Salts of avatrombopag

Abstract

The invention relates to improved process to prepare avatrombopag hydrogenmaleate form C from the mixture of acetone and water The invention further relates to the novel salts of avatrombopag, their crystalline forms and preparation thereof. The salts are selected from hydrogenmalonate, fumarate, sulphate, besylate and tosylate salts.

Description

[0001] SALTS OF AVATROMBOPAG

[0002] The invention relates to improved process to prepare avatrombopag hydrogenmaleate form C.

[0003] The invention further relates to the novel salts of avatrombopag and their crystalline forms.

[0004] BACKGROUND OF THE PRESENT INVENTION

[0005] Avatrombopag, l-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-l-yl)-l,3- thiazol-2-yl]carbamoyl} pyridin-2-yl)piperidine-4-carboxylic acid, compound of formula (I), in the form of maleate salt (molar ratio 1:1; also called hydrogenmaleate) is a small molecule TPO- receptor agonist that is approved for the treatment of severe and primary chronic immune thrombocytopenia in adult patients.

[0006] Avatrombopag was first disclosed in W02003062233 (Y amanouchi). Avatrombopag is practically insoluble in water below pH 12 and 0.1N hydrochloride. In addition, studies with LLC-PK cells have shown that avatrombopag has low to moderate in vitro permeability.

[0007] Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. The salts can possess improved properties such as solubility or bioavailability that is advantageous in preparation of final formulations. Because of good crystallinity the salts can be also used for purification of avatrombopag. W02004029049 (Y amanouchi) discloses avatrombopag in the form of maleate salt (also called hydrogenmaleate; ratio of free base to maleic acid molecule 1 : 1), that has been proved to have good oral bioavailability. The salt forming reaction is performed in the mixture of water and ethanol solvent. According to the later disclosure, the process results in form A crystals that cannot be isolated when scaled up for mass production using the process disclosed in example 1 of W02004029049. WO2013018362 (Astellas) discloses crystalline forms A, B and C of avatrombopag maleate.

[0008] According to the disclosure, forms A and B can be obtained by crystallisation from a mixture of water and an alcohol (methanol, ethanol, 2-propanol and the like), for example 80% ethanol and 20% water. The document reports that form A crystals can morph depending on the scale of production and are therefore not suitable as drug substance for medicines. Furthermore, form B crystals were found to exhibit poor oral absorption even though they can be stably supplied in industrial production. Form C on the other hand was found to be devoid of these drawbacks. Form C of avatrombopag maleate is used in the commercial Doptelet® tablets marketed by Swedish Orphan Biovitrum.

[0009] Form C crystals of avatrombopag maleate according to WO2013018362 can be obtained by salt preparation / crystallisation in acetone / water mixtures, methyl ethyl ketone / water mixtures or acetonitrile / water mixtures, which also contain dimethyl sulfoxide (DMSO). In the examples, mixtures of water, acetone and DMSO (2:2:1 V / V / V) are used.

[0010] Use of DMSO as a solvent in preparation of avatrombopag maleate form C is useful as it increases the solubility of avatrombopag. Thus, form C can be obtained via simple cooling crystallization. While the process using DMSO as a solvent provides crystals in reasonable yield, the product contains excessive amount of residual DMSO solvent.

[0011] CN106749226 discloses the preparation of form C of avatrombopag maleate including dissolving avatrombopag maleate in dimethylformamide (DMF) and the addition of methylene chloride as an anti-solvent.

[0012] The preparation of form C is also disclosed in IN429420 (My lan). According to the document, avatrombopag form C can be prepared by treating avatrombopag maleate with a ketone solvent (selected from acetone, methyl ethyl ketone and methyl isobutyl ketone) at 25±5°C and requires long stirring time (14-18 hours).

