Ivosidenib Forms and Pharmaceutical Compositions

Abstract

Formulations of ivosidenib are provided that include multiple polymorphs. Formulations of ivosidenib that contain multiple known impurities are further provided. Stable compositions of ivosidenib are still further provided. [Selection diagram] Figure 37

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 694,596, filed July 6, 2018, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) and the other NADP(+) as the electron acceptor. Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases localized in the mitochondrial matrix, and two NADP(+)-dependent dehydrogenases, one of which is mitochondrial and the other is primarily cytosolic. Each NADP(+)-dependent isozyme is a homodimer.

[0003] IDH1 (Isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH, IDP, IDCD, IDPC, or PICD. The protein encoded by this gene is an NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests a role in the regeneration of NADPH for intraperoxisomal reductions such as the conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme plays a significant role in cytoplasmic NADPH production.

[0004] The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences for human IDH1 can be found in GenBank accessions NM_005896.2 and NP_005887.2, respectively. The nucleotide and amino acid sequences for IDH1 have also been described, for example, in Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684 (1998), Geisbrecht et al., J. Biol. Chem. 274:30527-30533 (1999), Wiemann et al., Genome Res. 11:422-435 (2001), The MGC Project Team, Genome Res. 14:2121-2127 (2004), Lubec et al., submitted to UniProtKB (December 2008), Kullmann et al., submitted to the EMBL / GenBank / DDBJ database (June 1996), and Sjoeblom et al., Science 314:268-274 (2006).

[0005] Non-mutant, eg, wild-type, IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate.

[0006] It has been discovered that mutations in IDH1 present in certain cancer cells confer a new ability for the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is thought to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44).

[0007] IDH2 (Isocitrate dehydrogenase 2 (NADP+), mitochondrial type) is also known as IDH, IDP, IDHM, IDPM, ICD-M, or mNADP-IDH. The protein encoded by this gene is an NADP(+)-dependent isocitrate dehydrogenase found in mitochondria. It plays a role in intermediary metabolism and energy production. The protein may be closely related or interact with the pyruvate dehydrogenase complex. The human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found in GenBank accessions NM_002168.2 and NP_002159.2, respectively. The nucleotide and amino acid sequences of human IDH2 are described, for example, in Huh et al., submitted to the EMBL / GenBank / DDBJ database (November 1992), and in The MGC Project Team, Genome Res. 14:2121-2127 (2004).

[0008] Non-mutant, eg, wild-type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG).

[0009] It has been discovered that mutations in IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH2. The production of 2HG is thought to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462: 739-44). Mutations in IDH1 or IDH2 occur in more than 70% of diffuse low-grade malignant glioma (LGG) tumors. IDH mutations lead to the accumulation of 2-HG, which is believed to promote tumorigenesis by DNA hypermethylation, increased methylation of repressive histones, and inhibition of differentiation processes. Studies conducted with a tool compound known as AGI-5198, which has been shown to inhibit mutant IDH1 (mIDH1) but not mutant IDH2 (mIDH2), have demonstrated that inhibition of mIDH1 protein can suppress the growth of gliomas driven by mIDH1 in several model systems (D. Rohle et al. Science 340:626-630 (2013)). U.S. Publication No. 2013 / 0190249(A1) discloses a compound described by the chemical name (S)-N-((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyridine-2-carboxamide, which has been shown to act as an inhibitor of mutant IDH1 protein in biochemical and cellular assays. Depending on the naming convention, this compound may also be referred to as (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. Furthermore, in 2015, INN assigned the name ivosidenib to the compound. The structure of ivosidenib is set forth herein as formula (I). [ka] In this application, "ivosidenib" and "compound of formula (I)" are used interchangeably. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] US Patent Application Publication No. 2013 / 0190249 [Non-patent literature]

[0011] [Non-Patent Document 1] Nekrutenko et al.,Mol.Biol.Evol.15:1674-1684(1998) [Non-Patent Document 2] Geisbrecht et al.,J.Biol.Chem.274:30527-30533(1999) [Non-Patent Document 3] Wiemann et al.,Genome Res.11:422-435(2001) [Non-Patent Document 4] The MGC Project Team,Genome Res.14:2121-2127(2004) [Non-Patent Document 5] Sjoeblom et al.,Science 314:268-274(2006) [Non-Patent Document 6] Dang,L et al.,Nature 2009,462:739-44 [Non-Patent Document 7] D.Rohle et al.Science 340:626-630(2013) Summary of the Invention

[0012] One aspect of the disclosure provides various solid forms of a compound of formula (I): [ka] wherein each solid form may be individually anhydrous, hydrated, or solvated. In some embodiments, the solid form is designated as Form E, G, M, or N, each form may be individually anhydrous, hydrated, or solvated. One embodiment of the present disclosure is Form E of the compound of formula (I), [ka] or a hydrate or solvate thereof. In one embodiment, Form E is a solvated form. In another embodiment, Form E is an isopropyl acetate solvate of the compound of formula I.

[0013] One embodiment of the present disclosure is form G of the compound of formula (I): [ka] or a hydrate or solvate thereof. In another embodiment, Form G is a solvated or hydrated form of the compound of formula I.

[0014] One embodiment of the present disclosure is form M of the compound of formula (I): [ka] or a hydrate or solvate thereof. In another embodiment, Form M is an anhydrous form of the compound of formula I.

[0015] One embodiment of the present disclosure is form N of the compound of formula (I): [ka] or a hydrate or solvate thereof. In another embodiment, Form N is an anhydrous form of the compound of formula I.

[0016] One embodiment of the present disclosure is a pharmaceutical composition comprising one or more of Forms E, G, M, or N, each individually in anhydrous, hydrated, or solvated form.

[0017] Another aspect of the disclosure provides one or more solid forms of a compound of formula I, [ka] This form is partially crystalline. In one embodiment, the one or more partially crystalline forms are selected from A, C, D, E, F, G, H, I, J, K, M, or N, or hydrates or solvates thereof. In one embodiment, the one or more partially crystalline forms are selected from form A, I, or K, each of which is individually anhydrous, hydrated, or solvated. In another embodiment, the one or more partially crystalline forms are selected from form L or form B, each of which is individually anhydrous, hydrated, or solvated.

[0018] In one embodiment of the disclosure, the partially crystalline form is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% crystalline form B. In another embodiment, the partially crystalline form is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% crystalline form L. In another embodiment, the partially crystalline form is Form A, which is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% crystalline. In another embodiment, the partially crystalline form is Form I, which is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% crystalline. In another embodiment, the partially crystalline form is form K that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% crystalline.

[0019] In another aspect, the disclosure provides a process for making form L of ivosidenib, the process comprising making one or more metastable forms of ivosidenib that are anhydrous, hydrated, or solvated forms, and converting such one or more metastable forms of ivosidenib to form L. One aspect provides a process, wherein the one or more metastable forms are selected from forms C, D, E, F, H, J, M, or N, each of which is individually anhydrous, hydrated, or solvated form.

[0020] In another aspect, the disclosure provides a pharmaceutical composition comprising ivosidenib in a mixture of two or more solid forms selected from Form L, Form B, Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, and Form N, each of which individually is anhydrous, hydrated, or solvated form. In one embodiment, the pharmaceutical composition comprises 0.15% (area % by HPLC) or less of: (i) 2-((2S)-2-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)carbamoyl)-5-oxopyrrolidin-1-yl)isonicotinamide; (ii) (S)—N(—(S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxo-N-(pyridin-3-yl)pyrrolidine-2-carboxamide; (iii) (S)—N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)- (iv) (R)—N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (iv) (R)—N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, and (v) (R)—N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. In one embodiment, the pharmaceutical composition comprises Form L together with one or more of Form B, Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, and Form N, each individually in anhydrous, hydrated, or solvated form. In another embodiment, the pharmaceutical composition may optionally contain amorphous ivosidenib.In yet another aspect, the pharmaceutical composition comprises one or more forms of ivosidenib selected from Form B, Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, or Form N, each individually in anhydrous, hydrated, or solvated form, and the pharmaceutical composition is substantially free of Form L. In other embodiments, such compositions may optionally contain amorphous ivosidenib. In another embodiment, the pharmaceutical composition comprises one of Form L or Form B, each individually in anhydrous, hydrated, or solvated form, together with amorphous ivosidenib. In some embodiments, Form L is an anhydrous form. In other embodiments, Form B is a hydrate or solvated form. In still other embodiments, the pharmaceutical composition comprises up to about 10% w / w of either Form L or Form B, each individually in anhydrous, hydrated, or solvated form, together with amorphous ivosidenib. In yet other embodiments, the pharmaceutical composition comprises up to about 6% w / w of either Form L or Form B, each individually in anhydrous, hydrated, or solvated form, together with amorphous ivosidenib.

[0021] In another aspect, the disclosure provides a solid dosage form comprising a Form L formulation, the Form L formulation being made via any one or more of Form B, Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, or Form N, each individually being an anhydrous, hydrated, or solvated form. In another aspect, the solid dosage form comprises a Form L formulation containing Form L and one or more of Form B, Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, or Form N, each individually being an anhydrous, hydrated, or solvated form. In some embodiments, the solid dosage form optionally contains amorphous ivosidenib.

[0022] In another aspect, the disclosure provides a solid dosage form comprising a substantially amorphous formulation intermediate and further comprising any one or more of Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, or Form N, each individually in anhydrous, hydrated, or solvated form.

[0023] In another aspect, the disclosure provides a solid dosage form comprising ivosidenib in a substantially amorphous form and further comprising any one or more of crystalline Forms L, B, A, C, D, E, F, G, H, I, J, K, M, or N, each individually in anhydrous, hydrated, or solvated form, and one or more pharma- ceutically acceptable excipients. In one aspect, the disclosure provides a solid dosage form comprising ivosidenib in a substantially amorphous form and further comprising any one or more crystalline Forms L, B, A, C, D, E, F, G, H, I, J, K, M, or N, each individually in anhydrous, hydrated, or solvated form, and one or more pharma- ceutically acceptable excipients. In one aspect, the disclosure provides a solid dosage form comprising ivosidenib in a substantially amorphous form and further comprising any one or more crystalline Forms L, B, A, C, D, E, F, G, H, I, J, K, M, or N, each individually in an anhydrous, hydrated, or solvated form, and one or more pharma- ceutically acceptable excipients. (iii) (S)-N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxo-N-(pyridin-3-yl)pyrrolidine-2-carboxamide, (iii) (S)-N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine -2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (iv) (R)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide and (v) (R)—N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide.In another embodiment, the solid dosage form further comprises a polymer selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), ethyl cellulose, or cellulose acetate phthalate; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP); acrylates, polyvinylpyrrolidone-vinyl acetate (PVP-VA), polyvinylcaprolactam-polyvinyl, and acetate-polyethylene glycol copolymers, methylacrylic acid / methacrylic acid copolymers; Soluplus; copovidone; and mixtures thereof. In another embodiment, the polymer is selected from HPMC, HPMCP, HPMCAS, PVAP, and copovidone.

[0024] In another aspect, the disclosure provides a solid dosage form comprising a substantially amorphous formulation intermediate made from any one or more of Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, or Form N, each individually in anhydrous, hydrated, or solvated form. In some embodiments, the substantially amorphous formulation intermediate is a solid dispersion.

[0025] In another aspect, the disclosure provides a compound of formula (I) selected from one of forms E, G, M, or N, each individually in anhydrous, hydrated, or solvated form; [ka] Provided is a compound that is substantially free of one or more of any other solid forms of the compound of formula (I).

[0026] One embodiment of the disclosure provides a solid form of ivosidenib, Form E, having an X-ray powder diffraction pattern including 1 peak, or 2 peaks, or 3 peaks, or 4 peaks, or 5 peaks, or 6 peaks, or 7 peaks, or 8 peaks, or 9 peaks in 2-theta, the peaks being at 6.3±0.2 degrees 2θ and one or more of the following peaks: 11.6±0.2 degrees 2θ, 12.0±0.2 degrees 2θ, 17.1±0.2 degrees 2θ, and 21.0±0.2 degrees 2θ.

[0027] One embodiment of the disclosure provides a solid form of ivosidenib, Form M, having an X-ray powder diffraction pattern containing 1 peak, or 2 peaks, or 3 peaks, or 4 peaks, or 5 peaks, or 6 peaks, or 7 peaks, or 8 peaks, or 9 peaks in 2-theta, the peaks being at 11.4±0.2 degrees 2θ, 17.7±0.2 degrees 2θ, 17.8±0.2 degrees 2θ, 19.7±0.2 degrees 2θ, and 21.4±0.2 degrees 2θ.

[0028] One embodiment of the disclosure provides a solid form of ivosidenib, Form N, having an X-ray powder diffraction pattern containing 1 peak, or 2 peaks, or 3 peaks, or 4 peaks, or 5 peaks, or 6 peaks, or 7 peaks, or 8 peaks, or 9 peaks in 2-theta, the peaks being at 8.6±0.2 degrees 2θ, 14.4±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 20.3±0.2 degrees 2θ, and 22.9±0.2 degrees 2θ.

[0029] One embodiment of the present disclosure provides a solid form of ivosidenib (Form M) having a differential scanning calorimetry thermogram comprising an endothermic peak at 170.0° C.

[0030] One embodiment of the present disclosure provides a solid form of ivosidenib (Form M) having a differential scanning calorimetry thermogram comprising an endothermic peak at 170.5° C.

[0031] One embodiment of the present disclosure provides a solid form of ivosidenib (Form N) having a differential scanning calorimetry thermogram comprising an endothermic peak at 214.8° C.

[0032] One embodiment of the present disclosure provides a solid form of ivosidenib (Form N) having a differential scanning calorimetry thermogram comprising an endothermic peak at 215.4° C.

[0033] One aspect of the disclosure provides a pharmaceutical composition comprising ivosidenib in any solid form described herein, wherein the pharmaceutical composition comprises at least 1% by weight of the total sample of ivosidenib.

[0034] One aspect of the disclosure provides a pharmaceutical composition comprising ivosidenib in any solid form described herein, wherein the pharmaceutical composition comprises at least 2% by weight of the total sample of ivosidenib.

[0035] One aspect of the disclosure provides a pharmaceutical composition comprising ivosidenib in any solid form described herein, wherein the pharmaceutical composition comprises at least 3% by weight of the total sample of ivosidenib.

[0036] One aspect of the disclosure provides a pharmaceutical composition comprising ivosidenib in any solid form described herein, wherein the pharmaceutical composition comprises at least 4% by weight of a total sample of ivosidenib.

[0037] One aspect of the disclosure provides a pharmaceutical composition comprising ivosidenib in any solid form described herein, wherein the pharmaceutical composition comprises at least 5% by weight of the total sample of ivosidenib.

[0038] One aspect of the disclosure provides a pharmaceutical composition comprising ivosidenib in any solid form described herein, each individually in anhydrous, hydrated, or solvated form, and one or more pharma- ceutically acceptable excipients.

[0039] In one aspect, the disclosure provides a pharmaceutical composition comprising ivosidenib and a second molecule, wherein the second molecule is 2-((2S)-2-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)carbamoyl)-5-oxopyrrolidin-1-yl)isonicotinamide, (S)-N(-(S)-1-( 2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxo-N-(pyridin-3-yl)pyrrolidine-2-carboxamide, (S)-N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin (R)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, and and (R)-N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, wherein the second molecule is present in an amount of 0.15% area % or less as determined by HPLC analysis.

