EA024825B1 - Cocrystal of ticagrelor with 3-hydroxy-2-naphthoic acid, process for preparation thereof and use - Google Patents

Abstract

Solid state structures of (1S,2S,3R,5S)-3-[7-[1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (hereafter referred to as Ticagrelor) in the form of a stable 3-hydroxy-2-naphthoic acid co-crystal form, a process for the preparation thereof and the use for preparation of a pharmaceutical composition.

Description

The present invention relates to new solid forms of ticagrelor (I), as well as to methods for their preparation. The particular claimed solid forms are a ticagrelor co-crystal derived from 3-hydroxy-2-naphthoic acid.

State of the art

The compound (18.2§, 3K, 5§) -3- [7 - [(1K, 2§) -2- (3,4-difluorophenyl) cyclopropylamino] -5- (propylthio) 3H- [1,2 3] triazolo [4,5-b] pyrimidin-3-yl] -5- (2-hydroxyethoxy) cyclopentane-1,2-diol (also known as ticagrelor) of formula I

It is known as a platelet aggregation inhibitor, which is indicated to prevent thrombosis in patients with myocardial infarction. Details of the synthesis method for isolating ticagrelor can be found in νθ 00/34283. At least four anhydrous polymorphic forms of ticagrelor are known in the prior art and further details can be found in EP 1289992. In addition, a number of ticagrelor co-crystals are described in the prior art, in particular in νθ 2011067571. Investigations (Iatagkak aib C1agk, Sagbyuodu η Ps \ ss \ u. 19 (2), March / April 2011, 95-100) showed that in patients with acute coronary syndrome, treatment with ticagrelor compared with clopidogrel significantly reduced mortality from vascular diseases, myocardial infarction, or stroke. When compared with clopidogrel, ticagrelor is a new class of platelet inhibitors. Unlike clopidogrel, ticagrelor is not thienopyridine, but is described as cyclopentyl-triazolo-pyrimidine.

Ticagrelor is a low solubility active pharmaceutical ingredient (API) with low permeability and is classified as a class IV compound according to the biopharmaceutical classification system (BC8). Such APIs are usually used to prepare salts in order to improve their solubility and thus bioavailability. Another possibility and more and more popular is to obtain an API crystal. A co-crystal is defined herein as a separate solid form of API, consisting of a stoichiometric ratio of API and guest molecule (also known as a co-conformer) to produce a periodically repeating crystalline form. Co-crystals usually impart various physicochemical properties to the API under consideration. Co-crystals usually give significant functionality, since they modify the physicochemical properties of APIs without affecting the chemical structure of APIs. Moreover, co-crystallization is independent of the presence of ionizable functional groups, in contrast to the requirements for salt formation. It is known that cocrystals dissociate into a solution at a rate faster than the time required to reach the active site API. Thus, the therapeutic effect is achieved due to one API with a cocrystal, which rapidly dissociates when it is placed in water.

Despite the limitations associated with the bioavailability of the solid dosage form, those skilled in the art will be aware that crystalline solid forms of APIs are preferred over amorphous forms because crystalline forms are thermodynamically stable and provide more predictable processing and storage conditions. An obvious objection consistent with this course is related to the problem of enhancing the solubility and bioavailability of APIs, which favors an amorphous form. Neither polymorphic forms nor API API co-crystals are obvious prior to long-term crystallization experiments. Moreover, those skilled in the art are familiar with preliminary literary examples of attempts to conduct co-crystallization experiments, which instead lead to new polymorphic forms of APIs or disappearing polymorphic forms of APIs after characterization of supposedly stable new crystalline forms.

Methods for the preparation and characterization of cocrystals are little described in the literature. For example, see: Tgakk e1 a1. Eat. Sottip., 2004, 890-891; and O. A1tagkkop, M.T. Ζ; · ι \\ όγο11 <ο. Eat. Sottip., 2004, 1889-1896; T. Ryksk apb V. 1pek, I. Ragtasu. Pagtasoduod, 2010, 62, 1547-1559. These methods, as well as other methods known to those skilled in the art, can be used to produce ticagrelor co-crystals, preferably comprising a co-co-molecule with at least one carboxyl group, or more preferably a co-co-microformant belonging to the general class of compounds known as hydroxybenzoic acids, or even more preferably a co-conformer such as 3-hydroxy-2-naphthoic acid.

