Vorasidenib co-crystal, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a co-crystal containing vorasidenib and a salicylic acid or malic acid, and a preparation method therefor and the use thereof. The co-crystal has a new structure and exhibits excellent properties, including low hygroscopicity, excellent thermal, humidity and light stability, and excellent mechanical stability. Moreover, the co-crystal exhibits an excellent equilibrium solubility in various media. The preparation method features simple operation, ease of control, stable reproducibility, high yield, good crystal form purity, high crystallinity and low solvent residue.

Description

Voracinyl eutectic, its preparation method and application Technical Field

[0001] This invention belongs to the field of pharmaceuticals and relates to a novel eutectic form of voracinib, its preparation method, and its application. Background Technology

[0002] Vorasidenib (also known as Vorasidenib), CAS number 1644545-52-7, chemical name 1,3,5-triazine-2,4-diamine, 6-(6-chloro-2-pyridyl)-N 2 N 4 -Bis[(1R)-2,2,2-trifluoro-1-methylethyl], with the following structural formula:

[0003] Brain tumors are divided into two categories: metastatic tumors, which are tumors that have spread from other parts of the body, such as metastatic brain cancer formed from breast cancer. These tumors are generally treated as primary tumors. The other type is primary brain cancer, where the brain is the primary site of infection. Gliomas are the most common type of malignant primary brain tumor in adults. They are tumors originating from glial cells in the brain and account for 40% to 60% of all primary central nervous system tumors. Common types include astrocytomas and oligodendrogliomas.

[0004] Isocitrate dehydrogenase (IDH) mutations are independent prognostic factors for gliomas, independent of other factors. IDH1 and IDH2 are the more common IDH mutation types. Both IDH1 and IDH2 gene mutations can lead to a decrease in the affinity of isocitrate dehydrogenase for isocitrate and an increase in its affinity for α-ketoglutarate and NADPH, thereby promoting the reduction of α-ketoglutarate to 2-hydroxyglutarate. High levels of 2-hydroxyglutarate can competitively inhibit the activity of α-ketoglutarate-dependent enzymes, thereby affecting cell metabolism, increasing the methylation level of DNA / histone, and ultimately potentially promoting tumorigenesis by blocking cell differentiation. In August 2024, the FDA approved voracinib for the treatment of dual inhibitors of isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) in adult and pediatric patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma who are susceptible to isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutations following surgery (including biopsy, subtotal resection, or total resection). It is marketed under the brand name VORANIGO.

[0005] Cocrystals are crystals formed when two or more compounds are arranged in a specific molar ratio and ordered within the same crystal lattice through non-covalent interactions such as hydrogen bonding, π-π interactions, and / or electrostatic interactions. Drug cocrystals, without altering the chemical structure of the active pharmaceutical ingredient (API), may improve the physicochemical and biopharmaceutical properties of drugs, such as increasing solubility, improving hydrothermal stability, and reducing hygroscopicity, which is of great significance for drug development. Whether a drug can form a cocrystal is primarily determined by the structure of the active pharmaceutical ingredient molecule itself (including the properties of functional groups, molecular shape and size), and the properties of the cocrystal ligands. Cocrystal ligands are diverse, and whether different active pharmaceutical ingredients can combine with different cocrystal ligands to form cocrystals is unpredictable. Therefore, finding suitable cocrystal ligands is a crucial step in cocrystal research.

[0006] The prior art WO2019090059A1 discloses two cocrystals of voracinide: a cocrystal of voracinide and citric acid, and a cocrystal of voracinide and maleic acid, wherein the cocrystal with citric acid is a hydrate.

[0007] The marketed drug VORANIGO uses VORANIGO hemicitric acid hemihydrate cocrystal of VORANIGO.

[0008] Therefore, it is still necessary to develop other eutectic forms of volacini. This invention provides a new volacini eutectic with excellent properties such as low hygroscopicity and high thermal and hygroscopic stability. Summary of the Invention

[0009] This invention provides a voracini eutectic with excellent properties, which can be prepared by a convenient method and is suitable for industrial production.

[0010] In one embodiment of the invention, the eutectic is a eutectic containing voracinol and salicylic acid or malic acid.