[0040] In another aspect, the disclosure provides a pharmaceutical composition comprising ivosidenib and a second molecule, the second molecule being 3-amino-5-fluoropyridine, 2-chloro-4-cyanopyridine, (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, 2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-((5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, Lysin-3-yl)amino)acetamide, (S)-5-(((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)amino)-4-((4-cyanopyridin-2-yl)amino)-5-oxopentanoic acid, (S)-4-(bis(4-cyanopyridin-2-yl)amino)-5-(((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)amino) (S)-2-(2-chlorophenyl)-2-((5-((4-cyanopyridin-2-yl)amino)-2-oxo-3,4-dihydro-2H-pyran-6-yl)(5-fluoropyridin-3-yl)amino)-N-(3,3-difluorocyclobutyl)acetamide, (2S)-N-((1S)-2-(2-chloro-3,3-difluorocyclobutyl)amino)-1-(2-chlorophenyl)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)amino)-5-oxopentanoic acid, Lysin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(2,4-dichlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (S)-1-(4-cyanopyridin-2-yl)-N((S)-1-(2,3-dichlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (S)-N-((S)-1-(4-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, 3-((2S)-1-(4-carbamoylpyridin-2-yl)-N-(1-(2-chlorophenyl)-2-((3, 3-difluorocyclobutyl)amino)-2-oxoethyl)-5-oxopyrrolidine-2-carboxamido)-5-fluoropyridine 1-oxide, and 4-carbamoyl-2-((2S)-2-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)carbamoyl)-5-oxopyrrolidin-1-yl)pyridine 1-oxide, the second molecule being present in an amount of 0.15% area percent or less as determined by HPLC analysis.

[0041] In another aspect, the disclosure provides a pharmaceutical composition comprising ivosidenib and a second molecule, wherein the second molecule is selected from among benzaldehyde, benzyl chloride, 2-chlorobenzyl chloride, 1-chloro-2-(chloromethyl)benzene, 1-chloro-2-(dichloromethyl)benzene, phenol, and benzene, and wherein the second molecule is present in an amount of 2 ppm or less.

[0042] In another aspect, the disclosure provides a pharmaceutical composition comprising ivosidenib and one or more pharma- ceutically acceptable excipients, the composition containing no more than trace amounts of palladium, molybdenum, cadmium, lead, arsenic, mercury, cobalt, vanadium, and nickel.

[0043] In another aspect, the disclosure provides a pharmaceutical composition comprising ivosidenib and one or more pharma- ceutically acceptable excipients, the composition containing no more than 5000 ppm each of isopropyl acetate, no more than 5000 ppm of n-heptane, no more than 600 ppm of dichloromethane, and no more than 2 ppm of benzene.

[0044] In another aspect, the present disclosure provides a process comprising, at one or more stages, 2-((2S)-2-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)carbamoyl)-5-oxopyrrolidin-1-yl)isonicotinamide, (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-5-oxo-N-(pyridin-3-yl)pyrrolidine-2-carboxamide, (S)-N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5 ivosidenib, (R)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (R)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, and (R)-N-((R)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, or a salt, hydrate, or solvate thereof.

[0045] In another aspect, the present disclosure provides a process comprising, at one or more stages, 3-amino-5-fluoropyridine, 2-chloro-4-cyanopyridine, (S)—N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, 2-(2-chlorophenyl)-N-(3,3-difluorocyclobutyl)-2-((5-fluoropyridin-3-yl)amino)acetamide, (S)-5-(((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)amino)-4-((4-cyanopyridin-2-yl)amino)-5-oxopentanoic acid, (S)-4-(bis(4-cyanopyridin-2-yl)amino)-5-(((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)amino)-5-oxopentanoic acid, (S)-2-(2-chlorophenyl)-2-((5-((4-cyanopyridin-2-yl)amino)-2-oxo-3,4-dihydro-2H-pyran-6-yl)(5-fluoropyridin-3-yl)amino)-N-(3,3-difluorocyclobutyl)acetamide, (2S)-N-((1S)-2-((2-chloro-3,3-difluorocyclobutyl)amino)-1-(2-chlorophenyl)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(2,4-dichlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(2,3-dichlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, (S)—N-((S)-1-(4-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, 3-((2S)-1-(4-carbamoylpyridin-2-yl)-N-(1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-5-oxopyrrolidine-2-carboxamido)-5-fluoropyridine 1-oxide, 4-Carbamoyl-2-((2S)-2-((1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(5-fluoropyridin-3-yl)carbamoyl)-5-oxopyrrolidin-1-yl)pyridine 1-oxide, and The present invention provides a process for making ivosidenib, comprising testing one or more of (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(3,3-difluorocyclobutyl)-2-oxoindolin-3-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide.

[0046] In another aspect, the disclosure provides a process for making ivosidenib, comprising testing for one or more of benzaldehyde, benzyl chloride, 2-chlorobenzyl chloride, 1-chloro-2-(chloromethyl)benzene, 1-chloro-2-(dichloromethyl)benzene, phenol, benzene, palladium, and molybdenum at one or more stages of the process.

[0047] One or more aspects and embodiments, although not specifically described, may be combined in different embodiments, i.e., all aspects and embodiments may be combined in any way or combination. In certain embodiments, for example, the following are provided: (Item 1) Solid form E of compound of formula (I), [ka] or a hydrate or solvate thereof. (Item 2) Item 2. The compound according to item 1, wherein said Form E is a solvated form. (Item 3) 3. The compound according to item 2, wherein the compound is form E of an isopropyl acetate solvate. (Item 4) Solid form G of the compound of formula (I), [ka] or a hydrate or solvate thereof. (Item 5) 5. The compound according to item 4, wherein said Form G is a solvated or hydrated form. (Item 6) Solid form M of the compound of formula (I), [ka] or a hydrate or solvate thereof. (Item 7) 8. The compound according to item 7, wherein said Form M is anhydrous. (Item 8) Solid form N of the compound of formula (I), [ka] or a hydrate or solvate thereof. (Item 9) 10. The compound according to item 9, wherein said Form N is anhydrous. (Item 10) 10. A pharmaceutical composition comprising one or more compounds according to any one of items 1 to 9. (Item 11) A solid form of a compound of formula I selected from A, C, D, E, F, G, H, I, J, K, M, or N;

change

change

[0048] [Figure 1] FIG. 1 is an X-ray powder diffraction (XRPD) overlay showing characteristic peak readouts from an XRPD run on various polymorphs of ivosidenib. [Diagram 2] 1 is a differential scanning calorimetry (DSC) profile of ivosidenib form L. [Diagram 3] 1 is a thermogravimetric analysis (TGA) result of the study of ivosidenib form L. [Figure 4] 1 is a DSC profile of ivosidenib form B. [Diagram 5] 1 is a TGA result of a study of ivosidenib form B. [Figure 6] 1 is a TGA / differential thermal analysis (DTA) result of the study of form N of ivosidenib. [Figure 7] FIG. 1 is a DSC profile of ivosidenib form N. [Figure 8] FIG. 1 is an HPLC profile of ivosidenib form N. [Figure 9] 1 is a TGA / DTA result of a study of form M of ivosidenib. [Figure 10] FIG. 1 is a DSC profile of ivosidenib form M. [Figure 11] FIG. 1 is an HPLC profile of ivosidenib form M. [Figure 12] FIG. 1 is an XRPD diffractogram of ivosidenib form A. [Figure 13] 1 is a composite plot of TGA and DSC analysis of ivosidenib form A. [Figure 14] FIG. 1 is an XRPD diffractogram of ivosidenib form C. [Figure 15] 1 is a composite plot of TGA and DSC analysis of ivosidenib form C. [Figure 16] FIG. 1 is an NMR spectrum of ivosidenib form C. [Figure 17] FIG. 1 is an XRPD diffractogram of ivosidenib form D. [Figure 18] 1 is a composite plot of TGA and DSC analysis of ivosidenib form D. [Figure 19] FIG. 1 is an NMR spectrum of ivosidenib form D. [Figure 20] FIG. 1 is an XRPD diffractogram of ivosidenib form E. [Figure 21] 1 is a composite plot of TGA and DSC analysis of ivosidenib form E. [Figure 22] FIG. 1 is an NMR spectrum of ivosidenib form E. [Diagram 23] FIG. 1 is an XRPD diffractogram of ivosidenib form F. [Figure 24] 1 is a composite plot of TGA and DSC analysis of ivosidenib form F. [Diagram 25] FIG. 1 is an XRPD diffractogram of ivosidenib form G. [Figure 26] 1 is a composite plot of TGA and DSC analysis of ivosidenib form G. [Figure 27] FIG. 1 is an XRPD diffractogram of ivosidenib form H. [Figure 28] 1 is a composite plot of TGA and DSC analysis of ivosidenib form H. [Figure 29] FIG. 1 is an XRPD diffractogram of ivosidenib form I. [Diagram 30] 1 is a composite plot of TGA and DSC analysis of ivosidenib Form I. [Diagram 31] FIG. 1 is an NMR spectrum of ivosidenib form I. [Diagram 32] FIG. 1 is an XRPD diffractogram of ivosidenib form J. [Diagram 33] 1 is a composite plot of TGA and DSC analysis of ivosidenib form J. [Diagram 34] FIG. 1 is an XRPD diffractogram of ivosidenib form K. [Diagram 35] 1 is an overlay of DSC curves of Forms L, M, and N described herein, showing the interconversion of these forms. [Diagram 36] FIG. 1 shows the interconversion of Form L and Form B of ivosidenib as described herein. [Figure 37] FIG. 1 is a graphical representation of the dissolution profiles of tablets spiked with ivosidenib Form L and Form B compared to the target formulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] The details of construction and the arrangement of components set forth in the following description or illustrated in the drawings are not meant to be limiting. Other embodiments and different ways of practicing the invention are expressly included. Also, the phraseology and terminology used herein are for the purpose of description and should not be considered as limiting. The use of "including," "comprising," "having," "containing," "involving," and variations thereof herein are meant to encompass the items listed thereafter and equivalents thereof, as well as additional items. definition

[0050] As used above, and throughout the description of the various aspects of this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0051] As used herein, "solid form" refers to one of Form L, Form B, Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, or Form N of ivosidenib as characterized herein. The term "form" refers to a solid form when used without a modifier. The term solid form encompasses anhydrous, hydrated, and solvated forms unless otherwise specified. Solid form is a general term that refers to both crystalline and amorphous materials. Crystalline forms can include polymorphs, hydrates, solvates, salts, and cocrystals.

[0052] As used herein, "crystal" refers to a solid having a highly regular chemical structure. In particular, a crystalline free base or salt form may be produced as one or more single crystal forms. For the purposes of this application, the terms "crystalline form", "single crystal form" and "polymorph" are synonymous, and these terms distinguish crystals with different properties (e.g., different XRPD patterns and / or different DSC scan results). The term "polymorph" includes pseudopolymorphs, which are typically different solvates of a material and therefore have different properties from each other. Thus, each distinct polymorph and pseudopolymorph of a free base or salt form is considered to be a distinct single crystal form herein.

[0053] The term "substantially crystalline" refers to a form that may be at least a certain weight percent crystalline. The certain weight percent may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%. In some embodiments, substantially crystalline refers to a solid form of the compound of formula I that is at least 70% crystalline. In other embodiments, substantially crystalline refers to a free base or salt form that is at least 90% crystalline. In some embodiments, a form of the compound of formula I that is less than about 90% crystalline may be referred to as "partially crystalline" to distinguish it from "substantially crystalline". In other embodiments, the partially crystalline form of the compound of formula I may be about 5% to 90% crystalline.

[0054] "Form L" or "ivosidenib Form L", which may be used interchangeably, describes the crystalline form as synthesized in Example 2 of the Examples section below and as described below, and is represented by the data presented in Figures 1, 2, and 3.

[0055] "Form B" or "ivosidenib Form B" are used interchangeably and describe the crystalline form as synthesized in Example 3 of the Examples section below and as described below, and in FIG. 1、 4 and 5 This is represented by the data shown in

[0056] As used herein, "amorphous" refers to a solid material that does not have long-range order in the positions of its atoms. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions, and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have a steep characteristic crystalline peak(s) in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids. Amorphous preparations of the compounds described herein are substantially free of any crystalline form of the same compound. The term "amorphous form" refers to a solid form that is non-crystalline.

[0057] The term "substantially free" refers to forms and compositions that may be free of impurities at least a certain weight percent or are free of other crystalline forms of the same compound. A certain weight percent indicates that a particular form is substantially free of other crystalline forms of the same compound when the particular form is present in a weight percent of about 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or about 99.9%. In other embodiments, a particular form is substantially free of other crystalline forms of the same compound when the particular form is present in an amount of about 60%-100% free (w / w), which may be expressed as the particular crystalline form being about 60%-100% phase pure. The phrase "phase purity" refers to the extent to which a material is not contaminated or mixed with other crystalline forms of the same material. In some embodiments, substantially free refers to a crystalline form of the compound of formula (I) that is at least 70% phase pure. In other embodiments, substantially crystalline refers to a crystalline form of the compound of formula I that is at least 90% phase pure. In other embodiments, substantially free of other crystalline forms refers to a crystalline form of the compound of formula I, or a composition comprising same, that has less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% of another crystalline form of the compound of formula I.

[0058] As used herein, the term "chemical purity" refers to the extent to which a compound of formula I is not contaminated or mixed with extraneous material, i.e., material that is not a compound of formula I. In various embodiments described herein, when a composition is described as containing one or more other compounds present in a particular amount or percentage, such as, for example, "not more than x percent by weight" or "not more than x percent by weight as measured by HPLC," it should be understood that such a statement is a description of chemical purity. In some instances, these other compounds are explicitly identified as impurities.

[0059] As used herein, the term "isolated" refers to a form that may be at least a particular percent by weight of a particular crystalline form of a compound, the particular percent by weight being 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 90% and 100%.

[0060] The term "solvate or solvate" refers to a physical association of a compound of the present invention (including its crystalline forms) with one or more solvent molecules. This physical association includes hydrogen bonds in the crystal lattice as well as incidental (or loosely associated on the surface) solvent molecules. This term includes stoichiometric and non-stoichiometric amounts of solvent molecules. In certain cases, the solvate form of the compound of formula I can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvates of the present disclosure include, for example, hydrates, ethanol adducts, or methanol adducts. Non-limiting examples of the present disclosure include isopropanol, acetonitrile, isopropyl acetate, and methyl isobutyl ketone solvates. The terms "solvate" and "solvate form" are used interchangeably throughout the present disclosure.

[0061] The term "hydrate" refers to a solvate in which the solvent molecule is H2O present in a defined stoichiometric or non-stoichiometric amount. Stoichiometric solvates can include, for example, hemihydrate, monohydrate, dihydrate, or trihydrate forms, among others. Non-stoichiometric solvates can include, for example, channel hydrates, including those in which the water content can vary depending on the humidity of the environment. The terms "hydrate" and "hydrated form" are used interchangeably throughout this disclosure.

[0062] The term "mixture" is used to refer to two or more elements or forms in intimate association, regardless of the phase state of the combination (eg, liquid or liquid / crystalline).

[0063] The term "seeding" is used to refer to the addition of crystalline material to initiate recrystallization or crystallization.