Description of the invention

The present invention relates to solid structures (1§, 2§, 3K, 58) -3- [7 - [(1K2§) -2- (3,4difluorophenyl) cyclopropylamino] -5- (propylthio) -3H- [1, 2,3] triazolo [4,5-k] pyrimidin-3-yl] -5- (2hydroxyethoxy) cyclopentan-1,2-diol (hereinafter referred to as Ticagrelor) as a stable co-crystalline solid form. Due to the appropriate use of anhydrous or solvated forms of API, it is possible to modulate and ensure the constancy of the physicochemical properties of the active pharmaceutical ingredient. According to EP 1289992, ticagrelor has four polymorphic forms, of which Form I is the most stable with a melting point of 146 to 152 ° C. However, Form II is used in a drug product and this polymorphic form is known for having a melting point in the range of 136 to 139 ° C. Forms I and II interconvert when heated / cooled, and this is illustrated in FIG. 2.

The co-crystal of ticagrelor and 3-hydroxy-2-naphthoic acid has the characteristic peaks ΧΡΡΌ shown in the table and the diffraction pattern ΧΚΡΌ shown in FIG. 3. The characteristic peaks of the x-ray powder diffraction pattern for the co-crystal are 3.6; 7.2; 9.3; 14.3; 16.2; 18.7 and 24.5 ± 0.2 ° 2θ. The cocrystal has an initial melting point of 136 ° C, which is approximately 2 ° C higher than the initial melting temperature of ticagrelor form II. HPLC co-crystal purity is also high and is 97.9%. One of the advantages of obtaining ticagrelor in the form of a co-crystal is its polymorphic behavior with respect to ticagrelor API. Polymorphism, the ability of a compound to crystallize into more than one crystalline form, is a major problem for the pharmaceutical industry when this happens unexpectedly. This is exactly the case with Ritonavir (Norvir), an antiretroviral drug from the class of protease inhibitors that is used to treat HIV infection and AIDS. It is known that the chemical structure of APIs in the original Norvir capsules exhibits conformational polymorphism, with various polymorphic forms exhibiting different physical properties. The therapeutically active polymorphic form of Ritonavir, used in the original preparation, is a metastable polymorphic form, which quickly transforms into a stable polymorphic form [Waieg c1 a1, Pbagshaseix1 Kekeagsk, 18 (6), 2001, 859-866.], Which exhibits low solubility and low biocompatibility. This polymorphic transformation was not foreseen by Norvir developers and caused significant problems. In the case of ticagrelor, there are similar problems. Namely, the polymorphic form II used in the drug product is a metastable form that quickly transforms through a reversible temperature-induced phase transition into a thermodynamically more stable form I when heated. Similarly, ritonavir and ticagrelor also exhibit significant conformational flexibility, making them susceptible to polymorphic changes depending on crystallization conditions (mainly temperature and solvent). A co-crystal of ticagrelor and 3-hydroxy-2-naphthoic acid provides better control of the properties of the solid state, since it is not sensitive to polymorphic changes depending on temperature and solvent (the latter is limited by time and availability). Since the temperature-induced polymorphic behavior of the cocrystal is of concern, FIG. 4 shows a DSC curve of a co-crystal that exhibits only one endotherm corresponding to the melting point of the co-crystal. Moreover, it has been shown that a co-crystal is not polymorphic within the limitations of manual crystallization techniques, depending on the crystallization solvent according to the results of lengthy experiments on the crystallization of a solution using various solvents. This is illustrated in FIG. 5, which shows identical diffraction patterns ла of a co-crystal when a crystallized ticagrelor is crystallized with 1 eq. 3-hydroxy-2-naphthoic acid from an acceptable solvent at a temperature in the range from 20 to 65 ° C. Typical acceptable solvents are, for example, water, nitromethane, ethanol, propanol, diethyl ether, 2-butanol, cyclohexane, dichloromethane, acetone, methyl ethyl ketone, 1,2-dimethoxyethane, ethyl format, methyl acetate, propyl acetate, isopropyl acetate, trichlorethylene, tetrahydrofu THF) or acetonitrile or mixtures thereof. To obtain a co-crystal, all known forms of ticagrelor can be used, for example Form I or Form II, III or IV, as described in EP 1289992. An amorphous form can also be used.