[0011] In one embodiment of the present invention, the molar ratio of voracinol to salicylic acid or malic acid in the eutectic is 1:1.

[0012] In one embodiment of the invention, the X-ray powder diffraction pattern of the cocrystal containing voracinil and salicylic acid is expressed as 2θ±0.20° and has characteristic peaks at 6.74, 9.74, 16.30, 17.17, 18.18, and 21.14.

[0013] In one embodiment of the invention, the X-ray powder diffraction pattern of the eutectic comprising volacini and salicylic acid is expressed in 2θ±0.20° and has characteristic peaks at 6.74, 9.74, 13.83, 16.30, 17.17, 18.18, 20.69, 21.14, 22.07, 25.00, 25.23, and 26.29; further, the eutectic also has one or more characteristic peaks selected from the following: 13.34, 14.61, 18.96, 19.60, 20.36, 25.66, and 36.98.

[0014] In one embodiment of the invention, the X-ray powder diffraction pattern of the eutectic containing voracinol and salicylic acid is expressed in 2θ±0.20° and has characteristic peaks at 6.74, 9.74, 13.34, 13.83, 14.61, 16.30, 17.17, 18.18, 18.96, 19.60, 20.36, 20.69, 21.14, 22.07, 25.00, 25.23, 25.66, 26.29, and 36.98.

[0015] In one embodiment of the present invention, the eutectic containing voracinide and salicylic acid is crystal form S1, and its X-ray powder diffraction pattern is shown in Figure 1 with 2θ±0.20°. Specific features are shown in Table 1.

[0016] Table 1. XRPD diffraction peak analysis data for crystal form S1

[0017] In one embodiment of the present invention, the TGA-DSC analysis of the eutectic crystal form S1 containing voracinol and salicylic acid is shown in Figure 2. The DSC results show that crystal form S1 has an endothermic peak at 163.6℃ and a melting point of 163.6℃. The TGA results show that crystal form S1 does not have significant weight loss before the melting point.

[0018] In one embodiment of the invention, the X-ray powder diffraction pattern of the cocrystal containing voracin and malic acid is expressed as 2θ±0.20° and has characteristic peaks at 5.87, 8.45, 15.35, 17.98, 19.52, and 22.41.

[0019] In one embodiment of the invention, the X-ray powder diffraction pattern of the eutectic comprising volacini and malic acid is expressed in 2θ±0.20° and has characteristic peaks at 5.87, 7.23, 8.45, 15.35, 17.98, 18.24, 19.18, 19.52, 20.17, 21.14, 22.41, 25.80, and 26.48; further, the eutectic also has one or more characteristic peaks selected from the following: 8.93, 14.06, 15.65, 17.22, 23.44, 25.47, 27.22, and 31.20.

[0020] In one embodiment of the invention, the X-ray powder diffraction pattern of the eutectic containing voracin and malic acid is expressed in 2θ±0.20° and has characteristic peaks at 5.87, 7.23, 8.45, 8.93, 14.06, 15.35, 15.65, 17.22, 17.98, 18.24, 19.18, 19.52, 20.17, 21.14, 22.41, 23.44, 25.47, 25.80, 26.48, 27.22, and 31.20.

[0021] In one embodiment of the present invention, the eutectic containing voracin and malic acid is crystal form M1, and its X-ray powder diffraction pattern is shown in Figure 5 as expressed in 2θ±0.20°, and its specific characteristics are shown in Table 2.

[0022] Table 2. XRPD diffraction peak analysis data for crystal form M1

[0023] In one embodiment of the present invention, the TGA-DSC analysis of the eutectic crystal form MI containing voracinol and malic acid is shown in Figure 6. The DSC results show that crystal form M1 has endothermic peaks at 66.4℃, 102.3℃, and 155.9℃, and a melting point of 102.3℃. The TGA results show that crystal form M1 has a weight loss of about 1.4% before 138.3℃.

[0024] In one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising the above-described voracini cocrystal.

[0025] In one embodiment of the present invention, the present invention provides a method for preparing a voracini co-crystal comprising the above-described voracini co-crystal.

