Novel avapritinib salts and methods for preparing the salts

Abstract

Novel avapritinib salts and methods for preparing the salts The present invention relates to new citrate and napsylate salts of avapritinib, their crystalline forms and processes for their preparation.

Description

[0001] Novel avapritinib salts and methods for preparing the salts

[0002] Field of the disclosure

[0003] The present invention relates to new salts of avapritinib (I) and their crystalline forms and processes for their preparation. Avapritinib (I), (lS)-l-(4-fluorophenyl)-l-[2-[4-[6-(l- methylpyrazol-4-yl)pyrrolo[2,l-f][l,2,4]triazin-4-yl]piperazin-l-yl]-pyrimidin-5- yl] ethanamine, is used for treatment of gastrointestinal stromal tumors (GIST) and for tumors of stomach and intestines.

[0004] Background of the disclosure

[0005] Avapritinib (I) is disclosed in WO 2015057873 international patent application and discloses process for preparing a mixture of avapritinib (I) and its enantiomer as well. The S-enantiomer (Formula I) is separated from the racemate by chiral chromatography.

[0006] Avapritinib (I) crystalline forms and salts are disclosed in International Publication No. W02020 / 210669, WO2021 / 004895, WO2021 / 079134, WO2021 / 183709, WO2021 / 257522 and Chinese patent application No. CN112125910.

[0007] However, plurality of the avapritinib salts disclosed in the mentioned publications are not suitable or their suitability is questionable for use them as active pharmaceutical ingredients because of toxicological or medical point of view.

[0008] WO202 1 / 257522 discloses avapritinib benzoate salt. Based on the acceptable daily intake (ADI) for benzoic acid (5 mg / kg / day) the planned maximum amount of benzoic acid in avapritinib tablets (73.2 mg) is approximately 30% of the safe intake of benzoic acid per 50 kg body weight (250 mg / day). Given the amount of benzoic acid from other sources, the amount of benzoic acid from the benzoate salt of avapritinib may be of concern for regulatory acceptance, as this amount is estimated by JECFA (Joint FAO / WHO Expert Committee on Food Additives) to be close to the ADI upper limit for adults (based on the Brand-loyal scenario, the average daily intake for adults is 4.6 mg / kg / day). The main medical risk of using benzoic acid / benzoates is that they displace bilirubin from albumin. The use of benzoic acid, taking into account the exposure of the adult population to benzoate from other sources, is medically and toxicologically not supported.

[0009] WO2021257522 discloses avapritinib R-mandelate salt. Mandelic acid is a substrate or product of many biochemical processes in the body. Mandelic acid derivatives are formed as a result of the metabolism of adrenaline and noradrenaline by monoamine oxidase and catechol-O- methyltransferase (3). Mandelic acid is used for therapeutic purposes as a urinary tract antiseptic and in topical products. ADI and GRAS (generally recognized as safe) status are not defined. Mandelic acid shows low acute toxicity in rats (LD50>2000 mg / kg). Mandelic acid is not mutagenic in the Ames test. No other toxicological data are available (4). Mandelic acid is listed in PhEur, but not in the FDA IIDB (Inactive Ingredients database). The small amount of preclinical literature data does not make it possible to support the harmlessness of the new salt form in the specified amount, and therefore its acceptance by the authorities may pose a risk. Mandelic acid is therefore its regulatory acceptance may pose a risk.

[0010] WO202 1257522 discloses avapritinib cinnamic acid salt. The Derived No Effect Level (DNEL) for cinnamic acid is 0.625 mg / kg / day. Of this value, the permitted intake is 31.25 mg / day based on a body weight of 50 kg. At the maximum daily dose of avapritinib, the planned saltforming dose is 89.15 mg / day, which is not supported from a toxicological point of view as the amount of salt ingested with avapritinib exceeds the DNEL.

[0011] WO202 1257522 discloses avapritinib p-hydroxybenzoic acid salt. The acute toxicity of p- hydroxybenzoic acid is low, in mice the LD50 is >2000 mg / kg. Parabens are esters of p- hydroxybenzoic acid. Parabens are widely used as preservatives in food, pharmaceuticals and cosmetics. The ADI value for parabens is 10 mg / kg / day. However, in the EMA 2019 "Excipients and information to be included in the package leaflet" guideline, the following is stated about parahydroxybenzoates: "may cause allergic reactions (which may only appear later). This warning is to be understood without a quantity limit”. Therefore, the use of p- hydroxybenzoic acid salt of avapritinib is not recommended from a medical point of view. Additionally, p-hydroxybenzoic acid is not in the FDA IIDB (Inactive Ingredients database).

[0012] Other avapritinib salts disclosed in the mentioned publications could be suitable for use them as active pharmaceutical ingredients from a toxicological or medical point of view, however, there are other characteristics which could be improved with new salts of avapritinib (I).

[0013] Different salts of an active pharmaceutical ingredient have different properties. Below can be found some properties, which could influence, determine the suitability of a salt for use it as a pharmaceutical ingredient:

[0014] Solubility in ethanol (96%, 70%, 50%, 20%) [mg / ml]: The material should preferably be soluble in diluted ethanol, most preferably in water, in order to facilitate cleanability from machine, equipment and other surfaces.

[0015] Solubility in aqueous buffer systems representing the gastrointestinal tract (3 distinguished pH- s ranging from 1.0 to 6.8): The required dose should preferably be soluble in at least one of the investigated pHs. Most preferably the dose should be soluble in all three investigated pHs in order to allow the evaluation of biological equivalence based on in vitro drug release tests.