[0064] The term "antisolvent" is used to refer to a solvent in which a compound, including its crystalline forms, is poorly soluble.

[0065] As used herein, the term "about" means approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value with a variance of 10% above and below the stated value.

[0066] As used herein, the term "high levels of 2HG" refers to 10%, 20%, 30%, 50%, 75%, 100%, 200%, 500% or more of 2HG than is present in a subject that does not carry a mutant IDH1 allele. The term "high levels of 2HG" can refer to the amount of 2HG in a cell, in a tumor, in a tumor, in an organ containing a tumor, or in a bodily fluid.

[0067] The term "body fluid" includes one or more of the amniotic fluid surrounding a fetus, aqueous humor, blood (e.g., plasma), serum, cerebrospinal fluid, earwax, chyle, Cowper's fluid, female body fluids, interstitial fluid, lymph, breast milk, mucus (e.g., nasal mucus or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretions, or vomit.

[0068] As used herein, the terms "inhibit" or "prevent" include both complete and partial inhibition and prevention. An inhibitor may completely or partially inhibit the intended target.

[0069] The term "treat" refers to reducing, inhibiting, attenuating, diminishing, halting, or stabilizing the development or progression of a disease / disorder (i.e., advanced solid tumors such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each of which are characterized by the presence of a mutant allele of IDH1), reducing the severity of a disease / disorder (i.e., advanced solid tumors such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each of which are characterized by the presence of a mutant allele of IDH1), or ameliorating symptoms associated with a disease / disorder (i.e., advanced solid tumors such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each of which are characterized by the presence of a mutant allele of IDH1).

[0070] As used herein, an amount of a compound effective to treat a disorder, or a "therapeutically effective amount," refers to the amount of a compound that, upon single or repeated administration to a subject, is effective in treating a cell or in curing, alleviating, relieving, or improving a subject having a disorder beyond the extent expected in the absence of such treatment.

[0071] As used herein, "% w / w" is used to mean weight as a percentage of the total weight used as the basis for calculating the weight percentage of an individual component. As an example, for a bulk composition, the % w / w of an individual component can be calculated as a percentage of the total weight of all components of the bulk composition. As another example, for a single oral dosage form, the % w / w of an individual component can be calculated as a percentage of the total weight of all components of the single oral dosage form. For example, if the single oral dosage form is a tablet, the total weight can be the total weight of all components of the tablet.

[0072] As used herein, the term "subject" is intended to mean a human. Exemplary human subjects include human patients (referred to as patients) having a disorder, e.g., a disorder described herein, or normal subjects. The term "subject" includes pediatric populations, where the pediatric population has a disorder described herein. In other embodiments, the subject is an adult human.

[0073] As used herein, the term "physically stable" means that a particular free base or salt form does not change to one or more alternative physical forms (e.g., different solid forms as measured by XRPD, DSC, etc.) when subjected to particular conditions, e.g., room temperature and ambient humidity, or 40°C / 75% relative humidity, for a particular period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months or more. In some embodiments, less than 25% of the form of the compound changes to one or more different physical forms when subjected to the particular conditions. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5% of the form of the particular compound changes to one or more different physical forms of the particular compound when subjected to the particular conditions. In some embodiments, a detectable amount of a particular form of the compound does not change to one or more different physical forms of the compound.

[0074] As used herein, the term "chemically stable" means that the chemical structure of a particular compound does not change (e.g., decompose) into another compound when subjected to certain conditions, such as room temperature and ambient humidity, or 40°C / 75% relative humidity, for a particular period of time, such as 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months or more. In some embodiments, less than 25% of the form of the particular compound changes into one or more other compounds when subjected to certain conditions. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5% of the form of the particular compound changes into one or more other compounds when subjected to certain conditions. In some embodiments, a detectable amount of the form of the particular compound does not change into one or more different physical forms of the particular compound.

[0075] The term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed in discrete units throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g., from colloidal particles of nanometer dimensions to multiple micron sizes). In general, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline therapeutically active compound (dispersed phase) in an amorphous polymer(s) (continuous phase), or alternatively, an amorphous therapeutically active compound (dispersed phase) in an amorphous polymer (continuous phase).

[0076] The term "amorphous solid dispersion" generally refers to a solid dispersion containing two or more components, usually a therapeutically active compound and a polymer (or polymers), but optionally other components such as surfactants or other pharmaceutical excipients, where the therapeutically active compound is in the amorphous phase and the physical stability and / or solubility and / or dissolution of the amorphous therapeutically active compound are enhanced by the other components. In some embodiments, the amorphous solid dispersion comprises a polymer(s) (and optionally a surfactant) that constitutes the dispersed phase, and the therapeutically active compound constitutes the continuous phase. In some embodiments, the amorphous solid dispersion comprises a polymer(s) (and optionally a surfactant) that constitutes the continuous phase, and the therapeutically active compound constitutes the dispersed phase.

[0077] An exemplary solid dispersion is a co-precipitate or co-melt of a particular therapeutically active compound with one or more polymer(s). A "co-precipitate" is produced after dissolving a therapeutically active compound and one or more polymer(s) in a solvent or solvent mixture, followed by removal of the solvent or solvent mixture. Sometimes, one or more polymer(s) can be suspended in a solvent or solvent mixture. The solvent or solvent mixture includes organic solvents and supercritical fluids. The solvent or solvent mixture can also contain non-volatile solvents. A "co-melt" is produced after heating a therapeutically active compound and one or more polymer(s) to melt, optionally in the presence of a solvent or solvent mixture, followed by mixing, removing at least a portion of the solvent, if applicable, and cooling to room temperature at a selected rate. In some cases, a solid dispersion is prepared by adding a solution of a therapeutically active compound and a solid polymer, followed by mixing and removal of the solvent or solvent mixture. To remove the solvent or solvent mixture, vacuum drying, spray drying, tray drying, freeze drying, and other drying procedures can be applied. Application of any of these methods using appropriate processing parameters according to the present disclosure provides a particular therapeutically active compound in an amorphous state in the final solid dispersion product.

[0078] As used herein, the term "direct compression dosage form" generally refers to a form (e.g., tablet) obtained by compression of a dry blend of powders (e.g., solid dispersions or agglomerated dispersions), comprising a compound, i.e., a therapeutic compound, for example, in a solid dispersion (e.g., a poorly soluble therapeutic compound, ivosidenib, amorphous ivosidenib), and also comprising one or more polymer(s), and optionally one or more surfactant(s), and optionally one or more excipients. For example, the product (e.g., solid dispersion) obtained from the process described herein may have improved properties (e.g., flowability) that allow it to be directly compressed into an oral dosage form, such as, for example, a tablet, or formulated into a capsule or sachet form.

[0079] Pharmaceutical compositions and methods of treatment Provided is a method of treating advanced solid tumors, such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each characterized by the presence of a mutant allele of IDH1, comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) the compound (S)—N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (ivosidenib) or a pharma- ceutically acceptable salt thereof, as part of a solid dispersion, and, optionally, (b) one or more pharma- ceutically acceptable carrier(s).

[0080] Also provided are compositions containing ivosidenib or a pharma- ceutically acceptable salt thereof as part of a solid dispersion (e.g., an amorphous solid dispersion).Also provided are pharmaceutical compositions comprising (a) ivosidenib or a pharma- ceutically acceptable salt thereof as part of a solid dispersion, and (b) one or more pharma- ceutically acceptable carrier(s).

[0081] These therapeutic methods and pharmaceutical compositions are further illustrated by the detailed description and illustrative examples provided below.

[0082] Pharmaceutical compositions comprising solid dispersions of a therapeutically active compound in a matrix can provide improved chemical and physical properties and can be prepared by forming a homogeneous solution or melt of the therapeutically active compound and the matrix material, followed by solidifying the mixture by cooling or removing the solvent. Such solid dispersions of a therapeutically active compound often exhibit improved bioavailability when administered orally, as compared to oral compositions comprising the non-dispersed compound.

[0083] Spray drying is the most widely used industrial process involving particle formation and drying and can be used to produce solid dispersions of therapeutically active compounds. It is highly suitable for the continuous production of dry solids in powder, granular, or agglomerated form from liquid feedstocks as solutions, emulsions, and pumpable suspensions. Therefore, spray drying is a useful process where the final product must comply with precise quality standards regarding particle size distribution, residual moisture content, bulk density, and particle shape.

[0084] Important quality attributes of spray dried dispersions include potency, related substances, residual solvent content, homogeneity, lack of crystallinity, dissolution performance, particle morphology, and bulk powder flow properties.

[0085] Process parameters include spray solution composition and viscosity, nozzle type and size, atomization pressure, spray solution feed rate, drying gas flow rate, inlet and outlet temperatures, condenser temperature (e.g., for closed-loop drying processes), and secondary drying parameters.

[0086] In one embodiment, at least a certain weight percent of ivosidenib is crystalline. The certain weight percent can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%. When a certain weight percent of ivosidenib is crystalline, the remaining portion of ivosidenib is an amorphous form of ivosidenib. In some embodiments, a certain weight percent of ivosidenib can include one crystalline form of ivosidenib, or a mixture of two or more crystalline forms of ivosidenib. In some embodiments, ivosidenib is at least 90% crystalline by weight. In some other embodiments, ivosidenib is at least 95% crystalline by weight. In some other embodiments, ivosidenib is at least 99% crystalline by weight.

[0087] In another embodiment, the particular weight percentage of ivosidenib is a particular single form or combination of forms. The particular weight percentage can be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%. In another embodiment, ivosidenib is at least 90% by weight of a single form. In another embodiment, ivosidenib is at least 95% by weight of a single form. In another embodiment, ivosidenib is at least 99% by weight of a single form.

[0088] In the following description of ivosidenib, the embodiments of the present disclosure may be described with reference to a specific form of ivosidenib that is characterized by one or more characteristics discussed herein.The description that characterizes a form may also be used to describe the mixture of different forms that may exist in ivosidenib formulations.However, a specific form of ivosidenib may also be characterized by one or more of the characteristics of the form disclosed herein, regardless of whether or not it refers to a specific form itself.

[0089] The forms are further illustrated by the detailed description and illustrative examples provided below. The XRPD peaks listed in the tables for each form may vary by ±0.2 depending on the instrument used to acquire the data.

[0090] Forms of ivosidenib At least 15 different polymorphs of ivosidenib have been identified and characterized. Polymorph screening was performed by producing solid ivosidenib under a variety of conditions and characterizing the resulting samples. Multiple crystalline forms of ivosidenib have been identified by solution evaporation, slurry, recrystallization, and solvent / antisolvent precipitation experiments, which are listed in Table 1. [Table 1]

[0091] The morphology was characterized by X-ray powder diffraction (XRPD), which is overlaid in Figure 1. The morphology was further characterized by differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).

[0092] Some of the polymorphs of ivosidenib disclosed herein are ,phase For example, the anhydrous form L can be converted to the anhydrous form N by treatment with an isopropyl acetate (iPrOAc):heptane mixture containing up to 25% iPrOAc at 70° C.

[0093] Form L Form L is an anhydrous form of ivosidenib with a melting point as determined by differential scanning calorimetry (DSC) of 150 C and weight loss in thermogravimetric analysis (TGA) of 0.44%.

[0094] In one embodiment, to synthesize form L of ivosidenib, a mixture of ivosidenib (3.5 kg, 7.28 mol) in 1,4-dioxane (35 L) is degassed by N2 bubbling for up to 20 minutes. 2-Chloro-4-cyanopyridine (1.21 kg, 8.73 mol), tris(dibenzylideneacetone)-dipalladium(0) (167 g, 0.18 mol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (211 g, 0.36 mol) are added and the reaction mixture is degassed by N2 bubbling for up to 10 minutes. K2CO3 (1.21 kg, 8.73 mol) is added and the reaction mixture is degassed by N2 bubbling for up to 30 minutes. The reaction mixture is heated at 90-100 °C for 4-24 hours until the reaction is complete. The reaction mixture is then cooled to 15-25° C., filtered through Celite, washed with ethyl acetate, and the filtrate and washings are combined and concentrated.

[0095] The 1,4-dioxane is removed and the residual solid is dissolved in ethyl acetate (77.5 L). The ethyl acetate solution is washed successively with a 5% aqueous solution of NaHSO3, a 2% aqueous solution of disodium EDTA, and a 1% aqueous solution of disodium salt of EDTA. The organic phase is treated with activated charcoal at 55-65 °C for up to 2 hours and purified by silica gel chromatography. After chromatography, the product obtained is purified by two recrystallizations. The first compound 1 is dissolved in ethyl acetate, heated to 60-70 °C, and heptane is added. The reaction mixture is cooled to 15-25 °C and stirred for 1-3 hours. The product is filtered, dissolved in dichloromethane, then filtered, precipitated with heptane, filtered and dried to produce Form L.

[0096] In one embodiment, a single crystalline form of ivosidenib, Form L, is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 1 and the data shown in Table 2 obtained using CuKa radiation. In certain embodiments, the polymorph may be characterized by one or more peaks obtained from Figure 1 and shown in Table 2. For example, the polymorph may be characterized by 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 peaks shown in Table 2. [Table 2]

[0097] In another embodiment, form L can be characterized by peaks identified at 2θ angles of 8.7, 15.7, 18.5, 20.7, 21.5, and 26.4°. In another embodiment, form L can be characterized by peaks identified at 2θ angles of 8.7, 15.7, 18.5, and 21.5°.

[0098] In another embodiment, Form L is 2 The sample can be characterized by a differential scanning calorimetry profile (DSC) shown in Figure 1. The DSC graph plots the heat flow as a function of temperature from the sample, with a temperature rate change of about 10°C / min. The profile is characterized by an endothermic transition with an onset temperature of about 140.1°C and a melt at about 149.9°C.

[0099] In another embodiment, Form L is 3 The sample can be characterized by thermogravimetric analysis (TGA) as shown in Figure 1. The TGA profile graphs the percent loss in weight of the sample as a function of temperature, with a temperature rate change of about 10°C / min. The weight loss represents a decrease of about 0.44% in the weight of the sample as the temperature changes from about 29.0°C to 125.0°C.

[0100] Form B Ivosidenib Form B is a channel hydrate form with a melting point of 154C by DSC and a weight loss of 2.0% by TGA.

[0101] Form B can be synthesized in a number of ways. In the first method, about 100 mg of ivosidenib is mixed with 0.4 mL of MeOH and stirred at room temperature for 12 hours. The suspension is then centrifuged to isolate the white solid.

[0102] In the second method, approximately 10 mg of ivosidenib is mixed in 0.2-0.4 mL of a mixture of MeOH:HO (9:1) in a 3 mL glass vial. The resulting visually clear solution is covered with a cap and subjected to slow evaporation to induce precipitation. The solid is isolated.

[0103] In the third method, about 15 mg of compound 1 is dissolved in a mixture of EtOH:H2O (8:7 v / v) or methyl ethyl ketone (MEK) at 50° C. and stirred for 30 minutes at 50° C. The solution is then slowly cooled at 0.1° C. / min to 5° C. and stirred overnight at 5° C. The solid is isolated.

[0104] In one embodiment, a single crystalline form of ivosidenib, Form B, is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 1 and the data shown in Table 3 obtained using CuKa radiation. In certain embodiments, the polymorph may be characterized by one or more peaks obtained from Figure 1, as shown in Table 2. For example, the polymorph may be characterized by 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10 peaks shown in Table 2. [Table 3]

[0105] In another embodiment, form B can be characterized by peaks identified at 2θ angles of 9.9, 11.7, 19.6, 22.5, 23.0, and 31.4°. In another embodiment, form B can be characterized by peaks identified at 2θ angles of 9.9, 11.7, 19.6, and 23.0°.