[0026] In one embodiment of the present invention, the method for preparing the above-described voracini eutectic comprises the step of crystallizing voracini and salicylic acid or malic acid in a solvent.

[0027] In one embodiment of the present invention, the solvent in the above preparation method includes a good solvent and an anti-solvent. The good solvent is selected from alcohols (such as methanol, ethanol, isopropanol, etc.), ketones (such as acetone, butanone, etc.), esters (such as ethyl acetate, isopropyl acetate, etc.), ethers (such as methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), acetonitrile, dichloromethane, dimethyl sulfoxide, etc., and mixed solvents thereof. The anti-solvent is selected from water and alkanes (such as n-heptane, n-hexane, etc.). Further, in the above preparation method, the good solvent is ethanol or acetone, and the anti-solvent is water. Further, in the above preparation method, the above-mentioned voracini co-crystal is obtained by methods such as cooling crystallization, adding anti-solvent, and evaporation.

[0028] In one embodiment of the invention, the invention provides the use of the above-described voracinib cocrystal in the preparation of a medicament containing voracinib.

[0029] This invention provides various voracinib cocrystals, offering more options for their preparation and application. Furthermore, the voracinib cocrystals provided by this invention possess excellent properties, including low hygroscopicity, excellent thermal, moisture, and light stability, excellent mechanical stability, and good equilibrium solubility in various media. They are more suitable for preparing formulations containing voracinib, providing more and better options for the preparation and application of voracinib-containing formulations, and better leveraging their efficacy.

[0030] The preparation method provided by this invention is simple to operate, easy to control, stable and repeatable, with high yield, good crystal purity, high crystallinity, and low solvent residue. Attached Figure Description

[0031] Figure 1 shows the XPRD pattern of crystal form S1 of the present invention.

[0032] Figure 2 shows the TGA-DSC spectrum of crystal form S1 of the present invention.

[0033] Figure 3 is a SEM image of crystal form S1 of the present invention.

[0034] Figure 4 shows the ellipsoidal diagram of the three-dimensional structure of a single molecule obtained from the single-crystal XRD data of crystal form S1 of the present invention.

[0035] Figure 5 shows the XPRD pattern of crystal form M1 of the present invention.

[0036] Figure 6 shows the TGA-DSC spectrum of crystal form M1 of the present invention.

[0037] Figure 7 is a DVS diagram of crystal form A in Comparative Example 1.

[0038] Figure 8 is a DVS diagram of crystal form S1 of the present invention.

[0039] Figure 9 is a superimposed image of the XPRD patterns of crystal form A before and after grinding in Comparative Example 1.

[0040] Figure 10 is a superimposed image of the XPRD patterns of crystal form S1 before and after grinding according to the present invention. Detailed Implementation

[0041] The present invention is further illustrated below by way of examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the invention.

[0042] The instruments and methods used for data collection are as follows:

[0043] X-ray powder diffraction (XRPD)

[0044] Solid samples were analyzed using an X-ray powder diffractometer (Aeris). An appropriate amount of fine powder was taken and placed in the groove of the sample holder. A glass slide was used to press the powder into a flat and dense plane. The XRPD measurement parameters are shown in Table 3.

[0045] Table 3 XRPD Test Parameters

[0046] Simultaneous thermal analysis (TGA-DSC)

[0047] Thermogravimetric-differential scanning calorimetry (TGC) analysis of solids was performed using a Mettler Toledo simultaneous thermal analyzer. An appropriate amount of the sample was placed in a crucible using a small spoon, ensuring even distribution, and weighed. The sample was heated according to the parameters listed in Table 4, and the data were analyzed using STARE.

[0048] Table 4 Parameters of TGA-DSC Analysis Method

[0049] 1H NMR spectrum 1 H-NMR)

[0050] The NMR measurements were performed using a Bruker NEO 400 NMR instrument, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent.

[0051] High-performance liquid chromatography (HPLC)

[0052] Column: Agilent Poroshell EC 120 C18, 4.6 mm × 100 mm, 2.7 μm;

[0053] Mobile phase A: 0.1% phosphoric acid solution - methanol (60:40);

[0054] Mobile phase B: Methanol;

[0055] Injection volume: 5 μl; Flow rate: 1.2 ml / min; Column temperature: 40℃;

[0056] Detector: Ultraviolet detector: Detection wavelength: 218nm.