[0016] Forced degradation study results (resistance to acidic-, basic environments, water, elevated temperature, light and oxidizing agents): During forced degradation studies, the material is subjected to different conditions, acidic or basic environment, elevated heat, water, temperature, light and oxidizing agents, that normally enhance the degradation of chemical substances. The material preferably does not degrade in at least some of the above investigated conditions in order to facilitate drug product formulation. Most preferably the material is resistant to all the above listed conditions, making the formulation of a robust drug product possible with ease. pKa value of the API: pKa is the negative log base ten of the acid dissociation constant value. It measures the strength of an acid, how tightly a proton is held by a Bronsted acid. The lower the value of pKa, the stronger the acid and the greater its ability to donate its protons. If an acid is too strong, it may be irritative to the gastrointestinal tract, in extreme cases may even cause ulcer formation in the stomach, as well as it may cause corrosion in the processing equipment. Ideally the pKa value of the active ingredient should be somewhere between 2.0 - 6.0. logP: The log P value for a compound is the logarithm (base 10) of the partition coefficient (P). The partition coefficient (P) describes the propensity of a neutral (uncharged) compound to dissolve in an immiscible biphasic system of lipid (fats, oils, organic solvents) and water. In simple terms, it measures how much of a solute dissolves in the water portion versus an organic portion. A negative value for logP means the compound has a higher affinity for the aqueous phase (it is more hydrophilic); when logP = 0 the compound is equally partitioned between the lipid and aqueous phases; a positive value for logP denotes a higher concentration in the lipid phase (i.e., the compound is more lipophilic). The logP value should preferably be a small number (either negative, or positive) meaning that the molecule will readily be soluble in aqueous media, and still have the ease of permeating through the lipid bilayer membranes of the gastrointestinal tract.

[0017] Stability properties: stability properties may be defined by thermal stability, hygroscopicity or long term stability.

[0018] Thermal stability: thermal stability may be measured with Thermogravimetric analysis (TGA) and Differential scanning calorimetry (DSC).

[0019] Hygroscopicity: hygroscopicity is the ability of the material to absorb moisture from the air. Hygroscopicity may be measured with dynamic vapor sorption (DVS) studies. The higher the moisture content of the air that causes absorbance in the investigated material, the less hygroscopic it is. Hygroscopicity can hinder manufacturability, may cause shelf-life to be shorter and may facilitate further degradation in the drug product.

[0020] Long-term stability: may be predicted with accelerated stability tests measuring the water content and the amount of impurities of the samples after storage for several weeks (for example 8 weeks) under several conditions such as different temperatures, humidities (RH) and packages. The water content and the amount of the impurities should be below 0,5% in the sample to be suitable for use as active ingredient in pharmaceutical product (The limits are defined in ICH: International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)

[0021] Brief description of the Figures

[0022] Figure 1: The X-ray powder diffractogram of the avapritinib citrate 2:1 salt

[0023] Figure 2: The X-ray powder diffractogram of of the avapritinib napsylate 1: 1 salt

[0024] Figure 3: The X-ray powder diffractograms of the avapritinib fumarate samples prepared in milligram scale

[0025] Figure 4: The X-ray powder diffractograms of the avapritinib fumarate samples prepared in 5- fold larger scale (Exp_F7, Exp_F8 and Exp_F9)

[0026] Figure 5: The X-ray powder diffractograms of the avapritinib fumarate samples prepared in 5- fold larger scale (Exp_F10, Exp_Fl l and Exp_F12)

[0027] Figure 6. The X-ray powder diffractograms of the avapritinib fumarate samples prepared in 5- fold larger scale (Exp_F14, Exp_F16 and Exp_F17)

[0028] Figure 7. The X-ray powder diffractograms of the avapritinib fumarate samples prepared in 5- fold larger scale (Exp_F4 and Exp_F13)

[0029] Figure 8. The X-ray powder diffractograms of the three avapritinib adipate samples prepared

[0030] (Exp_Al, Exp_A2 and Exp_A3)

[0031] Figure 9: TGA curve of the avapritinib citrate 2:1 salt

[0032] Figure 10: DSC curve of the avapritinib citrate 2:1 salt

[0033] Figure 11 : TGA curve of the avapritinib HC1 salt

[0034] Figure 12: DSC curve of the avapritinib HC1 salt

[0035] Figure 13: TGA curve of the avapritinib acetate salt

[0036] Figure 14: DSC curve of the avapritinib acetate salt

[0037] Figure 15: TGA curve of the avapritinib napsylate 1:1 salt

[0038] Figure 16: DSC curve of the avapritinib napsylate 1:1 salt Figure 17: Water sorption isotherm of the avapritinib citrate salt (25 °C, 2. cycle)

[0039] Figure 18. Water sorption isotherm of the avapritinib HC1 salt (25 °C, 2. cycle)

[0040] Figure 19. Water sorption isotherm of the avapritinib acetate salt (25 °C, 2. cycle)

[0041] Figure 20. Water sorption isotherm of the avapritinib napsylate salt (25 °C, 2. cycle)

[0042] Summary of the invention

[0043] The present invention relates to novel salts of avapritinib (I), (lS)-l-(4-fhiorophenyl)-l-[2-[4- [6-(l-methylpyrazol-4-yl)pyrrolo[2,l-f][l,2,4]triazin-4-yl]piperazin-l-yl]-pyrimidin-5- yl] ethanamine.

[0044] In one embodiment, the present invention relates to citrate salts of avapritinib (I).

[0045] In another embodiment, the present invention relates to the crystalline avapritinib citrate 2:1 salt and process for the preparation of it.

[0046] The present invention also provides uses of avapritinib citrate salts for the manufacture of pharmaceutical composition.

[0047] The present invention also provides uses of avapritinib citrate salts and the pharmaceutical compositions comprising it as medicament, for the treatment of gastrointestinal stromal tumors (GIST) and for tumors of stomach and intestines, and Advanced Systemic Mastocytosis, preferably gastrointestinal stromal tumors (GIST).

[0048] In another embodiment, the invention relates to napsylate salts of avapritinib (I).

[0049] In another embodiment, the invention relates to the crystalline avapritinib napsylate 1 : 1 salt and process for the preparation of it.

[0050] The present invention also provides uses of avapritinib napsylate salts for the manufacture of pharmaceutical composition.