[0106] In another embodiment, Form B is 4 The sample can be characterized by a differential scanning calorimetry profile (DSC) shown in Figure 1. The DSC graph plots the heat flow as a function of temperature from the sample, with the temperature rate change being about 10°C / min. The profile is characterized by an endothermic transition having an onset temperature of about 62.7°C and melting at about 72.5°C, and an endothermic transition having an onset temperature of about 145.6°C and melting at about 153.6°C.

[0107] In another embodiment, Form B is 5 The sample can be characterized by thermogravimetric analysis (TGA), shown in Figure 1. The TGA profile graphs the percent loss in weight of the sample as a function of temperature, with a temperature rate change of about 10°C / min. The weight loss represents a decrease of about 0.57% of the sample's weight as the temperature changes from about 29.3°C to 170.3°C.

[0108] Form M and Form N Forms M and N of ivosidenib are anhydrous forms obtained at high heptane concentrations: Form N is obtained at high heptane concentrations of 75-95% at 70° C., and Form M is obtained at very high heptane concentrations (95%) at 40° C.

[0109] To determine the most stable anhydrous form, competitive slurries using Form L, Form M, and Form N were performed in dichloromethane, heptane, tBME, and acetone. These experiments showed that Form N was the stable anhydrous form under the conditions evaluated, correlating with the thermal data obtained, which showed a significantly higher melting temperature of about 215° C. and melting enthalpy of about 53 mJ / mg for Form N compared to the melting temperature (about 170° C.) and enthalpy (about 33 mJ / mg) for Form M. To determine the feasibility of obtaining these forms during crystallization, a slurry conversion experiment was performed using a crystallization procedure that involved mixing 141.6 g of ivosidenib Form B with 432 mL of iPrOAc in a 1 L vessel and stirring at 50° C. and 210 rpm. The temperature was increased to 70° C. to dissolve the material. Antisolvent addition (60 mL heptane) at 60 mL / hr was performed at 70° C. Upon completion of the anti-solvent addition, the reaction was cooled to 60° C. and seeded with 0.63 g of ivosidenib form B, which was stirred at 60° C. for 4 hours and then cooled to 15° C. over 10 hours. Anti-solvent addition (308 mL of heptane) was started at 75 mL / hr, 15° C., 200 rpm. Upon completion of the anti-solvent addition, the mixture was stirred at 15° C. for 2 hours and then the solid was isolated by filtration using a Buchner funnel (120 mm diameter) and washed with 246 mL of iPrOAc:heptane (1:1 v / v). Isopropyl acetate:heptane 5:95 v / v retained form N, while isopropyl acetate:heptane 20:80 v / v gave a mixture of form B and form N.

[0110] For the competitive slurry trials of Form L, Form M, and Form N polymorphs, the following procedure was followed: Approximately 50 or 75 mg of each of the different solid forms were weighed into 1.5 mL screw-cap vials. 75 mg of each form was used for the high temperature experiments and 50 mg of each form was used for the ambient temperature experiments, except for the acetone experiments, where 100 mg of each form was used.

[0111] Appropriate 50:50 weight / weight combinations prepared from Form L, Form M, and Form N (see Table 4 for details).

[0112] Aliquots (100 μL or 25 μL) of the appropriate solvent were added as necessary to obtain a fluid slurry, which was then stirred at either ambient temperature (approximately 23° C.) or elevated temperature (35 or 50° C.) for approximately 21 or 68.5 hours (see Table 4 for details). Solids were isolated by centrifugation and analyzed by XRPD. If a mixture of patterns was still present, the experiment was continued until a single form was obtained (see Table 4 for details of experiment time). An additional 1 mL of the appropriate solvent was added to experiments continued at elevated temperature. [Table 4]

[0113] Characterization of Form N A sample of Form N was poorly soluble in 5:95 v / v iPrOAc:heptane and remained a thick slurry throughout the experiment. XRPD analysis of both the centrifuged sample (taken after 15 hours at 70° C.) and the dried product were consistent with Form N, with excellent agreement between the diffractograms of the scale-up material and the sample isolated from the solid form mapping experiment.

[0114] Both the slurry and the dried material were birefringent by PLM analysis and had a needle-like morphology. TG analysis of the dried material showed essentially no weight loss, consistent with an anhydrous form of Form N (Figure 1). 6 See Figure 1. 6 As shown in Figure 1, the DTA showed an endothermic event with an onset of about 212.0°C (peaking at about 215.8°C), likely due to melting of the material.

[0115] DSC analysis of a small sample removed after 15 h and dried under vacuum for about 2 h shows that 7 As shown in Figure 1, it showed an endothermic event with an onset of about 212.7 °C (peak at about 214.8 °C, enthalpy 53.0 mJ / mg), likely due to melting of the material. 7 As shown in Figure 1, DSC analysis of the bulk dried material showed an endothermic event with an onset of about 212.6°C (peak at about 215.4°C, enthalpy 52.7 mJ / mg), likely due to melting of the material.

[0116] HPLC analysis of the filtrate (filtration time less than 1 min, 80 mm Buchner funnel, 101 mL of isolated mother liquor) gave a mother liquor purity of 91.4%. The isolated yield was 4.66 g, 93%. The purity of the isolated solid was found to be 99.9% by HPLC analysis. 8 Please refer to.

[0117] GC analysis of the material showed that both the iPrOAc content and the heptane content were below the LOQ (performed with LOQ solutions of iPrOAc (100 ppm) and heptane (200 ppm)).

[0118] The solubility of Form N in methanol was 113 mg / ml.

[0119] The XRPD peaks of form N of ivosidenib are defined as follows: Form N may be characterized by 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 peaks as shown in Table 5. [Table 5-1] [Table 5-2]

[0120] Characterization of Form M The Form M material was poorly soluble in 5:95 v / v iPrOAc:heptane and remained a thick slurry throughout the experiment. XRPD analysis of both the centrifuged sample (taken after 13 hours at 40° C.) and the dried product were consistent with Pattern 5, with excellent agreement between the diffractograms of the scale-up material and the sample isolated from the solid form mapping experiment (see FIG. 1).

[0121] Both the slurry and the dry material were very slightly birefringent by PLM analysis and had no clearly defined morphology.

[0122] TG analysis of the dried material showed essentially no weight loss, consistent with the anhydrous form of Pattern 5. (Figure 2) 9 See Figure. 9 As can be seen, the DTA showed a broad endothermic event with an onset of about 160.4° C. (peaking at about 172.4° C.), likely due to melting of the material.

[0123] DSC analysis of a small sample removed after 13 hours and dried under vacuum for approximately 1.5 hours showed As shown in Figure 10, It showed an endothermic event with an onset of about 161.7° C. (peaking at about 170.0° C., enthalpy 32.0 mJ / mg), possibly due to melting of the material. . DSC analysis of the bulk dried material showed an endothermic event with an onset of about 161.5° C. (peak at about 170.5° C., enthalpy 33.9 mJ / mg), likely due to melting of the material.

[0124] HPLC analysis of the filtrate (filtration time less than 1 min, 80 mm Buchner funnel, 110 mL isolated mother liquor) gave a mother liquor purity of 91.8%. The isolated yield was 4.63 g, 92%. The purity of the isolated solid was found to be 99.9% by HPLC analysis. (Figure 1 1 reference.)

[0125] GC analysis of the pattern 5 material showed that the iPrOAc content was about 299 ppm, while the heptane content was about 339 ppm (performed with LOQ solutions of iPrOAc (100 ppm) and heptane (200 ppm)).

[0126] The solubility of Form M in methanol was 109 mg / ml.

[0127] The XRPD peaks of form M of ivosidenib are defined as follows: Form M may be characterized by 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 peaks as shown in Table 6. [Table 6-1] [Table 6-2]

[0128] Form A Figure 1 2 From the sample of ivosidenib that was partially crystalline as evidenced by the XRPD pattern shown in Figure 1, the crystalline form was designated free base Form A. DSC and TGA data are shown in Figure 1. 3 The DSC curve shows an endothermic peak at 30.8°C (onset). 3 In the TGA data shown in Figure 1, a weight loss of about 1.6% was observed below about 150.0°C.

[0129] Screening to discover additional polymorphs Different crystallization or solid-state transition methods were applied to discover various crystalline forms of the free base of ivosidenib, and some of the experiments were intended to identify the stable form. The methods utilized in this study are summarized in Table 7 and include slow evaporation, slurry conversion at room temperature, antisolvent addition, and slow cooling (50 °C to 5 °C). [Table 7]

[0130] The approximate solubility of ivosidenib free base was determined in 20 solvent systems at room temperature. In the experiment, approximately 2 mg of ivosidenib was added to a 3 mL glass vial, followed by the addition of the corresponding solvent. Solvent was added in 100 μL increments until the solution was visually clear or until a total volume of 2 mL was reached. The results are shown in Table 8. This solubility information was used to select solvents for polymorph screening. [Table 8]

[0131] Slurry conversion at room temperature (RT) Slurry conversion experiments were performed in 10 solvents or solvent mixtures by suspending approximately 15 mg of ivosidenib in about 0.5 mL of solvent in a 1.5 mL glass vial at room temperature. The suspension was stirred for 48 hours, after which the remaining solid was centrifuged for XRPD analysis. The results summarized in Table 9 show that seven forms of ivosidenib free base (Forms C, D, E, F, G, H, and I) were produced at room temperature. [Table 9]

[0132] Antisolvent addition A total of eight anti-solvent addition experiments were performed by dissolving approximately 10 mg of ivosidenib free base in 0.1-0.2 mL of solvent to obtain a saturated solution, followed by the addition of 0.1-0.7 mL of anti-solvent. The precipitate was isolated for XRPD analysis. The results, summarized in Table 10, show that two crystalline forms (free base form B and form K) were produced. [Table 10]

[0133] Slow cooling Slow cooling experiments were carried out in 15 solvents or solvent mixtures. Saturated solutions were prepared by dissolving about 15 mg of ivosidenib free base in various solvents at 50° C. and stirring at 50° C. for 30 minutes. The solutions were then slowly cooled to 5° C. at 0.1° C. / min and then stirred at 5° C. overnight. Solids were isolated for XRPD analysis. The clear solutions were allowed to evaporate at room temperature for one week and the solids were examined by XRPD. The results summarized in Table 11 show that five forms of ivosidenib free base (forms B, C, G, E, and J) were discovered in the slow cooling experiments. [Table 11]

[0134] Slow evaporation Slow evaporation experiments were performed in 15 solvents by dissolving approximately 10 mg of ivosidenib free base in 0.2-0.4 mL of solvent in a 3 mL glass vial. The resulting visually clear solution was capped and subjected to slow evaporation to induce precipitation. Solids were isolated for XRPD analysis, and the results summarized in Table 12 indicate that free base Form B and Form C were produced. [Table 12]

[0135] Characterization of Form C Figure 1 4 The XRPD pattern of a sample of ivosidenib free base form C shown in Figure 1 indicates that it is a crystalline form. DSC and TGA overlay of ivosidenib free base form C shown in Figure 1 5 The TGA data shows a weight loss of about 8.3 wt% before 192.2°C. Three endothermic peaks were observed in the DSC curve at 52.7°C, 99.3°C, and 133.7°C (onset) due to evaporation of residual solvent. 1 NMR spectrum (Figure 1 6 ) indicates that IPA is the primary solvent contained in free base form C. NMR results indicate that the IPA content is 8.0%, which is consistent with the weight loss of 8.3 wt% in the TGA curve. The results suggest that free base form C is an IPA solvate. [Table 13]

[0136] Form D Figure 1 7 The XRPD pattern of a sample of ivosidenib free base form D, shown in Figure 1, indicates that it is a different crystalline form than that of ivosidenib free base form A. The DSC and TGA overlay of form D is shown in Figure 1. 8The TGA data shows a weight loss of about 8.1 wt% before 127.3°C. An endotherm was observed at 90.6°C in the DSC curve due to the evaporation of residual solvent. 19 As shown in 1 H NMR results show that methyl acetonitrile (ACN) 1 The H peak is 2.08 ppm, and the H peak is (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. 1 The H NMR peaks are shown to be between 8.57 and 7.48 ppm. According to the area ratio, the molar equivalents of (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide and ACN are approximately 1:1.2, which is consistent with the weight loss in the TGA curve and indicates that the free base form D is an acetonitrile solvate, more specifically, a mono-ACN solvate. [Table 14]

[0137] Form E Figure 2 0 The XRPD pattern of a sample of ivosidenib free base form E, shown in Figure 2, indicates that it is a different crystalline form from that of form A. The DSC and TGA overlay of ivosidenib free base form E is shown in Figure 2. 1 The TGA data shows a weight loss of about 9.5 wt% before 145.0° C. An endotherm was observed at 93.1° C. in the DSC curve due to evaporation of residual solvent. The TGA and DSC results suggest that free base form E is a solvate. 2 As shown in 1H NMR results show two methyl groups of isobutyl from methyl isobutyl ketone (MIBK) at 0.92 ppm. 1 H NMR peaks, and one peak representing ivosidenib at 8.73 ppm are shown. By area ratio, the molar equivalents of (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide and MIBK are approximately 1:0.7, which is consistent with the TGA weight loss and indicates that the free base form E is MIBK solvated. With things This suggests that there is.

[0138] The XRPD peaks of form E of ivosidenib are defined as follows: Form E may be characterized by 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 peaks as shown in Table 15. [Table 15-1] [Table 15-2]

[0139] Form F Figure 2 3 The XRPD pattern of a sample of ivosidenib free base form F, shown in Figure 2, indicates that it is a different crystalline form from that of form A. The DSC and TGA overlay of ivosidenib free base form F is shown in Figure 2. 4 The TGA data shows a weight loss of about 11.5 wt % before 152.8° C. In the DSC curve, an endotherm was observed at 105.6° C. The TGA and DSC results suggest that free base form F is likely a solvate or hydrate. [Table 16-1] [Table 16-2]

[0140] Form G Figure 2 5 The XRPD pattern of a sample of ivosidenib free base form G, shown in Figure 2, indicates that it is a different crystalline form from that of form A. The DSC and TGA overlay of ivosidenib free base form G is shown in Figure 2. 6 The TGA data shows a weight loss of about 5.1 wt% before 147.9° C. In the DSC curve, three endothermic peaks were observed at 42.5° C., 113.5° C., and 135.5° C. (onset). The TGA and DSC results suggest that free base form G is likely a solvate or hydrate.

[0141] Form H Figure 2 7 The XRPD pattern of a sample of ivosidenib free base form H, shown in Figure 2, indicates that it is a different crystalline form from that of form A. The DSC and TGA overlay of ivosidenib free base form H is shown in Figure 2. 8 The TGA data shows a weight loss of about 3.7 wt% before 171.4° C. In the DSC curve, two endothermic peaks were observed at 69.0° C. and 153.7° C. (onset). The TGA and DSC results suggest that free base form H is likely a solvate or hydrate.