[0057] Install a ghost trap column (Ghost Trap DS, 7.6 mm × 30 mm) between the gradient mixer and the injector;

[0058] Gradient elution is as follows:

[0059] Solvent: 60% methanol solution.

[0060] Dynamic moisture adsorption-desorption analysis (DVS)

[0061] The hygroscopicity of the samples was determined using a DVS Intrinsic dynamic moisture adsorption analyzer. The samples were placed in a pre-peeled sample basket, and the instrument automatically weighed them. The samples were then analyzed according to the parameters in Table 5.

[0062] Table 5 Parameters of DVS Analysis Method

[0063] Scanning electron microscope (SEM)

[0064] Instrument model: ZEISS Sigma 300 scanning electron microscope.

[0065] Test method: Take an appropriate amount of the test sample, spread it evenly on the conductive tape, spray it with gold, and observe it under an electron microscope.

[0066] Single-crystal X-ray diffraction (single-crystal XRD)

[0067] The single-crystal X-ray diffractometer was a Bruker D8 Venture. The single-crystal sample was obtained by slow evaporation in an ethanol / n-heptane system. Single-crystal diffraction experiments were performed according to Method 1, Section IV, General Chapter 0451 of the 2020 edition of the Chinese Pharmacopoeia, under the following conditions: MoKα radiation. Scanning. The total number of diffraction points collected in the single-crystal diffraction experiment was 4975, the number of independent diffraction points was 4975, and the number of observable points (|F|2≥2σ|F|2) was 3820.

[0068] Example 1. Eutectic Screening

[0069] Weigh approximately 30 mg of voracinib and the corresponding stoichiometric ratio of the cocrystal ligand, add 0.5 mL of ethanol / water (1:1, v / v) or acetone / water (1:1, v / v), place at 50 °C and beat for 5 days, then take samples for XRD characterization.

[0070] The screening results for eutectic cocrystals in ethanol / water solvents are shown in Table 6. The results show that only eutectic crystal form S1, containing voracinol and salicylic acid, and eutectic crystal form M1, containing voracinol and malic acid, can be obtained. The screening results for eutectic cocrystals in acetone / water solvents are shown in Table 7. The results show that only crystal form S1 can be obtained.

[0071] Table 6. Screening results of eutectic esters in ethanol / water solvents

[0072] Table 7 Screening Results of Acetone / Water Solvent Eutectic

[0073] Example 2. Preparation of crystal form S1

[0074] Method 1:

[0075] 0.5 mL of ethanol / water (1:1, v / v) was added to 29.8 mg voracin and 12.2 mg salicylic acid, stirred at 50 °C for 5 days, filtered, and dried under vacuum at 25 °C for 3 h. The resulting solid was characterized by XRPD testing, and the solid was identified as crystalline form S1. The XRPD spectrum is shown in Figure 1.

[0076] Method 2:

[0077] Weigh 3.0080 g of voracinib and 1.0990 g of salicylic acid into a small vial, add 15 mL of anhydrous ethanol, and stir at 50 °C until dissolved. Filter into a single-necked flask and stir at 40 °C. Add 24.6 mg of crystal form S1 seed, and stir at this temperature for 0.5 h. Slowly cool to 20 °C over 1 h, and slowly add 30 mL of purified water dropwise over 2 h. After the addition is complete, stir at this temperature for 2 h, filter, and vacuum dry at 50 °C for 2 h to obtain 3.7023 g of voracinib crystal form. XRD characterization confirmed it to be crystal form S1, and TGA-DSC was performed. 1 Characterization was performed using H-NMR, SEM, and single-crystal XRD. The TGA-DSC spectrum is shown in Figure 2, the SEM image is shown in Figure 3, and the ellipsoidal diagram of the three-dimensional structure of a single molecule obtained from the single-crystal XRD data of crystal form S1 is shown in Figure 4.