[0051] The present invention also provides uses of avapritinib napsylate salts and the pharmaceutical compositions comprising it as medicament, for the treatment of gastrointestinal stromal tumors (GIST) and for tumors of stomach and intestines, and Advanced Systemic Mastocytosis, preferably gastrointestinal stromal tumors (GIST). Detailed description of the invention

[0052] The present invention relates to citrate salt of avapritinib (I). More particularly, the present invention relates to the crystalline avapritinib citrate 2:1 salt, the characteristic X-ray powder diffraction peaks of which are the following: 29 (±0.2° 29): 5.51; 16.03; 22.13. More specifically it may be characterized by the following X ray powder diffraction peaks: 29 (±0.2° 29): 3.09; 5.51; 11.10; 16.03; 16.47; 22.13; 24.38. Even more specifically it may be characterized by the following X-ray powder diffraction peaks: 29 (±0.2 °29): 3.09; 5.51; 6.19; 7.09; 9.33; 9.45; 10.61; 11.10; 12.36; 14.07; 14.62; 14.80; 15.11; 15.56; 16.03; 16.20; 16.47; 16.95; 17.30; 17.76; 17.92; 18.52; 18.75; 18.98; 19.39; 19.73; 19.98; 20.41; 20.81; 21.03;

[0053] 21.22; 21.46; 21.97; 22.13; 22.97; 23.29; 23.65; 24.38; 25.04; 25.56; 26.09; 26.38; 26.78;

[0054] 27.05; 27.26; 27.70; 27.87; 28.21; 28.39; 28.71; 29.35; 29.68; 29.78; 30.26; 30.55; 31.06;

[0055] 31.55; 31.71; 32.07; 32.77; 33.07; 33.43; 34.03; 34.28; 34.88. The characteristic X-ray powder diffractogram of the avapritinib citrate 2:1 salt may be seen in Figure 1., and the 1% or greater intensity peaks are summarized in Table 1.

[0056] Table 1. The X-ray powder diffraction data of avapritinib citrate 2:1 salt (relative intensities > 1%)

[0057] Instrument and Methodology details of X-ray Powder Diffraction (XRPD)

[0058] In the case of all crystalline forms presented here the X-ray diffraction data of the new avapritinib salts (citrate and napsylate) according to our invention were obtained under the following measurement conditions:

[0059] Instrument: PANalytical Empyrean X-ray powder diffractometer

[0060] Sample mode: Transmission

[0061] X-ray tube

[0062] Type: Empyrean Long Fine Focus High Resolution tube

[0063] Anode material: Cu

[0064] Wavelength: Ka (1.541874 A)

[0065] Focus mode: line focus

[0066] Incident beam optics

[0067] Divergence slit: Fixed slit 1 / 20

[0068] Mirror: Focusing elliptical mirror

[0069] Soller slit: 0.04 rad

[0070] Anti-scatter slit: Fixed slit 1 / 20

[0071] Diffracted beam optics

[0072] Anti-scatter slit: Programmable slit in fix mode: 1 / 20

[0073] Soller slit: 0.04 rad

[0074] Sample stage

[0075] Type: Reflection-transmission spinner stage

[0076] Sample rotation: 1 rps

[0077] Beam knife: Transmission beam stop used

[0078] Detector

[0079] Type: PIXcel 3D 1x1 area detector

[0080] Mode: Scanning line detector (ID) mode

[0081] Active length: 3.3473° Sample preparation: place powder samples (without grinding) between two Mylar foils in the sample holder

[0082] Measurement settings

[0083] Temperature: room temperature

[0084] Accelerating voltage: 45 kV

[0085] Anode heating current: 40 mA

[0086] Scan type: continuous gonio (9 / 9) scan

[0087] Measurement range: range: 2.0000 - 34.9964 °29

[0088] Step size: 0.0131 °29

[0089] Time per step: 109.650 s

[0090] Measurement cycles: 1

[0091] Measurement time: ~20 minutes

[0092] The present invention provides the process for the preparation of avapritinib citrate 2:1 salt comprising the steps of: a) dissolving avapritinib in a suitable solvent to form a solution b) adding citric acid solution to the solution of avapritinib c) waiting until formation of a white precipitation, or optionally inducing the crystallization by seeding d) cooling the suspension, preferably to room temperature e) filtering the reaction mixture, washing and drying under vacuum till constant weight.

[0093] In step a) avapritinib may be dissolved in a polar aprotic solvent and / or in a mixture thereof with a polar protic solvent. The polar protic solvent may be for example a C1-C4 alcohol. Preferably, avapritinib may be dissolved in DMSO / ethanol, ethanol / ethyl acetate, ethyl acetate / DMSO, ethanol / THF mixture, more preferably in ethanol / THF 10 / 8 mixture. Preferably, the solution may be heated to reflux temperature and it may be a saturated solution.

[0094] In step b) 0,2-2 equivalent of citric acid water solution may be added to the solution of avapritinib, preferably 0,4-1 equivalent, more preferably 0,5-0,55 equivalent of citric acid.

[0095] In step c) the stirring at reflux temperature is needed until the formation of a white precipitation (about 20-30 minutes), or optionally, crystallization may be induced and speeded up with seeding. In step d) slow cooling is preferred.

[0096] In step e) the reaction mixture may be filtered and washed with mother liquor (optional), and then washed with a solvent in which avapritinib citrate is poorly soluble, for example C1-C4 alcohol, acetone, C3-C6 esters or C4-C5 esters, preferably with ethanol.

[0097] The present invention relates to a pharmaceutical composition comprising a citrate salt of avapritinib of the present invention, in a therapeutically effective amount. Still further subject of the invention is a process for preparing pharmaceutical compositions, wherein avapritinib citrate of the present invention is mixed with the appropriate amount of a pharmaceutically acceptable carrier and, if desired, other pharmaceutical excipients.

[0098] Citrate salt of avapritinib of the present invention and the pharmaceutical compositions comprising it can be used as medicament, for the treatment of gastrointestinal stromal tumors (GIST) and for tumors of stomach and intestines, and Advanced Systemic Mastocytosis, preferably gastrointestinal stromal tumors (GIST).