[0142] Form I figure 29 The XRPD pattern of ivosidenib free base form I shown in Figure 3 indicates that it is a partially crystalline form. DSC and TGA overlay of ivosidenib free base form I shown in Figure 3 0 The TGA data shows a weight loss of about 1.1 wt% before 200.6°C, which is likely due to the presence of residual solvent. In the DSC curve, two endothermic peaks were observed at 63.9°C and 133.8°C (onset). 1 NMR spectrum (Figure 3 1) indicates that EtOH is the primary solvent contained in the free base Form I. The peak at 1.0 ppm represents the methyl group from EtOH and the peak at 7.5 ppm is from (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. Based on the area ratio, the molar equivalents of (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide and EtOH is 1:0.34.

[0143] The characteristic XRPD peak by which Form I can be identified occurs at about 8.1°.

[0144] Form I of ivosidenib is an anhydrate / solvate form.

[0145] Form J Figure 3 2 The XRPD pattern of ivosidenib free base form J, shown in Figure 3, indicates that it is a different crystalline form from free base form A. The DSC and TGA overlay of ivosidenib free base form J is shown in Figure 3. 3 The TGA data shows a weight loss of about 15.3 wt % before 132.0° C., likely due to the presence of residual solvent. An endotherm at 79.7° C. (onset) was observed in the DSC curve indicating that free base form J is a solvate or hydrate. [Table 17]

[0146] Form K XRPD pattern of ivosidenib free base form K is shown in Figure 3. 4 which indicates that it is in partially crystalline form.

[0147] Pattern 3 A solvate form of ivosidenib, designated Pattern 3, is observed when a slurry of any of the anhydrous forms (i.e., one or more of Form L, Form M, and Form N) in DCM converts to Pattern 3. However, upon vacuum drying, Pattern 3 converts to Form L.

[0148] Interconversion of forms of ivosidenib Polymorphs of ivosidenib can interconvert under certain conditions. For example, see Figure 3. 5 1 shows an overlay of the DSC curves of Forms L, M, and N described herein.

[0149] A 1:1 mixture of anhydrous forms L, M, and N was mixed with dichloromethane and all tests resulted in the formation of a solvate of form E. This solvent produces form L when dried.

[0150] Form L suspended and rotated in methanol at room temperature is shown in Figure 3. 6 Forms M and N also produce Form B when slurried in methanol. The solubility of Forms M and N is approximately 110 mg / mL, far exceeding the concentration of AG-120 in the SDI spray solution (approximately 70 mg / mL).

[0151] Form B is a thermodynamically stable hydrate form. All other forms (such as Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, and Form L) can be converted to Form B when subjected to the above conditions, i.e., the conditions listed under the heading "Form B". Form L is a thermodynamically stable form of ivosidenib when isolated from DCM, or a mixed solvent containing DCM and a hydrocarbon solvent. All other forms (i.e., any of Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, and Form K) can be made by crystallization in such a solution. Form L can also be obtained by drying Pattern 3. Thus, the present disclosure includes methods of synthesis of Form B and Form L via any one or more of the other identified forms of ivosidenib. Thus, Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form J, Form K, and Form L are considered to be synthetic intermediates of Form B, and one or more of these forms can be used to convert to Form B. Similarly, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, and Form K can be considered to be synthetic intermediates of Form L.

[0152] Crystallography Ivosidenib tablets may be manufactured using a spray-dried dispersion (50:50) intermediate of ivosidenib drug substance and at least one other additive such as HPMCAS. Ivosidenib and HPMCAS may be completely dissolved in methanol prior to spray drying. Ivosidenib spray-dried intermediate (SDI) may be consistently manufactured as an amorphous material and may be used to manufacture final formulations such as those used in clinical efficacy trials and registration stability studies.

[0153] To evaluate the effect of crystalline polymorphic form on the dissolution profile, variant tablets were made with SDI spiked with two different crystalline polymorphic forms of drug substance. Forms B and L are as described above. As used herein, the term "spiked" or "spiking" is used consistently with its use in the field of pharmaceutical manufacturing, i.e., the introduction of a particular form into a crystallization solution to promote nucleation and growth. These forms were chosen because it was determined that these two forms would most likely be present if SDI crystallized. However, it should be noted that SDI can be reliably made in a completely amorphous form, with no detectable crystalline forms even under stress conditions.

[0154] The 250 mg tablets were prepared by adding 50 mg (20% w / w) of crystalline form L or form B together with ivosidenib SDI (thus amorphous SDI was present at 80% w / w as a measure of the active ingredient).

[0155] In one embodiment, such tablets may be formulated as shown in Table 18. [Table 18]

[0156] To produce such tablets, HPMCAS MG can be combined with a crystalline form of ivosidenib (i.e., Form B or Form L) and combined with about half of the amorphous ivosidenib SDI and mixed at about 25 rpm for about 1 minute. The remaining amorphous SDI can then be added to the blender and mixed for an additional minute at about 25 rpm. Microcrystalline cellulose PH-103 can then be added to the blend and mixed for about 85 revolutions. The resulting preblend can be screened, for example, by using a Quadro comi 197S with a 093R screen at about 1800±100 rpm. The screened preblend can then be blended with croscarmellose sodium, sodium lauryl sulfate NF, and colloidal silicon dioxide for about 22 minutes 50 seconds ±10 seconds at about 25 rpm. The blend can be lubricated with magnesium stearate for about 4 minutes at about 25 rpm.

[0157] The preblend can then be roller compacted and milled, for example, by using a 1 mm screen. For example, one roller can be a smooth roller and the other roller can be a knurled roller with a roll compaction force of about 5.0 kilonewtons per centimeter (kN / cm), a roll gap of about 2.0 mm, and a roll speed of about 2 rpm.

[0158] The compacted milled granules can be blended with extragranular excipients microcrystalline cellulose PH 103, colloidal silicon dioxide, and croscarmellose sodium for about 22 minutes, followed by lubrication with magnesium stearate for 4 minutes at a speed of about 25 rpm to produce a final blend. The final blend can then be compressed into tablet form, for example, to a tablet hardness of about 18±2 kilopascals (kP), or about 27±4 kP, or about 37±2 kP. The tablets can be optionally film coated to a target coating weight gain, such as about 5.0% w / w weight gain.

[0159] The dissolution profile of the tablets formulated as described above is shown in Figure 3. 7Table 19 describes the dissolution of 250 mg tablets spiked with Form L ivosidenib in 12 individual containers containing a solution of pH 6.8 and 0.6% SDS, designated medium A. Table 20 lists the results of a similar trial of tablets spiked with Form B. [Table 19] [Table 20]

[0160] A similar dissolution test was performed using medium B (pH 6.8, 0.4% SDS). The similarity factor (f2) was calculated and the dissolution profile was evaluated and compared with the target formulation. The similarity factors are shown in Table 21. [Table 21]

[0161] As can be seen from the similarity factors listed above, medium A shows good discrimination between the target formulation and the formulation containing the polymorphic variant. The calculated f2 values ​​(28.9 and 26.0 for Forms L and B, respectively) indicate that the profiles are not similar.

[0162] Medium B also shows discrimination between the target formulation and the formulation containing the polymorph, but not to as great an extent as Medium A (f2 is 48.5 and 43.1 for Forms L and B, respectively).

[0163] impurities In some embodiments, the formulation of ivosidenib may contain additional compounds that may be considered impurities. In some embodiments, these additional compounds may be degradation products of ivosidenib and may form under stress conditions such as high temperature, light, and / or humidity. In other embodiments, these additional compounds may form during the process of making ivosidenib. In some embodiments, the formulation contains less than 0.5% w / w of any single additional compound, or less than 0.45% w / w, or less than 0.4% w / w, or less than 0.35% w / w, or less than 0.3% w / w, or less than 0.25% w / w, or less than 0.2% w / w, or less than 0.15% w / w, or less than 0.10% w / w, or less than 0.05% w / w, or less than 0.04% w / w, or less than 0.03% w / w, or less than 0.02% w / w, or less than 0.01% w / w.

[0164] Potential impurities are listed in Table 22 and may form during manufacturing or storage of ivosidenib drug substance under stress conditions. All have been examined for their potential genotoxicity using Derek Nexus and Leadscope Model Applier. Additionally, all materials used in the synthesis of ivosidenib were included as part of the genotoxicity assessment.

[0165] The intended patient population has relapsed / refractory acute myeloid leukemia and is expected to receive ivosidenib at a total daily dose of up to 500 mg for 1-10 years. Based on the recommendations in the ICH M7 guideline: "Evaluation and control of DNA-reactive (mutagenic) impurities in pharmaceutical products to limit potential carcinogenic risk", the acceptable threshold of toxicological concern (TTC) limits are 10 μg per individual genotoxic impurity per day and 30 μg per day for all genotoxic impurities with the same mechanism of action as the drug is administered for 1-10 years. This implies a limit of 20 ppm for each individual genotoxic impurity and 60 ppm for all genotoxic impurities combined into the final drug substance.

[0166] Three potential impurities, benzene, benzaldehyde, and benzyl chloride, are known mutagens. Phenol is inconclusive in the literature and is treated as a potentially genotoxic impurity (PGI). Due to the benzyl chloride substructure in the molecule, both 2-chlorobenzyl chloride and 1-chloro-2-(dichloromethyl)benzene are traditionally treated as PGIs, even though they have been reported to be Ames negative (ECHA, European Chemical Agency, registered substances).

[0167] All compounds with structural alerts are negative in the in vitro bacterial reverse mutation assay (Ames test). Some analogs of (E)-1-(2-chlorophenyl)-N-(5-fluoropyridin-3-yl)methanimine formed from impurities in the starting materials 3-amino-5-fluoropyridine and 2-chlorobenzaldehyde are not evaluated by the Ames test because they have the same alert structure (arylmethanimine) as (E)-1-(2-chlorophenyl)-N-(5-fluoropyridin-3-yl)methanimine, which is negative in the Ames test. They are treated as normal impurities (specified or unspecified).

[0168] Control of these genotoxic impurities can be achieved in a number of ways, including treating the product with various reagents or solvents, or using specific starting materials. [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 22-5]

[0169] Elemental impurities in ivosidenib formulations Elemental impurities are controlled in the final formulation of ivosidenib. Metals controlled in this manner include palladium, molybdenum, cadmium, lead, arsenic, mercury, cobalt, vanadium, and nickel.

[0170] Residual Solvent Ivosidenib - Formulation Residual solvents are controlled in the final formulation of ivosidenib.Methods controlled in this manner include isopropyl acetate, n-heptane, dichloromethane, benzene, heptane, ethyl formate, methanol, isopropyl alcohol, and ethyl acetate.

[0171] Pharmaceutical intermediates including solid dispersions Compositions are provided that include formulation intermediates containing ivosidenib, or pharma- ceutically acceptable salts thereof, including at least one solid form of ivosidenib, or multiple solid forms of ivosidenib. In some embodiments, the formulation intermediates may optionally contain amorphous ivosidenib. In some cases, the compositions may include a second molecule as listed herein. In some embodiments, the formulation intermediates containing ivosidenib may be solid dispersions including ivosidenib, or a pharma- ceutically acceptable salt thereof, and one or more polymer(s). In some embodiments, the solid dispersions include ivosidenib, or a pharma- ceutically acceptable salt thereof, one or more polymer(s), and one or more surfactant(s). In some embodiments, the solid dispersions include ivosidenib, or any form thereof, or a pharma- ceutically acceptable salt thereof, and a polymer. In some embodiments, the solid dispersions include ivosidenib, or any form thereof, or a pharma- ceutically acceptable salt thereof, a polymer, and a surfactant.

[0172] The solid dispersions provided herein are formed using one or more forms of ivosidenib to enhance the solubility of ivosidenib compared to a neat form of ivosidenib (e.g., Form L or Form B), thus providing improved exposure upon oral administration of the solid dispersion to a subject. In one embodiment, the solid dispersion comprises ivosidenib or any form thereof, or a pharma- ceutically acceptable salt thereof, one or more polymer(s), and, optionally, one or more solubility-enhancing surfactants.

[0173] In some embodiments, at least a portion of ivosidenib in the solid dispersion is in an amorphous state (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%). In other embodiments, the solid dispersion is substantially free of crystalline ivosidenib, or a pharma- ceutically acceptable salt thereof. In some embodiments, two or more polymorphs of ivosidenib may exist. In some embodiments, a second form may exist that includes a crystalline form.

[0174] In some embodiments, the solid dispersion is an amorphous solid (e.g., spray-dried) dispersion that includes ivosidenib in any form and a polymer. The amorphous solid dispersion can include, for example, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of crystalline forms of ivosidenib, for example, crystalline forms that are substantially free of crystalline ivosidenib or its pharma- ceutically acceptable salts. In some embodiments, the amorphous solid dispersion can include two or more crystalline forms of ivosidenib. In some embodiments, a second molecule can be present.

[0175] In one embodiment, the solid dispersion exhibits a level of physical and / or chemical stability. For example, the solid dispersion retains about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99% of amorphous ivosidenib or a pharma- ceutically acceptable salt thereof when stored at 25°C in a sealed, watertight container (e.g., an amber glass vial, a high density polyethylene (HDPE) container, or a double polyethylene bag with twisted nylon bands in a HDPE container with a desiccant).

[0176] In some embodiments, the polymer increases the chemical or physical stability (e.g., as measured by modulated differential scanning calorimetry) of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any form, by at least about 10% (e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) when stored (e.g., at 2-8° C., or at about 4° C., or at room temperature) compared to amorphous ivosidenib, or a pharma-ceutically acceptable salt thereof, in any form, without the presence of the polymer.

[0177] A solid dispersion generally exhibits a glass transition temperature at which the dispersion transitions from a glassy solid to a rubbery composition. In general, the higher the glass transition temperature, the greater the physical stability of the dispersion. The presence of a glass transition temperature generally indicates that at least a majority of the composition (e.g., dispersion) is in an amorphous state. The glass transition temperature (Tg) of a solid dispersion suitable for pharmaceutical applications is generally at least about 50°C. In some embodiments, higher temperatures are desirable. Thus, in some embodiments, the solid dispersions disclosed herein have a Tg of at least about 100°C (e.g., at least about 100°C, at least about 105°C, at least about 110°C, at least about 115°C, at least about 120°C, at least about 125°C, at least about 130°C, at least about 135°C, at least about 140°C, at least about 150°C, at least about 160°C, at least about 170°C, at least about 175°C, at least about 180°C, or at least about 190°C). In some embodiments, the Tg is up to about 200° C. In some embodiments, the Tg is up to about 130° C. (e.g., at least about 110° C., at least about 111° C., at least about 112° C., at least about 113° C., at least about 114° C., at least about 115° C., at least about 116° C., at least about 117° C., at least about 118° C., at least about 119° C., at least about 120° C., at least about 121° C., at least about 122° C., at least about 123° C., at least about 124° C., at least about 125° C., at least about 1216° C., at least about 127° C., at least about 128° C., at least about 129° C., or at least about 130° C.). Unless otherwise specified, glass transition temperatures disclosed herein are measured under dry conditions.

[0178] In some embodiments, the solid dispersion has a glass transition temperature higher than the glass transition temperature of amorphous ivosidenib, or a pharma- ceutically acceptable salt thereof, in any form, without the presence of polymer(s). In some embodiments, the solid dispersion has a relaxation rate lower than the relaxation rate of amorphous ivosidenib, or a pharma- ceutically acceptable salt thereof, in any form, without the presence of polymer(s).