[0013] CN112409350 (Shanghai Desano Biopharmaceuticals) discloses form D of avatrombopag maleate and its use in the process to prepare form C of avatrombopag. Form D is obtained by providing a solution of avatrombopag maleate in a mixture of first and second solvent and the following addition of anti-solvent. First solvent is selected from the group comprising N- methylpyrrolidone, dimethyl sulfoxide, N,N -dimethylformamide and the second solvent is selected from the group comprising acetone, methylene chloride and acetonitrile. As an antisolvent water is used.

[0014] CN116135854 (Sechuan Kelun Pharm.) discloses the preparation of form C by mixing avatrombopag free base with solvent selected from acetone and acetonitrile and maleic acid. Similarly to the present invention, form C is obtained in the step of forming avatrombopag salt and requires no additional crystallization. However, the use of acetone as a single solvent results in high overall vapor pressure, which is disadvantageous in terms of safety and handling.

[0015] There is still a need for an alternative process to prepare form C of avatrombopag maleate that doesn’t require recrystallization, reduces the amount of organic solvents and overcomes other the drawbacks of prior art.

[0016] BRIEF DESCRIPTION OF THE INVENTION

[0017] The presented invention relates to a method for preparing form C of avatrombopag maleate, the method comprising following steps: a) Avatrombopag free base is suspended in the mixture of acetone and water and stirred; b) Maleic acid is added into suspension and stirred; c) Obtained solid is isolated, washed with acetone and dried.

[0018] The present invention further relates to novel salts of avatrombopag, their crystalline forms and the preparation thereof. The salts are selected from hydrogenmalonate, fumarate, sulphate, besylate and tosylate. In order to prepare the crystalline forms according to the invention, avatrombopag free base and the corresponding acid are dissolved in a solvent or a solvent mixture, at the defined temperature, followed by an isolation step.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of form C of avatrombopag maleate, prepared according to Examples 1.

[0021] Figure 2 depicts the X-Ray Powder Diffractogram (XRPD) of avatrombopag salt with fumaric acid, Form Bl, prepared according to Example 4. Figure 3 depicts the DSC pattern of avatrombopag salt with fumaric acid, Form Bl, prepared according to Example 4.

[0022] Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of avatrombopag salt with malonic acid, Form Cl, prepared according to Example 5.

[0023] Figure 5 depicts the DSC pattern of avatrombopag salt with malonic acid, Form Cl, prepared according to Example 5.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] The inventors have surprisingly found that from C of avatrombopag maleate can be obtained with good yield and purity from the mixed solvent of acetone and water. The process is relatively fast as form C of avatrombopag maleate is prepared directly from the reaction of avatrombopag free base and maleic acid. The process according to the present invention does not require the use of excessive amount of solvents or high crystallization temperatures. In contrary to prior art processes the method of the present invention is more environmentally friendly as the use of water in the mixed solvent can reduce the overall amount of organic solvents (in this case acetone) needed.

[0026] The presented invention relates to a method for preparing form C of avatrombopag maleate, the method comprising following steps: a) Avatrombopag free base is suspended in the mixture of acetone and water and stirred; b) Maleic acid is added into suspension and stirred; c) Obtained solid is isolated, washed with acetone and dried.

[0027] The volume ratio between acetone and water can be between 0.8:1 and 1:0.8. Preferably, the volume ratio is 1: 1. The mass volume ratio of avatrombopag free base and acetone, in g / mL, is between 1:10 to 1:30.

[0028] In step b), to the suspension obtained in step a) maleic acid is added and the suspension is stirred. The molar ratio between avatrombopag free base and added maleic acid can be between 1:1.05 and 1:1.25. The suspension is stirred for 1 - 3 hours at the temperature between 20 - 60°C. In step c), the solid obtained in step b) is isolated, optionally washed by a portion of acetone and dried. The obtained form C can be isolated by any suitable technique, for example using filtration or centrifuge.

[0029] The presented invention further relates to a novel avatrombopag salts. The invention relates to hydrogenmalonate, fumarate, sulphate, besylate and tosylate salts of avatrombopag and the preparation thereof. The invention also relates to solid forms of these salts.