[0099] The present invention relates to napsylate salt of avapritinib(I). More particularly, the present invention relates to the crystalline avapritinib napsylate 1 : 1 salt, the characteristic X-ray powder diffraction peaks of which are the following: 29 (±0.2° 29): 5.87; 15.66; 20.63. More specifically it may be characterized by the following X-ray powder diffraction peaks: 29 (±0.2° 29): 5.87; 10.72; 15.66; 20.63; 21.77; 26.10. Even more specifically it may be characterized by the following X-ray powder diffraction peaks: 29 (±0.2 °29): 5.35; 5.69; 5.87; 9.37; 9.70; 10.72; 11.41; 14.55; 15.66; 16.11; 17.31; 17.49; 17.82; 18.08; 18.51; 18.74; 19.50; 20.63; 21.06; 21.36; 21.56; 21.77; 22.55; 22.96; 23.59; 23.86; 24.28; 24.60; 25.06; 25.56; 26.10; 26.89; 27.28; 27.92; 28.74; 29.02; 29.79; 30.80; 31.22; 31.48; 32.87; 33.27; 33.56; 33.91; 34.43. The characteristic X-ray powder diffractogram of the avapritinib napsylate 1:1 salt may be seen in Figure 2., and the 1% or greater intensity peaks are summarized in Table 2.

[0100] Table 2. The X-ray powder diffraction data of avapritinib napsylate 1:1 salt ( relative intensities > 1%)

[0101] The present invention provides the process for the preparation of avapritinib napsylate 1:1 salt comprising the steps of: a) dissolving avapritinib in a suitable solvent to form a solution b) adding the solution of 2-naphthalenesulfonic acid to the solution of avapritinib c) after formation of a white precipitation cooling the suspension, preferably to room temperature d) filtering the reaction mixture, washing and drying under vacuum till constant weight.

[0102] In step a) avapritinib may be dissolved in a polar aprotic solvent and / or in a mixture thereof with a polar protic solvent. The polar protic solvent may be for example a C1-C4 alcohol. Preferably, avapritinib may be dissolved in DMSO / ethanol, ethanol / ethyl acetate, ethyl acetate / DMSO, ethanol / THF mixture, more preferably in ethanol / THF 10 / 8 mixture. Preferably, the solution may be heated to reflux temperature and it may be a saturated solution.

[0103] In step b) 0.8- 1.5 equivalent, preferably 0.8- 1.3 equivalent, more preferably 0.9- 1.1 equivalent of 2-naphthalenesulfonic acid dissolved in a polar aprotic solvent and / or in a mixture thereof with a polar protic solvent may be added to the solution of avapritinib. The solvent used for dissolving 2-naphthalenesulfonic acid may be the same solvent as used for dissolving avapritinib. Formation of a white precipitation is immediately detectable after the reaction, no stirring at high temperature or seeding is needed.

[0104] In step c) slow cooling is preferred.

[0105] In step d) the reaction mixture may be filtered and washed with mother liquor (optional), and then washed with a solvent in which avapritinib napsylate is poorly soluble, for example C1-C4 alcohol, acetone, C3-C6 esters or C4-C5 esters, preferably with ethanol.

[0106] The present invention relates to a pharmaceutical composition comprising a napsylate salt of avapritinib of the present invention, in a therapeutically effective amount. Still further subject of the invention is a process for preparing pharmaceutical compositions, wherein avapritinib napsylate of the present invention is mixed with the appropriate amount of a pharmaceutically acceptable carrier and, if desired, other pharmaceutical excipients.

[0107] Napsylate salt of avapritinib of the present invention and the pharmaceutical compositions comprising it can be used as medicament, for the treatment of gastrointestinal stromal tumors (GIST) and for tumors of stomach and intestines, and Advanced Systemic Mastocytosis, preferably gastrointestinal stromal tumors (GIST).

[0108] Avapritinib salts disclosed in W02020 / 210669, WO2021 / 004895, WO2021 / 079134, WO202 1 / 183709, WO2021 / 257522 and CN112125910 are: i) not suitable or their suitability is questionable for use them as active pharmaceutical ingedients because or toxicological or medical point of view: benzoate, R-mandelate, cinnamic acid and p-hydroxybenzoic acid salt of avapritinib detailed explanation is disclosed in the background of the disclosure, or ii) based on the disclosure of WO2021 / 257522, fumarate and adipate salts of avapritinib are not reproducible especially in industrial scale, or iii) their properties are less promising to use them in pharmaceutical products: hydrochloride and acetate salts of avapritinib

[0109] WO202 1 / 257522 discloses avapritinib fumarate salt (Form AC3), the process for preparing it is disclosed in Example 5, where avapritinib fumarate is prepared in milligram scale by ball milling in a Retsch Cryomill instrument with 5 mL milling jar. Reproduction of the example was possible with a very similar instrument (Retsch MM 301 instrument equipped with 10 mL milling jars) in milligram scale (Figure 3), which indicates that the difference between the apparatuses does not affect the the outcome of the synthesis and the crystalline structure of the product.

[0110] However, when the synthesis was performed in a slightly enlarged scale (starting from 500 mg avapritinib), 11 experiments from 14 resulted in XRPD patterns different from Form AC3 of WO202 1 / 257522. In 9 samples, XRPD peaks of avapritinib base Form A were identified with small intensities in addition to the peaks of avapritinib fumarate Form AC3, as shown in Figures 4-6, which indicates the presence of a small amount of avapritinib base in the samples, i. e. an incomplete salt formation. In 2 samples, XRPD revealed the presence of a crystalline chemical or polymorphic impurity in addition to avapritinib fumarate Form AC3, as shown in Figure 7. From the Figures above it is clear, that if an avapritinib salt can not be reproduced in a 500mg scale with the disclosed process, additionally, preparation methods comprising the use of ball mills are not suitable for even larger scales such as industrial scale.