[0179] Examples of polymers in solid dispersions include cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), also known as hypromellose, hydroxypropyl methylcellulose phthalate (HPMCP), also known as hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), also known as hypromellose acetate succinate, hydroxypropyl cellulose (HPC)), ethyl cellulose, or cellulose acetate phthalate; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA ... acrylates, such as polymethacrylates (e.g., Eudragit® E); cyclodextrins (e.g., beta-cyclodextrin); poly(D,L-lactide) (PLA), poly(D,L-lactide, co-glycolic acid (PLGA); and copolymers and derivatives thereof, including, for example, polyvinylpyrrolidone-vinyl acetate (PVP-VA), polyvinylcarrolactam-polyvinyl, and acetate-polyethylene glycol copolymers, methylacrylic acid / methacrylic acid copolymers; Soluplus; copovidone; and mixtures thereof.

[0180] In some embodiments, the solid dispersion comprises one water soluble polymer. In some embodiments, the solid dispersion comprises one partially water soluble polymer. In some embodiments, the polymer is a cellulose polymer.

[0181] In some embodiments, the polymer is HPMCAS (e.g., different grades of HPMCAS: HPMCAS-M, HPMCAS-MG, or HPMCAS-HG). In some embodiments, the polymer is PVAP. In some embodiments, the polymer is HPMC (e.g., different grades of HPMC: HMPC60SH50, HPMCE50, or HPMCE15). In some embodiments, the polymer is HPMCP (e.g., different grades of HPMCP: e.g., HMPCP-HP55).

[0182] In some embodiments, the polymer is a pH-dependent enteric polymer.Such pH-dependent enteric polymers include cellulose derivatives (e.g., cellulose acetate phthalate (CAP), HPMCP, HPMCAS, carboxymethylcellulose (CMC) or its salt (e.g., sodium salt such as (CMC-Na))); cellulose acetate trimelate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), polymethacrylic acid (e.g., Eudragit S), or mixtures thereof.

[0183] In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS), also known as hypromellose acetate succinate, e.g., HMPCAS-HG.

[0184] In another embodiment, the polymer(s) is an insoluble cross-linked polymer, such as polyvinylpyrrolidone (e.g., crospovidone). In another embodiment, the polymer(s) is polyvinylpyrrolidone (PVP).

[0185] In some embodiments, the one or more polymer(s) are present in the solid dispersion in an amount of about 10% w / w to 90% w / w (e.g., about 20% w / w to about 80% w / w, about 30% w / w to about 70% w / w, about 40% w / w to about 60% w / w, or about 15% w / w to about 35% w / w). In some embodiments, the polymer(s) are present in the solid dispersion in an amount of from about 10% w / w to about 80% w / w, e.g., from about 30% w / w to about 75% w / w, or from about 40% w / w to about 65% w / w, or from about 45% w / w to about 55% w / w, e.g., about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, or about 54% w / w. In some embodiments, the polymer(s) are present in the solid dispersion in an amount of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0186] In some embodiments, the polymer(s) are present in the solid dispersion in an amount of about 30% w / w to about 70% w / w. In some embodiments, the polymer(s) are present in the solid dispersion in an amount of about 35% w / w to about 65% w / w. In some embodiments, the polymer(s) are present in the solid dispersion in an amount of about 40% w / w to about 60% w / w. In some embodiments, the polymer(s) are present in the solid dispersion in an amount of about 45% w / w to about 55% w / w. In some embodiments, the polymer(s) are present in the solid dispersion in an amount of about 50% w / w.

[0187] In some embodiments, ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 10% w / w to about 90% w / w (e.g., about 20% w / w to about 80% w / w, about 30% w / w to about 70% w / w, about 40% w / w to about 60% w / w, or about 15% w / w to about 35% w / w). In some embodiments, ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 10% w / w to about 80% w / w, e.g., about 30% w / w to about 75% w / w, or about 40% w / w to about 65% w / w, or about 45% w / w to about 55% w / w, e.g., about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, or about 54% w / w. In some embodiments, ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w. In some embodiments, more than one polymorph of ivosidenib may be present. In some embodiments, a second molecule may be present.

[0188] In some embodiments, any solid form of ivosidenib, or a pharma- ceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 30% w / w to about 70% w / w. In some embodiments, any solid form of ivosidenib, or a pharma- ceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 35% w / w to about 65% w / w. In some embodiments, any solid form of ivosidenib, or a pharma- ceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 40% w / w to about 60% w / w. In some embodiments, any solid form of ivosidenib, or a pharma- ceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 45% w / w to about 55% w / w. In some embodiments, any solid form of ivosidenib, or a pharma- ceutically acceptable salt thereof, is present in the solid dispersion in an amount of about 50% w / w.

[0189] In another embodiment, the solid dispersion comprises about 20% w / w to about 80% w / w of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any solid form, and about 20% w / w to about 80% of the polymer(s). In another embodiment, the solid dispersion comprises about 25% w / w to about 75% w / w of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any solid form, and about 25% w / w to about 75% of the polymer(s). In another embodiment, the solid dispersion comprises about 30% w / w to about 70% w / w of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any solid form, and about 30% w / w to about 70% of the polymer(s). In another embodiment, the solid dispersion comprises about 35% w / w to about 65% w / w of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any solid form, and about 35% w / w to about 65% of the polymer(s). In another embodiment, the solid dispersion comprises about 40% w / w to about 60% w / w of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any solid form, and about 40% w / w to about 60% of the polymer(s). In another embodiment, the solid dispersion comprises about 45% w / w to about 55% w / w of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any solid form, and about 45% w / w to about 55% of the polymer(s). In another embodiment, the solid dispersion comprises about 50% w / w of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any solid form, and about 50% w / w of the polymer(s). In some embodiments, more than one polymorph of ivosidenib may exist. In some embodiments, a second molecule may exist.

[0190] In another embodiment, the solid dispersion comprises about 45% w / w to about 55% w / w of ivosidenib, in any solid form, or a pharma- ceutically acceptable salt thereof, and about 45% w / w to about 55% w / w of HPMCAS (e.g., HPMCAS-MG or HPMCAS-HG, or other grades such as LF, MF, HF, or LG) or PVAP. In another embodiment, the solid dispersion comprises about 50% w / w of ivosidenib, in any solid form, or a pharma- ceutically acceptable salt thereof, and about 50% w / w of HPMCAS.

[0191] In some embodiments, the solid dispersion also comprises a surfactant or an inert pharma- ceutically acceptable substance. In some embodiments, the solid dispersion comprises sodium lauryl sulfate (SLS), vitamin E or its derivatives (e.g., vitamin E TPGS), sodium docusate, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), poloxamers (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, Pluronic® copolymers (e.g., Pluronic F108, Pluronic P-123), and mixtures thereof. In some embodiments, the surfactant is SLS. In some embodiments, the surfactant is vitamin E or its derivatives (e.g., vitamin E TPGS).

[0192] In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.1% w / w to about 10% w / w, e.g., about 0.5% w / w to about 2% w / w, or about 1% w / w to about 3% w / w, or about 1% w / w to about 4% w / w, or about 1% w / w to about 5% w / w. In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, or about 1% w / w. In some embodiments, the surfactant is present in the solid dispersion in an amount of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, or about 5% w / w.

[0193] Process for preparing solid dispersions In some embodiments, solid dispersions may be prepared according to the process described herein. In general, methods that can be used include methods involving the rapid removal of a solvent or solvent mixture from a mixture or cooling of a molten sample. Such methods include, but are not limited to, rotary evaporation, lyophilization (i.e., freeze-drying), vacuum drying, melt congealing, and melt extrusion. One embodiment of the present disclosure includes solid dispersions obtained by spray drying. In one embodiment, the product obtained by spray drying is dried to remove the solvent or solvent mixture.

[0194] The preparations disclosed herein, e.g., pharmaceutical compositions, can be obtained by spray drying a mixture containing ivosidenib in any form, or its pharma- ceutically acceptable salt, one or more polymer(s), and a suitable solvent or solvent mixture. Spray drying involves, for example, atomization of a liquid mixture containing a solid and a solvent or solvent mixture, and removal of the solvent or solvent mixture. The solvent or solvent mixture can also contain a non-volatile solvent, such as glacial acetic acid. Atomization can be carried out, for example, through a two-fluid or pressure or electrosonic nozzle, or on a rotating disk.

[0195] Spray drying converts a liquid feed into a dry particulate form. Spray drying generally involves atomizing a liquid feed solution into a spray of droplets and contacting the droplets with hot air or gas in a drying chamber. The spray is generally produced by either a rotating (wheel) or nozzle atomizer. Evaporation of water from the droplets and formation of dry particles proceeds under controlled temperature and airflow conditions.

[0196] Optionally, a secondary drying process such as fluidized bed drying or vacuum drying may be used to reduce residual solvent (and other additives such as glacial acetic acid) to pharma- ceutically acceptable levels. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution (e.g., an atomized solution) with a sufficient volume of hot air or gas (e.g., nitrogen, e.g., pure nitrogen) to cause evaporation and drying of the liquid droplets. The preparation to be spray dried may be any solution, coarse suspension, slurry, colloidal dispersion, or paste that can be atomized using the selected spray drying equipment. In a standard procedure, the preparation is sprayed into a filtered warm air stream (or into a gas, e.g., nitrogen), which evaporates the solvent and conveys the dried product to a collector (e.g., a cyclone). The spent air or gas is then exhausted (e.g., then filtered) with the solvent (or solvent mixture with optional additives such as glacial acetic acid), or alternatively, the spent air or gas is sent to a condenser to capture and potentially recycle the solvent or solvent mixture. For example, when gas (e.g., nitrogen) is used, the gas is then optionally recycled, reheated, and returned to the unit in a closed loop system. Commercially available types of equipment can be used to perform spray drying. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray dryers manufactured by Niro).

[0197] Spray drying typically employs a solids loading of about 1% to about 30%, or up to about 50% of the material (i.e., therapeutically active compound plus excipients), preferably at least about 10%. In some embodiments, solids loadings less than 10% can result in low yields and unacceptably long run times. Generally, the upper limit of solids loading is controlled by the viscosity of the resulting solution (e.g., ability to pump) and the solubility of the components in the solution. Generally, the viscosity of the solution can determine the size of the particles in the resulting powder product.

[0198] Techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th Ed., RH Perry, DW Green & JO Maloney, eds., McGraw-Hill Book Co. (1984), and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). Generally, spray drying is carried out at an inlet temperature of about 40°C to about 200°C, e.g., about 70°C to about 150°C, preferably about 40°C to about 60°C, about 50°C to about 55°C, or about 80°C to about 110°C, e.g., about 90°C. Spray drying is generally carried out at an outlet temperature of about 20°C to about 100°C, for example, about 25°C to about 30°C (e.g., about 26°C), about 40°C to about 50°C, about 50°C to about 65°C, for example, about 56°C to about 58°C.

[0199] Removal of the solvent or solvent mixture may require a subsequent drying step, such as tray drying, fluidized bed drying (e.g., from about room temperature to about 100° C.), vacuum drying, microwave drying, rotary drum drying, or bi-cone vacuum drying (e.g., from about room temperature to about 200° C.).

[0200] In one embodiment, the spray drying is fluidized spray drying (FSD). The steps of FSD include, for example, preparing a liquid feed solution (e.g., containing ivosidenib in any form, or a pharma- ceutically acceptable salt thereof, and optionally polymer(s) and / or surfactant(s) dissolved or suspended in a solvent(s)), atomizing the feed solution (e.g., with a pressure nozzle, rotary atomizer or disk, two-fluid nozzle, or other atomization method) upon delivery to a drying chamber of a spray dryer (e.g., operating in FSD mode), and drying the feed solution in the drying chamber with heated air or heated gas (e.g., nitrogen) to produce a product (herein, a large amount of 100% ethanol). The method may include obtaining a product of large particles that precipitate, e.g., drop out, but fine particles are carried by air or gas flow (e.g., by natural convection) to the top of the drying chamber and into a cyclone, and reintroducing the fine particles into the drying chamber (e.g., at the top of the drying chamber or axially in the middle of the chamber), where the reintroduced fine particles can agglomerate with the newly formed product to produce an agglomerated product, which is precipitated if it is large enough, and if it is not large enough to precipitate, the agglomerated product is carried by convection to the top of the chamber and into the cyclone and reintroduced into the chamber. This process is repeated until an agglomerated product is formed that is large enough to drop out. The fine particles can be reintroduced into the drying chamber from the cyclone through a feed pipe.

[0201] In some embodiments, rather than drying the feed solution with heated air or heated gas, the feed solution can instead be spray-condensed, e.g., the chamber is at room temperature (e.g., 21±4° C.) or is cooled, e.g., a cooled gas (e.g., nitrogen) is used in the process.

[0202] The FSD may further include collecting the agglomerated product in the first fluidization chamber and subsequently discharging the agglomerated product from the first fluidization chamber to a second fluidization chamber where a post-drying process may occur.

[0203] The agglomerated product (e.g., precipitated in the drying chamber) can then be transferred from the second fluidization chamber to a third fluidization chamber where the agglomerated product is cooled. The agglomerated product (e.g., a solid dispersion of an amorphous compound) can then be further processed. For example, the product can be directly compressed. The product can optionally be blended with surfactants, excipients, or pharma- ceutically acceptable carriers, e.g., prior to direct compression. The product can optionally be further processed, e.g., milled, granulated, blended, and / or mixed with melt granules, surfactants, excipients, and / or pharma- ceutically acceptable carriers.

[0204] FSD can be carried out on commercial spray dryers operating in fluidized spray drying mode (FSD mode). FSD can be accomplished in either open cycle mode or closed cycle mode (e.g., dried gas, e.g., nitrogen, is recycled). Examples of suitable spray dryers for use in FSD include Niro dryers (e.g., PSD line of spray dryers manufactured by Niro: PHARMASD™, chemical or SD line dryers). FSD can be carried out on any spray dryer that is configured to reintroduce particulates into the drying chamber.

[0205] If necessary / applicable, additional post-drying can be carried out, for example in a vacuum or fluid bed dryer, or a double-cone or bi-cone post-dryer, or a rotary dryer, to remove further solvent. In some embodiments, a post-drying step is carried out.

[0206] Vacuum drying, spray drying, fluidized spray drying, tray drying, freeze drying, rotobapping, and other drying procedures may be applied to remove the solvent or solvent mixture. Application of any of these methods using appropriate processing parameters according to the present disclosure provides ivosidenib or a pharma- ceutically acceptable salt thereof in an amorphous state in the final solid dispersion product. The dispersion can be directly compressed into a dosage form upon use of appropriate conditions (e.g., low spray dryer outlet temperature, use of low boiling point solvents, use of heated gas) that result in a dry powder with desirable properties (e.g., median particle size (d50) of 40-200 microns (e.g., 40-150 microns), powder bulk density of greater than 0.2 g / ml (e.g., 0.2-0.5 g / ml) or greater than 0.25 g / ml, improved powder flowability (e.g., low cohesion, low interparticle internal friction); and / or a dry powder with low OVI (organic volatile impurities), e.g., below ICH limits and / or user specifications.

[0207] In some embodiments, the inlet temperature is from about 50°C to about 200°C, e.g., from about 60°C to about 150°C, from about 70°C to about 100°C, from about 60°C to about 95°C, from about 65°C to about 85°C, from about 70°C to about 90°C, from about 85°C to about 95°C, or from about 70°C to about 85°C.