[0030] In general, the salts of avatrombopag according to the invention are prepared by reacting avatrombopag free base with selected acid in a suitable solvent or a mixture of solvents at defined temperature, followed by an isolation step (precipitation or crystallization, or filtration). The present invention relates to avatrombopag sulphate, the solid form Al and the preparation thereof.

[0031] The solid form Al of avatrombopag sulphate can be characterized by XRPD pattern values having 20 values 6.7, 13.6, 18.8 and 20.3 degrees 2 theta (± 0.2 degrees 2 theta). The solid form Al can also be characterized by xrpd pattern having 6.7, 7.0, 13.6, 18.8, 20.3 and 24.0 degrees 2 theta (± 0.2 degrees 2 theta). The solid form can be further characterized by xrpd pattern described in table 1:

[0032] Table 1

[0033] Form Al of avatrombopag sulphate salt can be prepared by mixing avatrombopag free base with aqueous sulfuric acid in a solvent, heating the mixture, cooling and isolating form 1 of avatrombopag sulphate. The concentration of avatrombopag free base in a solvent(s) can be between 50 and 80 mg / ml.

[0034] The molar ratio of avatrombopag free base and sulfuric acid can be between 1:1 to 1.3. Solvent is preferably selected from acetonitrile, acetone or the mixture of acetone or acetonitrile and water. Most preferably acetonitrile or a mixture of acetone and water is used.

[0035] Avatrombopag free base in a solvent is heated to 55 to 80°C and aqueous sulfuric acid is added to the mixture. The mixture is subsequently stirred at the temperature of 55 to 80°C for a sufficient amount of time. The mixture is cooled to a temperature between 20°C and 25°C and the obtained solid is fdtered and dried. The solid Form Al can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.

[0036] The present invention also relates to fumaric salt of avatrombopag, form Bl of avatrombopag fumarate and their preparation.

[0037] The solid form Bl of avatrombopag fumarate can be characterized by XRPD pattern values having 20 values 6.9, 7.6 and 20.3 degrees 2 theta (± 0.2 degrees 2 theta). The solid form Bl can also be characterized by xrpd pattern having 6.9, 7.6, 13.2, 18.8, 19.4 and 20.3 degrees 2 theta (± 0.2 degrees 2 theta). The solid form can be further characterized by xrpd pattern described in table 2: Table 2:

[0038] The solid form Bl of avatrombopag fumarate can be further characterized by xrpd pattern depicted in figure 2. Form Bl of avatrombopag fumarate salt can be prepared by mixing avatrombopag free base with fumaric acid in a solvent or a mixture of solvents, heating the mixture, cooling and isolating form Bl of avatrombopag fumarate.

[0039] The concentration of avatrombopag free base in a solvent(s) can be between 50 and 75 mg / ml.

[0040] The molar ratio of avatrombopag free base and fumaric acid can be between 0.9:1 to 1.3. Solvent is preferably selected from methanol, ethanol or the mixture thereof. Preferably the mixture comprising avatrombopag free base and methanol or a mixture or ethanol and methanol is heated to a temperature between 55 to 65°C and to the mixture fumaric acid is added. Fumaric acid is preferably added in the form of solution in ethanol. The mixture is subsequently stirred at the temperature of 55 to 65°C for a sufficient amount of time. The mixture is cooled to a temperature between 20°C and 25°C. The solid Form Bl can be isolated by any suitable technique, for example using filtration or centrifuge.

[0041] Obtained solid can be optionally dried.

[0042] The present invention also relates to hydrogenmalonate salt of avatrombopag, form Cl of avatrombopag hydrogenmalonate and the preparation thereof.