[0078] The results showed that crystal form S1 was a eutectic of volacini and salicylic acid with a molar ratio of 1:1. Crystal form S1 was anhydrous, and DSC showed a melting point of 163.6℃. TGA showed no significant weight loss before the melting point. The salicylic acid content was 25.54%, ethanol residue was 0.02%, and water content was 0.03%. SEM showed a rod-like crystal habit. The single-crystal structure data and unit cell parameters of crystal form S1 are shown in Table 8. The single-crystal results showed no proton transfer between salicylic acid and volacini.

[0079] Table 8 Single crystal structure data and unit cell parameters of crystal form S1

[0080] 1 H NMR (400MHz, DMSO) δ8.63 (d, J=9.1Hz, 1H), 8.52 (d, J=8.9Hz, 1H), 8.37 (d, J=7.6Hz, 1H), 8.25 (t, J=7.9Hz, 1H), 8.04 (t, J=7.8Hz, 1H), 7.80 (dd, J=7.9, 1.8Hz, 1H), 7.69 (dd, J=7.9, 1.8Hz, 1H), 7.56-7.47 (m, 1H), 6.99-6.89 (m, 2H), 5.29-4.66 (m, 2H), 1.40-1.31 (m, 7H).

[0081] Example 3. Preparation of crystal form M1

[0082] 0.5 mL of ethanol / water (1:1, v / v) was added to 30.3 mg voracin and 12.0 mg malic acid, and the mixture was stirred at 50 °C for 5 days. The mixture was filtered and dried under vacuum at 25 °C for 3 h. The resulting solid was characterized by XRPD and TGA-DSC tests, and was identified as crystalline form M1. The XRPD spectrum is shown in Figure 5, and the TGA-DSC spectrum is shown in Figure 6. The results showed that crystalline form M1 exhibited endothermic peaks at 66.4 °C, 102.3 °C, and 155.9 °C, with a melting point of 102.3 °C. The TGA results showed that crystalline form M1 experienced a 1.4% weight loss before reaching 138.3 °C. Crystalline form M1 is anhydrous.

[0083] 1 H NMR (400MHz, DMSO) δ12.36 (s, 2H), 8.61 (d, J = 9.1Hz, 1H), 8.50 (d, J = 8.9Hz, 1H ), 8.36 (d, J = 7.6Hz, 1H), 8.24 (dd, J = 15.1, 8.3Hz, 1H), 8.04 (t, J = 7.8Hz, 1H), 7.69(d, J=7.9Hz, 1H), 5.33-4.78(m, 2H), 4.36-4.23(m, 1H), 4.15-4.02(m, 1H ), 2.69-2.58(m, 1H), 2.49-2.39(m, 2H), 1.40-1.31(m, 6H), 1.26-1.14(m, 1H).

[0084] Comparative Example 1. Preparation of Crystal Form A

[0085] Weigh 1.2943 g of voracin and 0.2983 g of citric acid monohydrate into a small vial, add 4 mL of acetone, and stir at room temperature. Slowly add 8 mL of n-heptane dropwise over 1 hour. After the addition is complete, maintain the temperature and stir for 1 hour, then filter. Dry under vacuum at 25 °C for 2 hours to obtain 1.4623 g of crystal form A. Characterization confirmed that this is the citric acid eutectic type A in WO2019090059A1.

[0086] Example 4. Hygroscopicity Test

[0087] Referencing the "Guidelines for Hygroscopicity Testing of Drugs" in the Chinese Pharmacopoeia, we tested the water adsorption / desorption data of the crystal form.

[0088] The DVS diagram for crystal form A is shown in Figure 7, and the DVS diagram for crystal form S1 is shown in Figure 8. The results show that crystal form A absorbs 2.8% moisture at 80% RH, exhibiting hygroscopicity, while crystal form S1 gains 0.51% weight at 80% RH, showing slight hygroscopicity. Compared to crystal form A, crystal form S1 has lower hygroscopicity.

[0089] Example 5. Thermal, Humidity, and Light Stability Test

[0090] Following the "Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Preparations" in the Chinese Pharmacopoeia, the stability of the crystal form under different temperatures and humidity conditions was investigated. Purity was determined by HPLC on days 0, 5, and 10, and crystal form was determined by XRPD.