The decisive additional advantage of obtaining ticagrelor in the form of a co-crystal is associated with the excellent water-sorption stability of the co-crystal against APIs at elevated values (%) of relative humidity. According to FIG. 6, with a relative humidity of 80% (25 ° C isotherm), the co-crystal has a water content of 3.2 wt.%, And this is comparable to 3.7 wt.% For ticagrelor form II. At 90% relative humidity, it was shown that the co-crystal has a water content of approximately 13.2 wt.%, Compared with 16.8 wt.% For ticagrelor form II. Both samples are stable with respect to water absorption up to 60% relative humidity.

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Diffraction peaks for ticagrelor co-crystal and 3-hydroxy-2-naphthoic acid

Position [° 2 Theta] Interatomic distance [A] Relative humidity [%] 3,58 24,654 95.6 5.19 17,025 13,2 7.15 12,353 51.0 9.33 9,472 100.0 13.43 6,586 19,2 14.33 6,178 36.7 16.22 5,459 52.7 18.70 4,741 51.1 19.44 4,563 5.1 20.54 4,321 5.1 21.59 4,113 13.1 22.93 3,876 6.1 24.50 3,631 34.7 25.32 3,514 12,4 25.78 3,453 7.1 26.49 3,363 6.7 29.00 3,040 9,4

Characteristic peaks: 3.6; 7.2; 9.3; 14.3; 16.2; 18.7 and 24.5 ± 0.2 ° 2-theta.

In a further aspect of the invention, the cocrystal according to this invention can be used directly for the pharmaceutical composition or as an intermediate product to obtain a pharmaceutically acceptable form.

A brief description of the graphic materials

FIG. 1: т diffraction pattern of ticagrelor form II.

FIG. 2: DSC curve for ticagrelor form II.

FIG. 3: ΧΚΡΌ diffraction pattern of ticagrelor co-crystal and 3-hydroxy-2-naphthoic acid.

FIG. 4: DSC curve for ticagrelor co-crystal and 3-hydroxy-2-naphthoic acid.

FIG. 5: Scheme ΧΚΡΌ crystallization patterns of ticagrelor co-crystal and 3-hydroxy-2-naphthoic acid in various solvents. The diagram illustrates the loss of polymorphism co-crystal.

FIG. 6: comparison of sorption-desorption isotherms (25 ° C) for A) ticagrelor of 3-hydroxy-2-naphthoic acid and B) ticagrelor of form II.

Examples

In the following examples, samples were evaluated using x-ray powder diffractometry using the following procedure:

The diffraction pattern was obtained using a powder diffractometer with a graphite monochromator, applied CuKa radiation (λ = 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2-40 ° 2Θ, increment: 0 , 01 ° 2Θ at a measurement time of 50 s, the measurement was carried out on flat samples with a surface area / thickness of 10 / 0.5 mm.

DSC curves were measured using the device Ργτίδ 1 (Regksh E1tag). Sample loading ranged from 3 to 4 mg, heating rate 10 ° C / min.

Temperature program:

1) 1 min at 50 ° C;

2) from 50 to 200 ° C at a speed of 10 ° C / min (excluding Prasugrel HC1 from 50 to 250 ° C at a speed of 10 ° C / min).

Carrier gas: Ν ₂ , 20 ml / min.

The amount of solvent was estimated by gas chromatography (GC) in AdPeSH 7890 with flame ionization detection.