[0208] In some embodiments, the outlet temperature is from about room temperature (e.g., USP room temperature (e.g., 21±4°C)) to about 80°C, e.g., from about 25°C to about 75°C, from about 30°C to about 65°C, from about 35°C to about 70°C, from about 40°C to about 65°C, from about 45°C to about 60°C, from about 35°C to about 45°C, from about 35°C to about 40°C, or from about 37°C to about 40°C.

[0209] In some embodiments, the temperature set point of the fluidized bed (the temperature of each bed selected independently from the temperature selected for another bed) is from about room temperature (e.g., USP room temperature (e.g., 21±4°C)) to about 100°C, e.g., from about 30°C to about 95°C, from about 40°C to about 90°C, from about 50°C to about 80°C, from about 60°C to about 85°C, from about 65°C to about 95°C, or from about 80°C to about 95°C.

[0210] FSD can be performed on a mixture containing a compound of interest (e.g., a therapeutic agent (e.g., a therapeutically active compound), such as ivosidenib in any form, or a pharma- ceutically acceptable salt thereof). For example, FSD can be performed on a mixture containing ivosidenib or a pharma- ceutically acceptable salt thereof (e.g., and one or more polymer(s), and optionally one or more surfactant(s), and optionally one or more additional excipient(s)) to obtain a solid dispersion of amorphous ivosidenib or a pharma- ceutically acceptable salt thereof, such as one that can be directly compressed into an oral dosage form (e.g., a tablet). Alternatively, the dispersion can be blended with one or more excipients prior to compression.

[0211] In one embodiment, the process for preparing a solid dispersion of an amorphous form or mixture of forms of ivosidenib comprises:

[0212] a) forming a mixture of ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, one or more polymer(s), and one or more solvent(s);

[0213] b) rapidly removing the solvent(s) from the solution to form a solid amorphous dispersion comprising ivosidenib, Form L alone or a mixture of forms, or a pharma- ceutically acceptable salt thereof, and one or more polymer(s). The one or more polymer(s) and one or more solvent(s) may be any of those disclosed herein.

[0214] In some embodiments of the process, more than one polymorph of ivosidenib may be present. In some embodiments, a second molecule may be present.

[0215] In some embodiments, the solvent is removed by spray drying. In some embodiments, the solid dispersion is tray dried using a convection tray dryer. In some embodiments, the solid dispersion is screened.

[0216] In one embodiment, ivosidenib or its pharmaceutically acceptable salt is crystalline.In another embodiment, ivosidenib or its pharmaceutically acceptable salt is amorphous.In some embodiments, two or more polymorphs of ivosidenib may exist.In some embodiments, a second molecule may exist.

[0217] As will be appreciated by those skilled in the art, spray drying may be performed, and is often performed, in the presence of an inert gas such as nitrogen. In certain embodiments, processes involving spray drying may be performed in the presence of a supercritical fluid with carbon dioxide or a mixture containing carbon dioxide.

[0218] In another embodiment, the process for preparing a solid dispersion of ivosidenib, or a pharma- ceutically acceptable salt thereof, in any form or mixture of forms, comprises:

[0219] a) forming a mixture of ivosidenib, in any form or mixture of forms, or a pharma- ceutically acceptable salt thereof, a polymer, and a solvent;

[0220] b) spray drying the mixture to form a solid dispersion comprising ivosidenib, or a pharma- ceutically acceptable salt thereof, in any form or mixture of forms, and a polymer.

[0221] Post-drying and / or polishing the wet spray dried dispersion to below a given specification for ICH or residual solvent can optionally be performed.

[0222] These processes can be used to prepare the pharmaceutical compositions disclosed herein. The amounts and characteristics of the ingredients used in the processes can be as disclosed herein.

[0223] In some embodiments, the solvent comprises one or more volatile solvent(s) for dissolving or suspending one or more forms of ivosidenib, or a pharma- ceutically acceptable salt thereof, and polymer(s). In some embodiments, the one or more solvent(s) completely dissolve such forms of ivosidenib, or a pharma- ceutically acceptable salt thereof, and polymer(s).

[0224] In some embodiments, the one or more solvent(s) is a volatile solvent (e.g., methylene chloride, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or mixtures thereof). Examples of suitable volatile solvents include solvents that dissolve or suspend the therapeutically active compound, either alone or in combination with another co-solvent. In some embodiments, the solvent(s) completely dissolves the therapeutically active compound. In some embodiments, the solvent is acetone. In some embodiments, the solvent is methanol.

[0225] In some embodiments, the solvent is a non-volatile solvent (e.g., an organic acid such as glacial acetic acid, dimethylsulfoxide (DMSO), dimethylformamide (DMF), or water). In some embodiments, the non-volatile solvent is a component in the solvent system. For example, the non-volatile solvent is present as a component in about 1% to about 20% w / w (e.g., about 3% w / w to about 15% w / w, about 4% w / w to about 12% w / w, or about 5% w / w to about 10% w / w) of the solvent.

[0226] In some embodiments, the solvent is a mixture of solvents. For example, the solvent can include about 0% to about 30% acetone and about 70% to about 100% methanol, or the solvent can include about 0% to about 40% acetone and about 60% to about 100% methanol. Other exemplary ratios of methanol to acetone include 80:20, 75:25, 70:30, 60:40, 55:45, and 50:50.

[0227] In some embodiments, the solvent is a combination of solvents including at least one non-volatile solvent. For example, the solvent is a combination of components including both volatile and non-volatile solvents. In some embodiments, the solvent system is a combination of a volatile solvent or a combination of solvents such as methanol and acetone, and a non-volatile solvent such as glacial acetic acid. For example, the solvent system includes about 40% to about 80% methanol, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (e.g., about 50% to about 70% methanol, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

[0228] In some embodiments, the solvent system is a volatile solvent or combination of solvents, such as methanol and acetone, combined with a non-volatile solvent, such as water. For example, the solvent system may include about 40% to about 80% methanol, about 20% to about 35% acetone, and about 0.1% to about 15% water (e.g., about 50% to about 70% methanol, about 25% to about 30% acetone, and about 1% to about 5% water).

[0229] Pharmaceutical Compositions A solid dispersion pharmaceutical composition may be made by the processes described herein, for example, a solid dispersion of (a) ivosidenib, or a pharma- ceutically acceptable salt thereof, in any of Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, and Form N, and (b) one or more polymer(s), and optionally one or more surfactant(s), and optionally one or more additional excipient(s).

[0230] Provided herein is a pharmaceutical composition comprising (a) ivosidenib, or a pharma- ceutically acceptable salt thereof, in any one of Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form M, and Form N, and (b) one or more pharma- ceutically acceptable carrier(s). Examples of pharma- ceutically acceptable carriers include fillers, disintegrants, wetting agents, lubricants, and lubricants. In some embodiments, two or more polymorphs of ivosidenib may be present in the pharmaceutical composition. In some embodiments, a second molecule may be present.

[0231] In some embodiments, the pharmaceutical compositions may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.

[0232] In some embodiments, the pharmaceutical composition is a tablet.

[0233] In some embodiments, the pharmaceutical composition comprises a direct compression dosage form of ivosidenib, or a pharma- ceutically acceptable salt thereof.

[0234] In some embodiments, the pharmaceutical composition also comprises a filler.The filler can be, for example, microcrystalline cellulose, lactose, mannitol, ethyl cellulose, sorbitol, starch, sucrose, calcium phosphate, powdered cellulose, silicified microcrystalline cellulose, isomalt, or a mixture thereof.In some embodiments, the filler is microcrystalline cellulose.

[0235] In some embodiments, the bulking agent is present in the pharmaceutical composition in an amount of about 10% w / w to about 50% w / w (e.g., about 15% w / w to about 45% w / w, about 20% w / w to about 40% w / w, about 25% w / w to about 35% w / w, or about 28% w / w to about 32% w / w). In some embodiments, the bulking agent is present in the pharmaceutical composition in an amount of about 20% w / w to about 35% w / w, e.g., about 25% w / w to about 34% w / w, or about 26% w / w to about 33% w / w, or about 27% w / w to about 32% w / w, e.g., about 28% w / w, about 28.5% w / w, about 29% w / w, about 29.5% w / w, about 30% w / w, about 30.5% w / w, about 31% w / w, or about 31.5% w / w. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 29% w / w, about 29.1% w / w, about 29.2% w / w, about 29.3% w / w, about 29.4% w / w, about 29.5% w / w, about 29.6% w / w, about 29.7% w / w, about 29.8% w / w, about 29.9% w / w, or about 30% w / w. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 25% w / w to about 35% w / w. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 29.5% w / w.

[0236] In some embodiments, the pharmaceutical composition also comprises a disintegrant.The disintegrant can be, for example, colloidal silicon dioxide, powdered cellulose, calcium silicate, crospovidone, calcium alginate, methylcellulose, chitosan, carboxymethylcellulose, croscarmellose sodium, carboxymethyl starch, sodium alginate, sodium starch glycolate, pregelatinized starch, or mixtures thereof.In some embodiments, the disintegrant is croscarmellose sodium.

[0237] In some embodiments, the disintegrant is present in the pharmaceutical composition in an amount of about 1% w / w to 15% w / w (e.g., about 3% w / w to about 12% w / w, about 4% w / w to about 10% w / w, about 5% w / w to about 7% w / w, or about 6% w / w to about 7% w / w). In some embodiments, the disintegrant is present in the pharmaceutical composition in an amount of about 3% w / w, about 3.5% w / w, about 4% w / w, about 49.5% w / w, about 5% w / w, about 5.5% w / w, about 6% w / w, or about 6.5% w / w, about 7% w / w, about 7.5% w / w, about 8% w / w, about 8.5% w / w, about 9% w / w, about 9.5% w / w, or about 10% w / w. In some embodiments, the disintegrant is present in the pharmaceutical composition in an amount of about 5% w / w to about 7% w / w, hi some embodiments, the disintegrant is present in the pharmaceutical composition in an amount of about 6% w / w.

[0238] In some embodiments, the pharmaceutical composition also includes a wetting agent. The wetting agent can be, for example, sodium lauryl sulfate, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), poloxamers (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, or mixtures thereof. In some embodiments, the wetting agent is sodium lauryl sulfate.

[0239] In some embodiments, the humectant is present in the pharmaceutical composition in an amount of about 0.1% w / w to 2% w / w (e.g., about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1.5% w / w, or about 1% w / w to about 1.5% w / w). In some embodiments, the wetting agent is present in the pharmaceutical composition in an amount of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, or about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, or about 2% w / w. In some embodiments, the wetting agent is present in the pharmaceutical composition in an amount of about 0.5% w / w to about 1.5% w / w. In some embodiments, the wetting agent is present in the pharmaceutical composition in an amount of about 1% w / w.

[0240] In some embodiments, the pharmaceutical composition also comprises a lubricant. The lubricant can be, for example, silicon dioxide, colloidal silicon dioxide, tribasic calcium phosphate, magnesium stearate, magnesium trisilicate, powdered cellulose, talc, starch, and mixtures thereof. In some embodiments, the lubricant is colloidal silicon dioxide.

[0241] In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% w / w to 5% w / w (e.g., about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, or about 1.5% w / w to about 2.5% w / w). In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, or about 4% w / w, about 4.5% w / w, or about 5% w / w. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, or about 3% w / w. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1% w / w to about 3% w / w. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 2% w / w.

[0242] In some embodiments, the pharmaceutical composition also includes a lubricant. The lubricant can be, for example, magnesium stearate, talc, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oil, zinc stearate, calcium stearate, sucrose stearate, polyvinyl alcohol, magnesium lauryl sulfate, or a mixture thereof. In some embodiments, the lubricant is magnesium stearate.

[0243] In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% w / w to 5% w / w (e.g., about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, or about 1% w / w to about 2% w / w). In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, or about 4% w / w, about 4.5% w / w, or about 5% w / w. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, or about 2.5% w / w. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% w / w to about 2.5% w / w, hi some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 1.5% w / w.

[0244] In some embodiments, the solid dispersion comprises about 25% to about 85% by weight of the total weight of the pharmaceutical composition. In some embodiments, the solid dispersion comprises about 50% to about 70% by weight of the total weight of the pharmaceutical composition.

[0245] In some embodiments, ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, comprises about 15%-45% of the total weight of the pharmaceutical composition, and the one or more polymer(s) comprise about 15%-45% of the total weight of the pharmaceutical composition.

[0246] In some embodiments, ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, comprises about 20% w / w of the pharmaceutical composition, and the one or more polymer(s) comprises about 40% w / w of the pharmaceutical composition.

[0247] In some embodiments, ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, comprises about 25% w / w of the pharmaceutical composition, and the one or more polymer(s) comprises about 35% w / w of the pharmaceutical composition.

[0248] In some embodiments, ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, comprises about 30% w / w of the pharmaceutical composition, and the one or more polymer(s) comprises about 30% w / w of the pharmaceutical composition.

[0249] In some embodiments, ivosidenib, in any form, or a pharma- ceutically acceptable salt thereof, comprises about 35% w / w of the pharmaceutical composition, and the one or more polymer(s) comprises about 25% w / w of the pharmaceutical composition.

[0250] In some embodiments, the solid dispersion comprises about 50% w / w to about 70% w / w of the pharmaceutical composition, the filler comprises about 25% w / w to about 35% w / w of the pharmaceutical composition, the disintegrant comprises about 5% w / w to about 7% w / w of the pharmaceutical composition, the wetting agent comprises about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, the lubricant comprises about 1% w / w to about 3% w / w of the pharmaceutical composition, and the lubricant comprises about 0.5% w / w to about 2.5% w / w of the pharmaceutical composition, totalling 100% by weight of the composition.

[0251] In some embodiments, the solid dispersion comprises about 60% w / w of the pharmaceutical composition, the filler comprises about 29.5% w / w, the disintegrant comprises about 6% w / w, the wetting agent comprises about 1% w / w, the glidant comprises about 2% w / w, and the lubricant comprises about 1.5% w / w.

[0252] In some embodiments, the pharmaceutical composition comprises about 25% w / w to about 35% w / w of ivosidenib in any form or a pharma- ceutically acceptable salt thereof, about 25% w / w to about 35% w / w of hypromellose acetate succinate (HPMCAS), about 25% w / w to about 35% w / w of microcrystalline cellulose, about 5% w / w to about 7% w / w of croscarmellose sodium, about 0.5% w / w to about 1.5% w / w of sodium lauryl sulfate, about 1% w / w to about 3% w / w of colloidal silicon dioxide, and about 0.5% w / w to about 2.5% w / w of magnesium stearate, totaling 100% by weight of the composition.

[0253] In some embodiments, the pharmaceutical composition comprises about 30% w / w ivosidenib or a pharma- ceutically acceptable salt thereof, about 30% w / w hypromellose acetate succinate (HPMCAS), about 29.5% w / w microcrystalline cellulose, about 6% w / w croscarmellose sodium, about 1% w / w sodium lauryl sulfate, about 2% w / w colloidal silicon dioxide, and about 1.5% magnesium stearate.

[0254] In some embodiments, the solid dispersion, filler, disintegrant, wetting agent, glidant, and lubricant are added intragranularly, in some embodiments, additional amounts of filler, disintegrant, glidant, and lubricant are added extragranularly.

