetic stirrer in a glass vial. The resulting solution was evaporated in a vacuum oven at 25 ° C and 20 kPa. X-ray powder recording in FIG. 2. DSC melting point 68 ° C. Example 5 - Preparation of semi-crystalline form III of calcium sacubitrile

The 103.6 mg sacubitrile calcium salt was dissolved in 0.2 ml tetrahydrofuran at 66 ° C in a glass vial while stirring on a magnetic stirrer. The resulting solution was evaporated in a vacuum oven at 25 ° C and 20 kPa. X-ray powder recording in Fig. 3. DSC melting point 124 ° C. Example 6 - Preparation of semi-crystalline form IV of calcium sacubitrile

The 104.5 mg sacubitrile calcium salt was dissolved in 0.2 ml chloroform at 58 ° C under magnetic stirring in a glass vial. The resulting solution was rapidly cooled to -20 ° C by insertion into an ice bath containing NaCl. The solid was removed from the solution by filtration. The filter cake was allowed to dry freely in a fume hood for 48 hours. X-ray powder recording in Fig. 4. DSC melting point 173 ° C.

Claims

PATENT CLAIMS

A calcium salt of (2R, 4S) -5- (biphenyl-4-yl) -4 - [(3-carboxypropionyl) amino] -2-methylpentanoic acid ethyl ester of Formula 1, characterized in that it is in solid form, preferably in crystalline or semi-crystalline form.

(1)

The crystalline Form I salt of claim 1 having characteristic reflections in X-ray powder recording using CuKα radiation: 3.6; 6.4; 14.5 and 19.6 ° ± 0.2 ° 2-theta.

Crystalline Form I according to claim 2, characterized by the following further reflections in X-ray powder recording using CuKα radiation: 8.4; 10.8; 17.7; 20.6 and 22.5 0 ± 0.2 ° 2-theta.

Crystalline Form I according to claim 2 or 3, characterized by a differential scanning calorimetric curve with a melting point at 86 ° C.

A process for preparing crystalline Form I according to any one of claims 2 to 4, comprising the steps of: a1 dissolving the saccharitrile calcium salt in one of a solvent selected from: ethanol, methanol, dimethylsulfoxide, butyl acetate, acetonitrile, isopropyl alcohol, butanol, acetone or mixtures of these solvents at a temperature in the range of 25 ° C to the boiling point of the solvent; b) precipitating the solid by crystallization or precipitation at temperatures of -30 ° C to the boiling point of the solvent or evaporation from the solution; c / isolating the precipitated solid.

The crystalline salt form II of claim 1, having characteristic reflections in X-ray powder recording using CuKα radiation: 3.2; 7.4; 12.9; 18.7 and 22.5 ± 0.2 ° 2-theta.

Crystalline Form II according to claim 6, characterized by the following additional reflections in X-ray powder recording: 11.4; 16.2; 23.7 and 27.1 ± 0.2 ° 2-theta.

Crystalline Form II according to claim 6 or 7, characterized by a differential scanning calorimetric curve with a melting point at 68 ° C.

A process for the preparation of crystalline form II according to any one of claims 6 to 8, comprising the steps of: a) dissolving the saccharitrile calcium salt in a mixture of dioxam water (1: 1) at a temperature ranging from 25 ° C to the boiling point of the solvent; b) precipitating the solid by crystallization or precipitation at temperatures of -30 ° C to the boiling point of the solvent or evaporation from the solution; c / isolating the precipitated solid.

The semi-crystalline salt form III of claim 1, having characteristic reflections in X-ray powder recording using CuKα radiation: 4.0 and 4.7 ± 0.2 ° 2-theta.

Semicrystalline form III according to claim 10, characterized by a differential scanning calorimetric curve with a melting point at 124 ° C.

A process for the preparation of semi-crystalline Form III according to any one of claims 10 or 11, comprising the steps of: a) dissolving the calcium salt of the sacubitrile in one of a solvent selected from tetrahydrofuran, toluene, xylene, dichloromethane or mixtures thereof at a range of from 25 ° C to the boiling point of the solvent; b) precipitating the solid by crystallization or precipitation at temperatures of -30 ° C to the boiling point of the solvent or evaporation from the solution; c / isolating the precipitated solid.

The semi-crystalline Form IV salt of claim 1, having characteristic reflections in X-ray powder recording using CuKα radiation: 4.6; 6.4 and 14.3 ± 0.2 ° 2-theta.

Semicrystalline form IV according to claim 13, characterized by a differential scanning calorimetric curve with a melting point at 173 ° C.

A process for preparing semi-crystalline Form IV according to any one of claims 13 or 14, comprising the steps of: a) dissolving the sacubitrile calcium salt in chloroform at a temperature ranging from 25 ° C to the boiling point of the solvent; b) precipitating the solid by crystallization or precipitation at temperatures ranging from -30 ° C to 0 ° C; c / isolating the precipitated solid.

Use of a semi-crystalline form of the sacubitrile calcium salt according to any one of claims 1 to 4, 6 to 8, 10, 11, 13 and 14 for the preparation of a pharmaceutical composition.

A pharmaceutical composition comprising at least one calcium salt of a sacubitrile according to any one of claims 1 to 4, 6 to 8, 10, 11, 13 and 14 and at least one pharmaceutically acceptable excipient.