[0043] The solid form Cl of avatrombopag hydrogenmalonate can be characterized by XRPD pattern values having 20 values 19.1, 20.6 and 23.9 degrees 2 theta (± 0.2 degrees 2 theta). The solid form Cl can also be characterized by xrpd pattern having 12.8, 19.1, 19.4, 20.6, 23.9 and 25.2 degrees 2 theta (± 0.2 degrees 2 theta). The solid form can be further characterized by xrpd pattern described in table 3:

[0044] Table 3:

[0045] The solid form Cl of avatrombopag hydrogenmalonate can be further characterized by xrpd pattern depicted in figure 4.

[0046] Form Cl can be prepared by mixing avatrombopag free base with malonic acid in a solvent or a mixture of solvents, heating the mixture, cooling and isolating form Cl of avatrombopag hydrogenmalonate.

[0047] The concentration of avatrombopag free base in a solvent(s) can be between 50 and 75 mg / ml.

[0048] The molar ratio of avatrombopag free base and malonic acid can be between 1: 1 to 1.3. Solvent is preferably selected from methanol or the mixture of methanol and water. Preferably the mixture comprising avatrombopag free base and methanol is heated to a temperature between 55 to 65°C and to the mixture malonic acid is added. Malonic acid is preferably added in the form of solution in ethanol. The mixture is subsequently stirred at the temperature of 55 to 65°C for a sufficient amount of time. The mixture is cooled to a temperature between 20°C and 25°C. The solid Form Cl can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried. The present invention further relates to besylate salt of avatrombopag, form D 1 of avatrombopag besylate and the preparation thereof.

[0049] The solid form DI of avatrombopag besylate was identified as a DMSO solvate. Form DI can be characterized by XRPD pattern values having 20 values 16.6, 19.9 and 21.8 degrees 2 theta (± 0.2 degrees 2 theta). The solid form DI can also be characterized by xrpd pattern having 8.3, 10.6, 13.7, 16.6, 19.9 and 21.8 degrees 2 theta (± 0.2 degrees 2 theta). The solid form can be further characterized by xrpd pattern described in table 4:

[0050] Table 4: Form DI can be prepared by mixing avatrombopag free base with benzenesulfonic acid in a mixture of solvents comprising DMSO, acetone and water, heating the mixture, cooling and isolating form DI of avatrombopag besylate.

[0051] The concentration of avatrombopag free base in a mixture of solvents can be between 10 and 20 mg / ml. The molar ratio of avatrombopag free base and benzene sulfonic acid can be between 1 : 1 to 1.3. The molar ration between DMSO, acetone and water is preferably around 1: 1:0.5. Preferably the mixture comprising avatrombopag free base and the solvent mixture is heated to a temperature between 55 to 75°C and to the mixture solid benzene sulfonic acid is added. The mixture is subsequently stirred at the temperature of 55 to 75°C for a 10 - 60 minutes. The mixture is cooled to a temperature between 2°C and 10°C. The solid Form DI can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.

[0052] The present invention also relates to tosylate salt of avatrombopag, form El of avatrombopag tosylate and the preparation thereof.

[0053] The solid form El of avatrombopag tosylate has been identified as DMSO solvate. Form El can be characterized by XRPD pattern values having 20 values 9.6, 20.5 and 21.3 degrees 2 theta (± 0.2 degrees 2 theta). The solid form El can also be characterized by xrpd pattern having 9.6, 10.2, 13.6, 14.5, 20.5 and 21.3 degrees 2 theta (± 0.2 degrees 2 theta). The solid form can be further characterized by xrpd pattern described in table 5 :

[0054] Table 5

[0055] Form El can be prepared by mixing avatrombopag free base with p-Toluenosulfonic acid in a mixture of solvents comprising DMSO, acetone and water, heating the mixture, cooling and isolating form DI of avatrombopag besylate. The concentration of avatrombopag free base in a mixture of solvents can be between 10 and 20 mg / ml. The molar ratio of avatrombopag free base and p-Toluenosulfonic acid can be between 1: 1 to 1.3. The molar ratio between DMSO, acetone and water is preferably around 1: 1:0.5. Preferably the mixture comprising avatrombopag free base and the solvent mixture is heated to a temperature between 55 to 75°C and to the mixture solid p-Toluenosulfonic acid is added. The mixture is subsequently stirred at the temperature of 55 to 75°C for a 10 - 60 minutes. The mixture is cooled to a temperature between 20°C and 25°C. The solid Form El can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.