Chromatography conditions: capillary column: ΌΒ-624 (30 m, 0.53 mm inner diameter (GO), 3.0 μm film thickness (άί) or equivalent.

Temperature program: 70 ° С - 2 min, gradient from 10 ° С / min to 170 ° С / 0 min.

Carrier gas: helium.

Injection: 1 μl.

Dispenser: 200 ° С, discharge ratio 5: 1.

Detector: flame ionization detector (PID), 260 ° С.

Example 1. A method for producing a cocrystal of ticagrelor and 3-hydroxy-2-naphthoic acid.

Approximately 870 mg of ticagrelor Form II was placed inside a 100 ml round bottom flask. To this was added 312 mg (1 mol equivalent) of 3-hydroxy-2-naphthenic acid. The flask was equipped with an air condenser and a thermometer. 50 ml of MeOH was added to the contents of the flask. The resulting suspension, 3 024825, was heated to a temperature of 50 ° C. The contents of the flask were cooled to 40 ° C and then again heated to 50 ° C under reflux. A distillation condenser was attached to a round bottom flask, and the suspension was heated to approximately 60 ° C to distill approximately 90 vol.% Methanol. The thick suspension was stirred and allowed to cool in an ice bath for 1 hour. Rapid precipitation was observed. Yield: 1.15 g (97.29% of theoretical maximum). HPLC purity: 97.9%.

The sample was characterized using x-ray powder diffractometry and a list of characteristic peaks is given in the table.

Example 2. Obtaining a cocrystal of ticagrelor and 3-hydroxy-2-naphthoic acid from the solvent range through suspension.

Approximately 40 mg of ticagrelor Form II was placed inside a 1 ml vessel. To it was added 14.34 mg (1 mol equivalent) of 3-hydroxy-2-naphthoic acid. 1 ml of one of the following solvents was added to the vessel to create a saturated suspension: water, nitromethane, ethanol, propanol, diethyl ether, 2-butanol, cyclohexane, dichloromethane, acetone, methyl ethyl ketone, 1,2-dimethoxyethane, ethyl format, methyl acetate, propyl acetate, isopropyl acetate trichlorethylene, THF or acetonitrile. The contents of the vessel were placed inside the HMC thermomixer (Model No.: MNC 23). The temperature of the suspension was kept constant at 35 ° C and stirred at 900 rpm for 9 days to study any polymorphic transformations induced by the solvent. Crystalline samples were evaluated using x-ray powder diffractometry. The diffraction patterns of all samples corresponded to the diffraction pattern obtained in Example 1. In FIG. 5 shows the diffraction patterns of the selected solvents.

Claims (7)

CLAIM 1. A co-crystal of ticagrelor of formula (I) with 3-hydroxy-2-naphthoic acid. 2. The co-crystal according to claim 1, characterized by a powder x-ray diffractogram measured using CuKa containing specific high-intensity peaks at 3.6; 7.2; 9.3; 14.3; 16.2; 18.7 and 24.5 ± 0.2 ° 2-theta. 3. The co-crystal according to claim 1 or 2, characterized in that the mass of 3-hydroxy-2-naphthoic acid to ticagrelor is in a 1: 1 molar stoichiometric ratio. 4. Co-crystal according to any one of claims 1 to 3, characterized by a differential scanning calorimetry curve, at which the onset of melting is observed at approximately 136 ° C. 5. The method for producing a co-crystal according to claim 1, wherein the ticagrelor is crystallized with 3-hydroxy-2-naphthoic acid from an acceptable solvent at a temperature in the range from 20 to 65 ° C. 6. The method according to claim 5, where the solvent is selected from the group consisting of water, nitromethane, ethanol, propanol, diethyl ether, 2-butanol, cyclohexane, dichloromethane, acetone, methyl ethyl ketone, 1,2-dimethoxyethane, ethyl formate, methyl acetate, propyl acetate , isopropyl acetate, trichlorethylene, THF (tetrahydrofuran) and acetonitrile. 7. The use of cocrystal according to claim 1 to obtain a pharmaceutical composition.