[0091] The stability data for crystal form A and crystal form S1 are shown in Tables 9 and 10, respectively. The results show that crystal form A exhibits increased impurities under high temperature and light exposure conditions, but is relatively stable under high humidity conditions. Crystal form S1 is relatively stable under high temperature, high humidity, and light exposure conditions. Compared to crystal form A, crystal form S1 demonstrates better thermal and optical stability.

[0092] Table 9. Data related to the stability of crystal form A

[0093] Table 10. Data related to the stability of crystal form S1

[0094] Example 6. Mechanical Stability Test

[0095] Approximately 0.2 g of crystal form A and approximately 0.2 g of crystal form S1 were placed in a mortar and manually ground for 5 minutes each. Samples were then taken for XRD analysis. The overlay of XRD patterns for crystal form A before and after grinding is shown in Figure 9, and the overlay of XRD patterns for crystal form S1 before and after grinding is shown in Figure 10. The results show that crystal form A essentially becomes amorphous after grinding, while the crystallinity of crystal form S1 decreases slightly after grinding. Compared to crystal form A, crystal form S1 exhibits better mechanical stability.

[0096] Example 7. Equilibrium Solubility Experiment

[0097] At 37℃, appropriate amounts of different crystal forms were dispersed in hydrochloric acid buffer medium (pH=1.2), acetic acid buffer medium (pH=4.5), phosphate buffer medium (pH=6.8), and purified water to prepare suspensions. After equilibration at 200 rpm for 2 h and 24 h, the concentration (mg / mL) of the samples in the solutions was determined by high performance liquid chromatography (HPLC). The results are shown in Table 11. The results show that the equilibrium solubility of crystal form S1 and crystal form A is comparable in each medium.

[0098] Table 11. Data related to the stability of crystal form S1

[0099] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A vorasidenib co-crystal, characterized in that, The co-crystal is a co-crystal comprising vorasidenib and salicylic acid or malic acid.

2. The co-crystal of claim 1, characterized in that, The co-crystal has a molar ratio of vorasidenib to salicylic acid or malic acid of 1 :

1.

3. The co-crystal of claim 1 or 2, characterized in that, The co-crystal comprising vorasidenib and salicylic acid has an X-ray powder diffraction pattern expressed in 2Q ± 0.20° with characteristic peaks at 6.74, 9.74, 16.30, 17.17, 18.18, 21.

14.

4. The co-crystal of claim 3, characterized in that, The co-crystal further has one or more characteristic peaks selected from the group consisting of 13.34, 13.83, 14.61, 18.96, 19.60, 20.36, 20.69, 22.07, 25.00, 25.23, 25.66, 26.29, 36.

98.

5. The co-crystal of claim 3 or 4, characterized in that, The co-crystal has a DSC pattern with an endothermic peak at 163.6 °C and a TGA pattern with no significant weight loss before the melting point.

6. The co-crystal of claim 1 or 2, characterized in that, The co-crystal comprising vorasidenib and malic acid has an X-ray powder diffraction pattern expressed in 2Q ± 0.20° with characteristic peaks at 5.87, 8.45, 15.35, 17.98, 19.52, 22.

41.

7. The co-crystal of any one of claims 1-2, 6, characterized in that, The co-crystal further has one or more characteristic peaks selected from the group consisting of 7.23, 8.93, 14.06, 15.65, 17.22, 18.24, 19.18, 20.17, 21.14, 23.44, 25.47, 25.80, 26.48, 27.22, 31.20; or it is characterized by a DSC pattern with endothermic peaks at 66.4 °C, 102.3 °C, 155.9 °C and a TGA pattern with a weight loss of 1.4% before 138.3 °C.

8. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising the co-crystal according to any one of the preceding claims.

9. A process for the preparation of the co-crystal according to any one of the preceding claims 1-7, characterized in that, A process for preparing a co-crystal comprising vorasidenib and salicylic acid or malic acid, comprising the steps of:

10. Use of a co-crystal according to any one of the preceding claims 1-7 for the preparation of a medicament comprising vorasidenib.

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