[0111] WO202 1 / 257522 discloses avapritinib adipate (Form AC4), the process for preparing it is disclosed in Example 6 of WO2021 / 257522, where avapritinib adipate is prepared by ball milling in a Retsch Cryomill instrument with 5 mL milling jar in milligram scale. For reproducing the example a Retsch MM 301 instrument equipped with 10 mL milling jars was used. However, reproduction of avapritinib adipate Form AC4 of WO2021 / 257522 was not possible even in milligram scale.

[0112] According to XRPD results as shown in Figure 8, crystalline structure of the obtained three solids was different from that of avapritinib adipate Form AC4.

[0113] Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) studies, dynamic vapor sorption (DVS) studies, stability tests after storage for 8 weeks at several temperatures, humidities (RH) and packages were carried out to learn about the stability properties of the avapritinib citrate and napsylate salts of the present invention and salts disclosed in the prior art which were not excluded as suitable pharmaceutical ingredient from toxicological or medical point of view, or were not excluded because of reproduction problems. Stability properties are critical for formulation processes and shelf life of a pharmaceutical product, therefore good stability properties of an active ingredient are crucial. However, the mentioned properties may not be predicted from the chemical characteristics of different salts.

[0114] For the measurements below, avapritinib HC1 was prepared as disclosed in Example 7 of W02020 / 210669 (Form H), and avapritinib acetate was prepared as disclosed in Example 6 of WO2021 / 183709 (Form AT4). The X-ray powder diffraction peaks of the reproduced samples were the same as disclosed in the prior art

[0115] Thermal stability, amount of volatile compounds and melting point can be possibly determined by TGA and DSC measurements.

[0116] In the TGA curve (Figure 9) of the avapritinib citrate only a small weight loss (0.1 w / w%) was detected up to 75 °C and still under 0.5 until 100 °C. Otherwise the salt was found to be stable up to ca. 150 °C, no other signals were detected below this temperature neither in the TGA, nor in the DSC curve (Figure 10). Above ca. 150 °C the thermal degradation of the sample was occurred indicated by an intensive weight decrease in the TGA curve. The sample did not melt until 180 °C. An endothermic peak was detected in the DSC curve in the ca. 150-190 °C range, which probably belongs to the thermal degradation process. The exact melting point of the salt could not be determined because of the degradation. Based on the thermoanalytical results avapritinib citrate is a water and solvent free anhydrous form.

[0117] In case of avapritinib napsylate a slightly higher amount of volatile compounds was detected: weight loss values were found to be below 0.5 w / w% until 100 °C, and a significantly higher amount of volatile compounds was detected in case of HC1 salt: 1.1 w / w% until 65 °C. By increasing the temperature, a slow and continuous decrease of mass was observed for both salts, which indicates thermal instability (even mild degradation processes). A quite well-defined weight loss was also detected in case of both salts in the temperature range of ca. 100-200 °C, which probably belongs to a specific part of the thermal degradation process. Above ca. 220 °C the decrease of mass was found to be faster in the TGA studies (Figure 11 and 15), which indicates a more intensive thermal degradation. In the DSC curve (Figure 12 and 16) an endotherm-exotherm-endotherm signal series can be detected for both salts between ca. 150 °C and 220 °C which also can be bound to thermal degradation processes. The exact melting point could not be detected for these salts either, because the melting process is accompanied by thermal degradation.

[0118] Avapritinib acetate contained a very low amount of volatile compounds: the detected weight loss in the TGA measurement (Figure 13) was found to be 0.2 w / w% until the temperature value of 60 °C. By increasing the temperature, a big (11.0 w / w%) and well-defined weight loss process could be observed, which indicated the evaporation of the acetic acid i. e. the disintegration of the original salt. The theoretical mass loss belongs to this process is 10.7 w / w% which is in good agreement with the measured value. The formation of avapritinib base due to this disintegration was also confirmed by X-ray powder diffraction (XRPD) measurement. In the DSC curve (Figure 14) a wide endothermic peak indicates the evaporation of acetic acid in the temperature range of ca. 80-140 °C. An additional endothermic peak was also observed in the DSC curve with an onset temperature value of 190.9 °C, which belongs to the melting of the avapritinib base.

[0119] Summarizing the thermal properties of the studied salts, it can be stated that avapritinib citrate has the most advantageous of that. It contains only a negligible amount of volatile compounds and it was found to be thermally stable up to ca. 150 °C. Avapritinib napsylate and HC1 salts were found to be a bit less stable (as showed by the continuous mass decrease in the TGA curves) with a bit higher amount of volatile compounds. Avapritinib acetate was found to be the less stable thermally: it disintegrated at relatively low temperature (the process started below 90 °C). Low thermal stability of an active ingredient can cause problems in formulation proceedings of pharmaceutical products such as dry granulation and may be related to the shelflife of pharmaceutical products as well.

[0120] Instrument and Methodology details of Thermo gravimetric analysis (TGA)

[0121] Device: TA Instruments Discovery TGA thermogravimetric analyzer

[0122] Atmosphere: N2 flow: 25 mL / min (furnace)

[0123] 10 mL / min (balance) Data sampling interval: 0,5 s / pt

[0124] Temperature program: 30 °C - end temperature* 10 °C / min

[0125] Pan: Platinum 100 pL

[0126] *: end temperature value: 180 °C (avapritinib citrate); 240 °C (avapritinib HC1); 250 °C (avapritinib acetate); 300 °C (avapritinib napsylate)

[0127] Instrument and Methodology details of Differential scanning calorimetry (DSC)

[0128] Device: TA Instruments Discovery DSC differential scanning calorimeter

[0129] Atmosphere: N2 flow (50 mL / min)

[0130] Data sampling interval: 0,1 s / pt

[0131] Temperature program: 35 °C - end temperature* 10 °C / min

[0132] Pan**: Standard Al sealed

[0133] *: end temperature value: 190 °C (avapritinib citrate); 205 °C (avapritinib acetate); 225 °C (avapritinib HC1); 230 °C (avapritinib napsylate)

[0134] **: except avapritinib acetate (Standard Al open pan)

[0135] Hygroscopic properties of avapritinib salts were studied by the dynamic vapor sorption (DVS) method. Measurements were carried out with the avapritinib citrate, napsylate, HC1 and acetate salts. Temperature was set to 25 °C for the measurements and two cycles were done between 0 and 95% of relative humidity (RH). After the DVS studies (Figures 17 to 20) XRPD tests were also carried out to check whether the crystalline structure of the investigated sample remained the same during the DVS measurement.