[0255] In some embodiments, the pharmaceutical composition comprises the following intragranular additive components: a solid dispersion making up about 50% w / w to about 70% w / w of the pharmaceutical composition, a filler making up about 18% w / w to about 26% w / w of the pharmaceutical composition, a disintegrant making up about 2% w / w to about 6% w / w of the pharmaceutical composition, a wetting agent making up about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, a lubricant making up about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, and a lubricant making up about 0.25% w / w to about 1% w / w of the pharmaceutical composition.

[0256] In some embodiments, the pharmaceutical composition comprises the following extragranular additive components: an additional amount of a filler that constitutes from about 4% w / w to about 12% w / w of the pharmaceutical composition, an additional amount of a disintegrant that constitutes from about 1% w / w to about 3% w / w of the pharmaceutical composition, an additional amount of a lubricant that constitutes from about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, and an additional amount of a lubricant that constitutes from about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, which are added extragranularly.

[0257] In some embodiments, the pharmaceutical composition comprises the following intragranular additive components: a solid dispersion that constitutes about 60% w / w of the pharmaceutical composition, a filler that constitutes about 21.5% w / w of the pharmaceutical composition, a disintegrant that constitutes about 4% w / w of the pharmaceutical composition, a wetting agent that constitutes about 1% w / w of the pharmaceutical composition, a glidant that constitutes about 1% w / w of the pharmaceutical composition, and a lubricant that constitutes about 0.5% w / w of the pharmaceutical composition.

[0258] In some embodiments, the pharmaceutical composition comprises the following extragranular additive components: an additional amount of a filler that constitutes about 8% w / w of the pharmaceutical composition, an additional amount of a disintegrant that constitutes about 2% w / w of the pharmaceutical composition, an additional amount of a lubricant that constitutes about 1% w / w of the pharmaceutical composition, and an additional amount of a lubricant that constitutes about 1% w / w of the pharmaceutical composition, which are added extragranularly.

[0259] In some embodiments, the pharmaceutical composition comprises the following intragranular additive components: a solid dispersion comprising ivosidenib or a pharma- ceutically acceptable salt thereof, and hypromellose acetate succinate (HPMCAS), constituting about 50% w / w to about 70% w / w of the pharmaceutical composition; microcrystalline cellulose, constituting about 18% w / w to about 26% w / w of the pharmaceutical composition; croscarmellose sodium, constituting about 2% w / w to about 6% w / w of the pharmaceutical composition; sodium lauryl sulfate, constituting about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition; colloidal silicon dioxide, constituting about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition; and magnesium stearate, constituting about 0.25% w / w to about 1% w / w of the pharmaceutical composition.

[0260] In some embodiments, the pharmaceutical composition comprises the following extragranular additives: an additional amount of microcrystalline cellulose that constitutes between about 4% w / w and about 12% w / w of the pharmaceutical composition, an additional amount of croscarmellose sodium that constitutes between about 1% w / w and about 3% w / w of the pharmaceutical composition, an additional amount of colloidal silicon dioxide that constitutes between about 0.5% w / w and about 1.5% w / w of the pharmaceutical composition, and an additional amount of magnesium stearate that constitutes between about 0.5% w / w and about 1.5% w / w of the pharmaceutical composition, which are added extragranularly.

[0261] In some embodiments, the pharmaceutical composition comprises the following intragranular additive components: a solid dispersion comprising ivosidenib or a pharma- ceutical acceptable salt thereof, and hypromellose acetate succinate (HPMCAS), constituting about 60% w / w of the pharmaceutical composition, microcrystalline cellulose, constituting about 21.5% w / w of the pharmaceutical composition, croscarmellose sodium, constituting about 4% w / w of the pharmaceutical composition, sodium lauryl sulfate, constituting about 1% w / w of the pharmaceutical composition, colloidal silicon dioxide, constituting about 1% w / w of the pharmaceutical composition, and magnesium stearate, constituting about 0.5% w / w of the pharmaceutical composition.

[0262] In some embodiments, the pharmaceutical composition comprises the following extragranular additive components added extragranularly: an additional amount of microcrystalline cellulose that constitutes about 8% w / w of the pharmaceutical composition, an additional amount of croscarmellose sodium that constitutes about 2% w / w of the pharmaceutical composition, an additional amount of colloidal silicon dioxide that constitutes about 1% w / w of the pharmaceutical composition, and an additional amount of magnesium stearate that constitutes about 1% w / w of the pharmaceutical composition.

[0263] Subjects can be administered the dose of ivosidenib or its pharmaceutically acceptable salt in any form.Lower or higher doses than those listed above may be required.The specific dosage and treatment regimen for any specific subject depends on various factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, excretion rate, drug combination, disease, condition or symptom severity and course, subject's predisposition to disease, condition or symptom, and the judgment of the treating physician.

[0264] With the improvement of the condition of the subject, a maintenance dose of the compound, composition or combination of one aspect of the present invention can be administered as necessary.After that, when the condition is alleviated to a desired level, the dosage or frequency of administration, or both, can be reduced to a level that correlates with the condition and maintains the improved condition.However, the subject may require long-term intermittent treatment upon any recurrence of disease symptoms.

[0265] How to use The inhibitory activity of ivosidenib, in any form provided herein, and pharma- ceutically acceptable salts thereof, against IDH1 mutants (e.g., IDH1R132H or IDH1R132C) can be tested by the methods described in Example A of PCT Publication No. WO2013 / 107291 and U.S. Publication No. US2013 / 0190249, which are incorporated by reference in their entireties.

[0266] A method is provided for treating advanced solid tumors, such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each of which is characterized by the presence of a mutant allele of IDH1, comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) ivosidenib or a pharmaceutically acceptable salt thereof as part of a solid dispersion, and optionally (b) one or more pharmaceutically acceptable carrier(s). In one embodiment, the advanced solid tumors, such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), to be treated are characterized by a mutant allele of IDH1, and the IDH1 mutation provides a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate in the patient. In one aspect of this embodiment, the mutant IDH1 has an R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In another aspect, the R132X mutation is R132H or R132C. In yet another aspect, the R132X mutation is R132H. In such a treatment method, there may be two or more polymorphs of ivosidenib. In some embodiments, there may be a second molecule.

[0267] Advanced solid tumors, such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each of which is characterized by the presence of a mutant allele of IDH1, can be analyzed by sequencing cell samples to determine the presence and specific nature of a mutation at amino acid 132 of IDH1 (e.g., the altered amino acid present therein).

[0268] Without being bound by theory, the applicant believes that IDH1 mutations confer new enzymatic capabilities, and that mutant alleles of IDH1 that catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate, particularly the IDH1 R132H mutation, characterize a subset of all types of cancer, regardless of their cellular nature or location in the body. Thus, the compounds and methods of one aspect of the present invention are useful for treating advanced solid tumors, such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), characterized by the presence of mutant alleles of IDH1, particularly the IDH1 R132H or R132C variants, each of which confers such activity.

[0269] In one embodiment, the efficacy of treatment of advanced solid tumors such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each characterized by the presence of a mutant allele of IDH1, is monitored by measuring the level of 2HG in the subject. Typically, the level of 2HG is measured before treatment, and a high level indicates the use of ivosidenib or a pharma- ceutically acceptable salt thereof to treat advanced solid tumors such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each characterized by the presence of a mutant allele of IDH1. Once a high level is established, the level of 2HG is determined during and / or after the course of treatment to establish efficacy. In certain embodiments, the level of 2HG is determined only during and / or after the course of treatment. A reduction in the level of 2HG during and after the course of treatment indicates efficacy. Similarly, the determination that 2HG levels are not elevated during or after the course of treatment also indicates efficacy.Typically, these 2HG measurements are utilized in conjunction with other well-known determinations of the efficacy of cancer treatment, such as the reduction in the number and size of tumors and / or other cancer-related lesions, the evaluation of bone marrow biopsy and / or bone marrow aspirate, complete blood count, and peripheral blood smear examination, the improvement of the subject's general health, and changes in other biomarkers related to the efficacy of cancer treatment.

[0270] 2HG can be detected in a sample by the methods of PCT Publication No. WO / 2011 / 050210 and US Publication No. US2012 / 0121515, which are incorporated by reference herein in their entireties, or by analogous methods.

[0271] In one embodiment, the advanced solid tumor, such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), is a tumor in which at least 30, 40, 50, 60, 70, 80, or 90% of the tumor cells have an IDH1 mutation, particularly an IDH1 R132H or R132C mutation, at the time of diagnosis or treatment.

[0272] In another embodiment, the advanced solid tumor to be treated is a glioma and is characterized by the presence of a mutant allele of IDH1. In another embodiment, the glioma recurs after standard therapy. In another embodiment, the glioma progresses after standard therapy. In another embodiment, the glioma does not respond to standard therapy.

[0273] In another embodiment, the advanced solid tumor to be treated is IHCC and is characterized by the presence of a mutant allele of IDH1. In another embodiment, the IHCC recurs after standard therapy. In another embodiment, the IHCC progresses after standard therapy. In another embodiment, the IHCC does not respond to standard therapy.

[0274] In another embodiment, the advanced solid tumor being treated is a chondrosarcoma and is characterized by the presence of a mutant allele of IDH1. In another embodiment, the chondrosarcoma has recurred after standard therapy. In another embodiment, the chondrosarcoma has progressed after standard therapy. In another embodiment, the chondrosarcoma has not responded to standard therapy.

[0275] In another embodiment, the advanced solid tumor to be treated is prostate cancer and is characterized by the presence of a mutant allele of IDH1.In another embodiment, the prostate cancer recurs after standard treatment.In another embodiment, the prostate cancer progresses after standard treatment.In another embodiment, the prostate cancer does not respond to standard treatment.

[0276] In another embodiment, the advanced solid tumor to be treated is colon cancer and is characterized by the presence of a mutant allele of IDH1. In another embodiment, the colon cancer recurs after standard therapy. In another embodiment, the colon cancer progresses after standard therapy. In another embodiment, the colon cancer does not respond to standard therapy.

[0277] In another embodiment, the advanced solid tumor to be treated is melanoma and is characterized by the presence of a mutant allele of IDH1. In another embodiment, the melanoma recurs after standard therapy. In another embodiment, the melanoma progresses after standard therapy. In another embodiment, the melanoma does not respond to standard therapy.

[0278] In another embodiment, the advanced solid tumor to be treated is non-small cell lung cancer (NSCLC) and is characterized by the presence of a mutant allele of IDH1. In another embodiment, the non-small cell lung cancer (NSCLC) has recurred after standard therapy. In another embodiment, the non-small cell lung cancer (NSCLC) has progressed after standard therapy. In another embodiment, the non-small cell lung cancer (NSCLC) has not responded to standard therapy.

[0279] The treatment methods described herein may further include various evaluation steps prior to and / or after treatment with a pharmaceutical composition comprising (a) ivosidenib or a pharma- ceutically acceptable salt thereof as part of a solid dispersion, and, optionally, (b) one or more pharma- ceutically acceptable carrier(s).

[0280] In one embodiment, before and / or after treatment with a pharmaceutical composition comprising (a) ivosidenib or a pharma- ceutically acceptable salt thereof as part of a solid dispersion, and optionally (b) one or more pharma- ceutically acceptable carrier(s), the method further comprises assessing the growth, size, weight, invasiveness, stage, and / or other phenotype of an advanced solid tumor, such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each characterized by the presence of a mutant allele of IDH1.

[0281] In one embodiment, before and / or after treatment with a pharmaceutical composition comprising (a) ivosidenib or a pharma- ceutically acceptable salt thereof as part of a solid dispersion, and optionally (b) one or more pharma- ceutically acceptable carrier(s), the method further comprises assessing the IDH1 genotype of advanced solid tumors, such as glioma, intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each of which is characterized by the presence of a mutant allele of IDH1. This may be accomplished by methods routine in the art, such as DNA sequencing, immunoassay, and / or assessing the presence, distribution, or levels of 2HG. In one embodiment, the method further comprises determining 2HG levels in the subject before and / or after treatment with a pharmaceutical composition comprising (a) ivosidenib or a pharma- ceutically acceptable salt thereof as part of a solid dispersion, and optionally (b) one or more pharma- ceutically acceptable carrier(s). This can be accomplished by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and / or MRS measurements, sample analysis of bodily fluids such as blood, plasma, urine, or spinal fluid analysis, or analysis of surgical material, e.g., gravimetric spectroscopy (e.g., LC-MS, GC-MS), or any of the methods described herein.

[0282] Test compounds for the experiments described herein were used in free or salt form.

[0283] The particular response observed will vary according to and depending on the particular active compound selected, or whether the carrier is present, as well as the type of formulation and method of administration used, and such expected variations or differences in results are contemplated in accordance with the practice of the present invention.

[0284] Although specific embodiments of the present invention have been illustrated and described in detail herein, the present invention is not limited thereto. The above-described detailed description is provided as an example of the present invention and should not be construed as constituting any limitation of the present invention. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present invention are intended to be included within the scope of the appended claims.

[0285] The patents and scientific literatures referred to in this specification establish knowledge available to those skilled in the art.Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs.The issued patents, applications, and references cited in this specification are incorporated herein by reference as if each was specifically and individually indicated to be incorporated by reference.In the event of discrepancy, the present disclosure, including definitions, shall prevail.

Claims

1. Compound of formula (I) characterized by a powder X-ray diffraction pattern comprising peaks at 11.4±0.2°2θ, 17.7±0.2°2θ, 17.8±0.2°2θ, 19.7±0.2°2θ, and 21.4±0.2°2θ. 【Chemistry 11】 (Ivosidenib) anhydrous solid form (Form M).

2. The solid is 9.2±0.2°2θ, 10.1±0.2°2θ, 10.6±0.2°2θ, 11.4±0.2°2θ, 11.9±0.2°2θ, 12.5±0 .2°2θ, 13.1±0.2°2θ, 13.4±0.2°2θ, 14.4±0.2°2θ, 15.8±0.2°2θ, 17.2±0 .. 2°2θ, 17.7±0.2°2θ, 17.8±0.2°2θ, 18.5±0.2°2θ, 19.5±0.2°2θ, 19.7±0.2°2θ, 19.9±0 .2°2θ, 20.4±0.2°2θ, 20.9±0.2°2θ, 21.4±0.2°2θ, 22.0±0.2°2θ, 22.9± 0.2°2θ, 23.2±0.2°2θ, 24.6±0.2°2θ, 24.7±0.2°2θ, 25.0±0.2°2θ, 25.8±0.2°2θ, 26.2 ±0.2°2θ, 26.6±0.2°2θ, 27.0±0.2°2θ, 27.3±0.2°2θ, 27.8±0.2°2θ, 29.1±0.2°2θ, 29.7 2. The solid form M of claim 1, characterized by an X-ray powder diffraction pattern including peaks at: ±0.2°2θ, 30.3±0.2°2θ, 31.3±0.2°2θ, 31.9±0.2°2θ, 33.1±0.2°2θ, 33.6±0.2°2θ, 33.8±0.2°2θ, and 34.6±0.2°2θ (Form M).

3. The solid is: (a) TGA / DTA profile showing an endothermic event with an onset at 160.4° C. and a peak at 172.4° C.; (b) A DSC profile showing an endothermic event with an onset at 161.7° C. and a peak at 170.0° C. with an enthalpy of 32.0 mJ / mg.

2. The solid form M of claim 1, characterized by one or more of the following:

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