[0056] The invention will be further described with reference to the following examples. EXAMPLES

[0057] DCS patterns were obtained using the following conditions: 10°C / min -> 350°C

[0058] XRPD spectrum was obtained using the following measurement conditions:

[0059] Panalytical Empyrean diffractometer with 0 / 20 geometry (transmition mode), equipped with a PixCell 3D detector;

[0060] Example 1 : Avatrombopag maleate form C

[0061] Avatrombopag free base (24.950 g, 38.4 mmol) form A was suspended into the mixture of 375 ml of acetone and 375 ml of water at ambient temperature. The suspension was stirred at 25°C for one hour at 300 RPM (mechanical stirrer, PTFE). To the suspension, solid maleic acid was added (4.46 g,

[0062] 38.4 mmol) upon constant stirring. The suspension was stirred for 3 hours. Solids were fdtered off, washed with additional 150 ml of acetone and suck dried in air for 3 hours.

[0063] Solids were measured by xrpd. Yield 85%.

[0064] Example 2: Avatrombopag maleate form C Avatrombopag free base form A (5 g, 7.70 mmol) was suspended into the mixture of acetone

[0065] (75 ml) and water (75 ml) at room temperature. The suspension was stirred at 25°C for one hour at 300 RPM (mechanical stirrer, PTFE). To the suspension, solid maleic acid (0.629 g, 8.62 mmol) was added upon constant stirring. The obtained suspension was stirred for another 3 hours at the same temperature. Solids were filtered off, washed by additional 20 ml of acetone and suck dried overnight. Solids were subsequently measured by xrpd that confirmed the same xrpd pattern as solids obtained in example 1. Yield: 87%.

[0066] Example 3: Avatrombopag sulphate tetrahydrate, form Al

[0067] Avatrombopag free base (250 mg, 0.385 mmol) was placed into 5 mL vial and to this, 2 mL of acetonitrile were added. The suspension was stirred and heated to 65 °C for 10 minutes.

[0068] Then, 1 mL of sulfuric acid solution (1 eq, 37.7 mg, 0.385 mmol) in water was added. To the suspension, another 1 mL of distilled water was added. The milky suspension was further stirred and heated to 65 °C for 24 hours. After that, the solid was vacuum filtrated and dried for 24 hours at 40°C at 100 mbar in nitrogen bleed. Yield: 74% (calculated for tetrahydrate).

[0069] Crystalline form Al proved to be stable when placed in open dish for 1 month at 40°C, 75% relative humidity and at 55°C, 90% relative humidity.

[0070] Example 4: Avatrombopag fumarate, Form Bl

[0071] Avatrombopag free base (250 mg, 0.396 mmol) was placed into 5 mL glass vial. To the vial, 2 mL of methanol was added and the mixture was ultrasonicated for 5 minutes and then stirred and heated to 65 °C. After 5 minutes, fumaric acid (leq,45.9 mg, 0.396 mmol) in 2.2mL of 10% aqueous ethanol was added and the mixture was stirred overnight at 65 °C. The solid was filtered off next day and dried freely in air for 24 hours. Yield: 75%.

[0072] Crystalline form Bl proved to be stable when placed in open dish for 1 month at 40°C, 75% relative humidity and at 55°C, 90% relative humidity.

[0073] Example 5: Avatrombopag hydrogenmalonate, Form Cl

[0074] Avatrombopag (250 mg, 0.396 mmol) was placed into 5 mL glass vial. To the vial, 2 mL of methanol was added and the mixture was ultrasonicated for 5 minutes and then stirred and heated to 65 °C. After 5 minutes, malonic acid (41.2 mg, 0.396 mrnol) in 2 rnL of water was added and the mixture was stirred overnight at 65 °C. The solid was fdtered off next day and dried freely in air for 24 hours. Crystalline form Cl proved to be stable when placed in open dish for 1 month at 40°C, 75% relative humidity and at 55°C, 90% relative humidity.