[0136] DVS studies showed that neither of the investigated samples were sensitive to the relative humidity of the environment: their dissolution did not occur, and their crystalline structure did not change either during the measurements according to XRPD results. However, some differences were observed in their hygroscopicity. Avapritinib HC1 was clearly found to be the most hygroscopic: its water uptake was 3.5 w / w% at 95% RH, and the change of water content in the practically relevant range (ca. 10-70% RH) was also quite high (about 1.4 w / w%). Avapritinib citrate was found to be the less hygroscopic: the maximum value of its water uptake was 1.1 w / w% (it was 1.4 w / w% for the acetate salt, and 1.6 w / w% for the napsylate salt, respectively) and its water content was also quite stable in the ca. 10-70% RH range (its fluctuation was about 0.5-0.6 w / w% in this range; it was 0.6 w / w% for the acetate salt, and 1.1 w / w% for the napsylate salt, respectively).

[0137] Since hygroscopicity can cause many problems in the pharmaceutical developments (e. g. stability, drug substance assay, protective packaging), it can be stated that avapritinib citrate was found to be the most favorable among the investigated salts from this point of view.

[0138] Instrument and Methodology details of Dynamic Vapor Sorption (DVS)

[0139] Instrument: TA Q5000SA dynamic vapour sorption analyser (DVS)

[0140] Atmosphere: Nitrogen

[0141] Total gas flow: 200 mL / min Solvent: Water

[0142] Balance purge flow: 10 mL / min

[0143] Balance temperature: 35 °C

[0144] Pan type: Platinum 100 pl, unsealed

[0145] Method: Custom

[0146] Drying: No

[0147] Conditioning: 30 min

[0148] Temperature: 25 °C, isotherm

[0149] Relative humidity range: 0% to 95% RH

[0150] Initial humidity: 50% RH

[0151] Humidity step stages: Desorption - adsorption - desorption

[0152] Humidity step size: 5% RH

[0153] Stabilization criteria: < 0.01% for 10 min

[0154] Maximum dwell time: 360 min

[0155] Data sampling interval: 5 sec / point

[0156] Number of cycles: 2

[0157] 8 week stability tests were carried out for avapritinib citrate, napsylate, HC1 and acetate salts. The samples were storaged for 8 weeks in polyethylene bags on several temperatures and humidities (RH): 25 °C with 60% RH; 25 °C with 90% RH and 40 °C with 75% and in sample vial in Argon atmosphere on 70 °C temperature. The stability of the avapritinib salts may be determined with the change of water content by Karl-Fisher measurements and with measuring the change of the impurity content as well. In case of long term storage keeping the water content and the amount of impurities under the specifiaction limit (0,5%) using polyethylene package might be an issue. Water content and the sum of impurities were measured at initial time, after 4 weeks and after 8 weeks (Tables 3 and 4)

[0158] Table 3: Change of water content and sum of impurities of avapritinib citrate, napsylate, HCl and acetate under storage condition 25°C / 60%RH in polyethylene bag and storage condition 25°C / 90%RH in polyethylene bag

[0159] Table 4: Change of water content and sum of impurities of avapritinib citrate, napsylate, HCl

[0160] Based on the 8 week stability test avapritinib citrate is considered to be non-hygroscopic at storage conditions of 25°C / 60%RH, 40°C / 75%RH and (70°C) in Ar atmosphere, and is considered hygroscopic at 25°C / 90%RH after 8 weeks, but still meets the requirements of suitability to be an active ingredient in a pharmaceutical product. A vapritinib citrate is considered to be stable in polyethylene bags even in spite of high humidity (25°C / 60%RH, 25°C / 90%RH, 40°C / 75%RH), the amount of impurities did not increase after 8 weeks. At higher temeperature (70°C) in Ar atmosphere the stability decreases, the total amount of impurities exceeds the specification limit (0,5%), but it is still less than 1%.

[0161] Based on the 8 week stability test avapritinib napsylate is considered to be hygroscopic at storage conditions of 25°C / 60%RH, 25°C / 90%RH, 40°C / 75%RH after 8 weeks, which results exceed the specification limit. Avapritinib napsylate is considered to be stable in polyethylene bags even in spite of high humidity (25°C / 60%RH, 25°C / 90%RH, 40°C / 75%RH) the amount of impurities did not increase after 8 weeks. At higher temeperature (70°C) in Ar atmosphere the stability decreases, the total amount of impurities exceeds the specification limit (0,5%), but it is still less than 1%.

[0162] Avapritinib HCl sample representing starting conditions presented very high (3-4%) water content and during the stability test avapritinib HCl showed further hygroscopic character (25°C / 60%RH, 25°C / 90%RH, 40°C / 75%RH after 8 weeks), which results exceed the specification limit. Avapritinib HC1 shows some instability under conditions with high humidity and increased temperature as well at 25°C / 60%RH, 25°C / 90%RH, 40°C / 75%RH, the total amount of impurities exceeds the specification limit (0,5%), but it is still less than l%.At higher temeperature (70°C) in Ar atmosphere the stability signifficantly decreases, the total amount of impurities grows to 3-4%.

[0163] Based on the 8 week stability test avapritinib acetate is considered to be hygroscopic at 25°C / 60%RH, 25°C / 90%RH, 40°C / 75%RH, after 8 weeks), which results slightly exceed the specification limit. Avapritinib acetate is considered to be stable in polyethylene bags even in spite of high humidity (25°C / 60%RH, 25°C / 90%RH, 40°C / 75%RH). At higher temeperature (70°C) in Ar atmosphere the stability decreases, the total amount of impurities exceeds the specification limit (0,5%), but it is still less than 1%.

[0164] Summarizing the 8 week stability tests it can be stated, that avapritinib citrate has the most advantageous properties. Avapritinib HC1 has a high water content already at initial measurements and has hygroscopic properties at all conditions. Avapritinib acetate and napsylate are hygroscopic in polyethylene bags at all conditions. Avapritinib citrate shows an increase in water content only at very high humidity (90%). The amount of impurities does not increase in the avapritinib citrate samples when storaged in polyethylene bags, only in sample vial in Ar atmosphere increases the amount of impurities. In avapritinib HC1 and acetate salts the amount of impurities increase in the polyethylene bags as well.

[0165] Instrument and Methodology details of impurity measurements

[0166] Chemicals used for analysis

[0167] Instrument: Waters Acquity I-Class UPLC system or equivalent

[0168] Analytical column: Waters Acquity BEH Cl 8, 2,1mm x 50 mm, 1,7pm

[0169] Solvent (Diluent): Acetonitrile : Water = 80:20 (V / V)%

[0170] Eluent: A: 0.1% TFA

[0171] B: Acetonitrile

[0172] Gradient profile:

[0173] Flow rate: 0.4 mL / min

[0174] Column temperature: 35 °C

[0175] Column pressure: ~ 500-600 bar

[0176] Sample temperature: 20 °C

[0177] Injection volume: 0.5 |1L

[0178] Detection: UV, 251 nm

[0179] Sample manager wash: Acetonitrile / Water = 20 / 80 (V / V)%

[0180] Wash: Acetonitrile / Water = 20 / 80 (V / V)%

[0181] Sample manager purge: Acetonitrile / Methanol / 2-propanol / Water = 25 / 25 / 25 / 25 (V IN IN IN)%

[0182] Evaluation: Area%

[0183] Disregard limit: 0.03%

[0184] Solutions:

[0185] Eluent „A”: Add 1.0 ml trifluoric acid to 1000 ml purified water and mix.

[0186] Eluent „B”: ACN

[0187] Solvent: Mix 800 ml acetonitrile and 200 ml purified water.

[0188] Blank solution:

[0189] The same as the Solvent.

[0190] Summarizing the results avapritinib citrate has the most advantageous salt. It is thermally stable, non-hygroscopic and the 8 week stability tests showed as well that avapritinib citrate is stable in polyethylene packages at high temperature or high humidity as well.

[0191] Examples

[0192] Example 1: Avapritinib citrate 2:1

[0193] Avapritinib (10.0 g; 20.1 mmol) was dissolved in EtOH / THF 10 / 8 mixture (140 ml) under magnetic strirring at 65 °C. Citric acid (2.12 g, 0.55 equiv.) dissolved in water (2.12 ml) was added to the clear solution and stirred at reflux temperature until the formation of a white precipitation (20-30 min). The obtained suspension was cooled to room temperature at 1.5 °C / min, then stirred for 1 h. The reaction mixture was filtered, washed with mother liquor followed by ethanol (50 ml), and dried under vacuum till constant weight to afford a white solid (11.5 g; 96%).

[0194] ’ H-NMR (DMSO-d6, 600 MHz) 6 (ppm): 8.40 (s, 4H), 8.04 (s, 2H), 7.99 (d, J=1.5 Hz, 2H), 7.88 (s, 2H), 7.83 (s, 2H), 7.46 (~dd, Jl=5.4 Hz, J2=8.8 Hz, 4H), 7.24 (d, J=1.5 Hz, 2H), 7.22 (~t, J=8.8 Hz, 4H), 4.11 (m, 8H), 3.94 (m, 8H), 3.86 (s, 6H), 2.57 (d, J=15.1 Hz, 2H), 2.51 (d, J=15.1 Hz, 2H), 1.87 (s, 6H).

[0195] 13C-NMR (DMSO-d6, 151 MHz) 6 (ppm): 177.3, 171.7, 161.3 (d, J=244.0 Hz), 160.2, 156.5, 153.9, 146.7, 142.3, 136.6, 128.4 (d, J=8.2 Hz), 128.0, 127.8, 118.1, 116.0, 115.7, 115.3 (d, J=21.3 Hz), 114.7, 101.9, 71.5, 56.6, 45.0, 44.6, 43.2, 38.8, 29.3.

[0196] Example 2: Avapritinib napsylate 1:1

[0197] Avapritinib (10.0 g; 20.1 mmol) was dissolved in EtOH / THF 10 / 8 mixture (120 ml) under magnetic strirring at 65 °C. 2-naphthalenesulfonic acid (4.59 g, 1.1 equiv.) dissolved in EtOH / THF 10 / 8 mixture (20 ml) was added to the vigorously stirred clear solution, which resulted in the immediate formation of a white precipitation. The obtained suspension was stirred at 65 °C for 10 min, then cooled to room temperature and stirred for 2 h. The reaction mixture was filtered, washed with mother liquor followed by ethanol (50 ml), and dried under vacuum till constant weight to afford a white solid (13.8 g; 97%).

[0198] XH-NMR (DMSO-d6, 600 MHz) 6 (ppm): 9.02 (br, 3H), 8.37 (s, 2H), 8.15 (br, 1H), 8.05 (br, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.97 (m, 1H), 7.90 (m, 1H), 7.89 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.71 (dd, Jl=8.5 Hz, J2=1.6 Hz, 1H), 7.53 (m, 2H), 7.44 (dd, Jl=8.9 Hz, J2=5.2 Hz, 2H), 7.32 (t, J1=J2=8.9 Hz, 2H), 7.24 (d, J=1.5 Hz, 1H), 4.12 (m, 4H), 3.95 (m, 4H), 3.86 (s, 3H), 2.01 (s, 3H).