[0075] Example 6: Avatrombopag besylate DMSO solvate, Form DI

[0076] Avatrombopag free base (250 mg, 0.396 mmol) was placed into 25 mL round-bottom flask. To the flask a mixture of DMSO / acetone / water (1: 1:0.5) was added (16 mL). The mixture was ultrasonicated for 5 minutes and then stirred (500RPM) and heated to 70 °C. After 5 minutes, solid benzenesulfonic acid (62.6 mg, 0.396 mmol) was added. Dissolution of solid was observed in seconds. Clear yellowish solution was obtained. This were stirred and heated for another 30 min and then laced into refrigerator (6 °C). Highly crystalline beige solid was filtrated off next day and dried freely in air. Yield: 62%.

[0077] Crystalline form DI proved to be stable when placed in open dish at accelerated conditions (40°C, 75% relative humidity) for 1 month.

[0078] Example 7: Avatrombopag tosylate DMSO solvate, Form El

[0079] Avatrombopag free base (250 mg, 0.396 mmol) was placed into 25 mL round-bottom flask. To the flask a mixture of DMSO / acetone / water (1: 1:0.5) was added (16 mL). The mixture was ultrasonicated for 5 minutes and then stirred (500RPM) and heated to 70°C. After 5 minutes, solid p- Toluene sulfonic acid (75 mg, 0.396 rnmol) was added. Clear yellowish solution was obtained. This were stirred and heated for another 30 min and then slowly cooled down to room temperature. Yellowish product was then filtered off and dried at 40 °C under vacuum (100 mbar) in nitrogen bleed for 6 hours. Yield: 51 %.

[0080] Crystalline form El proved to be stable when placed in open dish at accelerated conditions (40°C, 75% relative humidity) for 1 month.

Claims

CLAIMS1. A method for preparing the form C of avatrombopag maleate, the method comprising following steps: a) Avatrombopag free base is suspended in the mixture of acetone and water and stirred; b) Maleic acid is added into suspension and stirred; c) Obtained solid is isolated, optionally washed with acetone and dried.

2. A method according to claim 1, wherein the ratio of acetone and water is between 0.8: 1 to 1:0.8 (v / v).

3. A method according to claim 2, wherein the ratio is 1:1.

4. A method according to any of the previous claims, wherein the mass volume ratio of avatrombopag free base and acetone, in g / mL, is between 1:10 to 1:30.

5. Avatrombopag sulfonate.

6. Solid form of avatrombopag sulfonate, wherein the form is form Al and is characterized by XRPD pattern having 20 values 6.7, 13.6, 18.8 and 20.3 degrees 2 theta (± 0.2 degrees 2 theta).

7. Avatrombopag fumarate.

8. Solid form of avatrombopag fumarate, wherein the form is form Bl and is characterized by XRPD pattern having 20 values 6.9, 7.6 and 20.3 degrees 2 theta (± 0.2 degrees 2 theta).

9. Avatrombopag hydrogenmalonate.

10. Solid form of avatrombopag hydrogenmalonate, wherein the form is form Cl and is characterized by XRPD pattern having 20 values 19.1, 20.6 and 23.9 degrees 2 theta (± 0.2 degrees 2 theta).

11. Avatrombopag be sy late .

12. Solid form of avatrombopag besylate, wherein the form is DI and is characterized by XRPD pattern having 20 values 116.6, 19.9 and 21.8 degrees 2 theta (± 0.2 degrees 2 theta).

13. Avatrombopag tosylate.

14. Solid form of avatrombopag tosylate, wherein the form is form El and is characterized byXRPD pattern having 20 values 9.6, 20.5 and 21.3 degrees 2 theta (± 0.2 degrees 2 theta).