[0199] 13C-NMR (DMSO-d6, 151 MHz) 6 (ppm): 161.9 (d, J=246 Hz), 160.4, 156.7, 153.9, 146.7,

[0200] 145.5, 138.1 (d, J=2.8 Hz), 136.6, 133.0, 132.3, 128.7, 128.6 (d, J=8.3 Hz), 127.8 (br), 127.7,

[0201] 127.6, 126.7, 126.6, 124.3, 124.1, 123.8 (br), 118.1, 116.0, 115.9 (d, J=21.7 Hz), 115.7, 114.7, 101.9, 58.2, 44.9 (br), 43.1, 38.8, 27.0.

Claims

Claims1. The crystalline avapritinib citrate salt.

2. The crystalline avapritinib citrate 2:1 salt.

3. The crystalline avapritinib citrate 2:1 salt according to claim 2, characterized by an X-ray powder diffractogram having peaks at 29 (±0.2 °29): 5.51; 16.03; 22.13.

4. The crystalline avapritinib citrate 2:1 salt according to claim 2, characterized by an X-ray powder diffractogram having peaks at 29 (±0.2° 29): 3.09; 5.51; 11.10; 16.03; 16.47; 22.13; 24.38.

5. The crystalline avapritinib citrate 2:1 salt according to claim 2, characterized by an X-ray powder diffractogram having peaks at 29 (±0.2 °29): 3.09; 5.51; 6.19; 7.09; 9.33; 9.45; 10.61; 11.10; 12.36; 14.07; 14.62; 14.80; 15.11; 15.56; 16.03; 16.20; 16.47; 16.95; 17.30;17.76; 17.92; 18.52; 18.75; 18.98; 19.39; 19.73; 19.98; 20.41; 20.81; 21.03; 21.22; 21.46;21.97; 22.13; 22.97; 23.29; 23.65; 24.38; 25.04; 25.56; 26.09; 26.38; 26.78; 27.05; 27.26;27.70; 27.87; 28.21; 28.39; 28.71; 29.35; 29.68; 29.78; 30.26; 30.55; 31.06; 31.55; 31.71;32.07; 32.77; 33.07; 33.43; 34.03; 34.28; 34.88.

6. The crystalline avapritinib citrate 2:1 salt according to claim 2, characterized by an X-ray powder diffractogram substantially as shown in Figure 1.

7. Process for the preparation of avapritinib citrate salt according to any of claims 1 to 6, comprising the steps of: a) dissolving avapritinib in a solvent to form a solution b) adding citric acid solution to the solution of avapritinib c) waiting until formation of a white precipitation, or optionally inducing the crystallization by seeding d) cooling the suspension, preferably to room temperature e) filtering the reaction mixture, washing and drying under vacuum till constant weight.

8. Process according to claim 7, where avapritinib is dissolved in a polar aprotic solvent and / or in a mixture thereof with a polar protic solvent, preferably in DMSO / ethanol, ethanol / ethyl acetate, ethyl acetate / DMSO, ethanol / THF mixture, more preferably in ethanol / THF 10 / 8 mixture.Process according to claim 7 or 8, where 0.2-2 equivalent of citric acid water solution is added to the solution of avapritinib, preferably 0.4-1 equivalent, more preferably 0.5-0.55 equivalent of citric acid. Process according to any of claims 7, 8 or 9, where in step e) the reaction mixture is washed with a solvent in which avapritinib citrate is poorly soluble, preferably with C1-C4 alcohol, acetone, C3-C6 esters or C4-C5 esters, more preferably with ethanol. The crystalline napsylate salt of avapritinib. The crystalline avapritinib napsylate 1:1 salt. The crystalline avapritinib napsylate 1:1 salt according to claim 12, characterized by an X- ray powder diffractogram having peaks at 29 (±0.2 °29): 5.87; 15.66; 20.

63. The crystalline avapritinib napsylate 1:1 salt according to claim 12, characterized by an X- ray powder diffractogram having peaks at 29 (±0.2 °29): 5.87; 10.72; 15.66; 20.63; 21.77; 26.

10. The crystalline avapritinib napsylate 1:1 salt according to claim 12, characterized by an X- ray powder diffractogram having peaks at 29 (±0.2 °29): 5.35; 5.69; 5.87; 9.37; 9.70; 10.72; 11.41; 14.55; 15.66; 16.11; 17.31; 17.49; 17.82; 18.08; 18.51; 18.74; 19.50; 20.63; 21.06; 21.36; 21.56; 21.77; 22.55; 22.96; 23.59; 23.86; 24.28; 24.60; 25.06; 25.56; 26.10; 26.89; 27.28; 27.92; 28.74; 29.02; 29.79; 30.80; 31.22; 31.48; 32.87; 33.27; 33.56; 33.91; 34.

43. The crystalline avapritinib napsylate 1:1 salt according to claim 12, characterized by an X- ray powder diffractogram substantially as shown in Figure 2. Process for the preparation of avapritinib napsylate salt according to any of claims 11 to 16, comprising the steps of: a) dissolving avapritinib in a solvent to form a solution b) adding the solution of 2-naphthalenesulfonic acid to the solution of avapritinib c) after formation of a white precipitation cooling the suspension, preferably to room temperature d) filtering the reaction mixture, washing and drying under vacuum till constant weight. Process according to claim 17, where avapritinib is dissolved in a polar aprotic solvent and / or in a mixture thereof with a polar protic solvent, preferably in DMSO / ethanol, ethanol / ethyl acetate, ethyl acetate / DMSO, ethanol / THF mixture, more preferably in ethanol / THF 10 / 8 mixture.Process according to claim 17 or 18, where 0.8-1.5 equivalent, preferably 0.8-1.3 equivalent, more preferably 0.9-1.1 equivalent of 2-naphthalenesulfonic acid dissolved in a polar aprotic solvent and / or in a mixture thereof with a polar protic solvent is added to the solution of avapritinib Process according to any of claims 17, 18 or 19, where in step d) the reaction mixture is washed with a solvent in which avapritinib napsylate is poorly soluble, preferably with Ci- C4 alcohol, acetone, C3-C6 esters or C4-C5 esters, more preferably with ethanol

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