Crystalline solid of the MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and its use

Abstract

The present disclosure relates to a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) a pharmaceutical composition comprising one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and optionally one or more pharma- ceutical acceptable carriers; c) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; The present invention relates to a method for treating a tumor, cancer, or Rasopathy disorder by administering one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need of such treatment; and a method for producing essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

Description

Technical Field

[0001] The present disclosure relates to: a) a method for synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; c) a pharmaceutical composition comprising one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and optionally one or more pharmaceutically acceptable carriers; and a method for treating a tumor, cancer, or Rasopathy disorder by administering to a subject in need thereof one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

Background Art

[0002] N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide ("Mirdametinib" or "PD-0325901") is a small molecule drug designed to inhibit mitogen-activated protein kinase kinase 1 ("MEK1") and mitogen-activated protein kinase kinase 2 ("MEK2"). MEK1 and MEK2 are proteins that play crucial roles in the mitogen-activated protein kinase ("MAPK") signaling pathway. The MAPK pathway is essential for cell survival and proliferation, and overactivation of this pathway has been shown to lead to tumor development and growth. Mildametinib is a highly potent and specific allosteric non-ATP competitive inhibitor of MEK1 and MEK2. Thanks to its mechanism of action, mildametinib significantly inhibits the phosphorylation of extracellular regulatory MAP kinases ERK1 and ERK2, thereby resulting in impaired tumor cell growth both in vitro and in vivo. Furthermore, there is evidence that increased inflammatory cytokine-induced activity of MEK / ERK contributes to inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

[0003] The crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are described above. WO2002 / 006213 describes crystalline forms I and II. U.S. Patent No. 7,060,856 ("'856 Patent") describes a method for producing form IV. The '856 Patent shows that the material produced by this method was more than 90% form IV ('856 Patent, Example 1). The '856 Patent also states that differential scanning calorimetry ("DSC") of the produced material shows small peaks with the onset of melting at 110°C and then again at 117°C, consistent with a mixture of the two forms.

[0004] WO2006 / 134469 ("'469PCT Publication") also describes a method for synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. The '469PCT Publication reports that this method yields a product conforming to polymorphic form IV disclosed in U.S. Patent Application No. 10 / 969,681, issued as the '856 Patent.

[0005] Differences in the properties of different polymorphic forms can result in differences in effective dose or physical properties that affect the processability of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, caused by differences in solubility or bioavailability. Therefore, there is a need for compositions of polymorphic forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide for use in the treatment of tumors, cancer, or rasopathy disorders. [Brief explanation of the drawing]

[0006] [Figure 1A] Figure 1A shows the X-ray powder diffraction pattern ("XRPD") corresponding to the essentially pure crystalline form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. [Figure 1B] Figure 1B shows the thermogravimetric thermogram ("TGA") and differential scanning calorimetry thermogram ("DSC") corresponding to the essentially pure crystalline form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. [Figure 2A] Figure 2A shows the X-ray powder diffraction pattern ("XRPD") corresponding to crystal morphology V. [Figure 2B]Figure 2B shows the thermogravimetric thermogram ("TGA") and differential scanning calorimetry thermogram ("DSC") corresponding to crystal morphology V. [Figure 3A] Figure 3A is the XRPD corresponding to crystal morphology VI. [Figure 3B] Figure 3B shows DSC and TGA corresponding to crystal morphology VI. [Figure 4A] Figure 4A shows the XRPD corresponding to crystal morphology VII. [Figure 4B] Figure 4B shows DSC and TGA corresponding to crystal morphology VII. [Figure 5A] Figure 5A shows the XRPD corresponding to crystal morphology VIII. [Figure 5B] Figure 5B shows DSC and TGA corresponding to crystal morphology VIII. [Figure 6A] Figure 6A shows the XRPD corresponding to crystal morphology IX. [Figure 6B] Figure 6B shows DSC and TGA corresponding to crystal morphology IX. [Figure 7A] Figure 7A shows the XRPD corresponding to crystal morphology X. [Figure 7B] Figure 7B shows the DSC and TGA corresponding to crystal morphology X. [Figure 8A] Figure 8A shows the XRPD corresponding to crystal morphology XI. [Figure 8B] Figure 8B shows DSC and TGA corresponding to crystal morphology XI. [Figure 9A] Figure 9A shows the XRPD corresponding to crystal morphology XII. [Figure 9B] Figure 9B shows DSC and TGA corresponding to crystal morphology XII. [Figure 10A] Figure 10A shows the XRPD corresponding to crystal morphology XIII. [Figure 10B] Figure 10B shows DSC and TGA corresponding to crystal morphology XIII. [Figure 11A] Figure 11A shows the XRPD corresponding to crystal morphology IV and the overlaid XRPD corresponding to crystal morphology XIV. [Figure 11B] Figure 11B shows the DSC and TGA corresponding to crystalline form XIV. [Figure 12A] Figure 12A shows the XRPD corresponding to crystalline form XV. [Figure 12B] Figure 12B shows the DSC and TGA corresponding to crystalline form XV. [Figure 13A] Figure 13A shows the XRPD corresponding to crystalline form XVI. [Figure 13B] Figure 13B shows the DSC and TGA corresponding to crystalline form XVI. [Figure 14A] Figure 14A shows the XRPD corresponding to crystalline form XVII. [Figure 14B] Figure 14B shows the DSC and TGA corresponding to crystalline form XVII. [Figure 15A] Figure 15A shows the XRPD corresponding to crystalline form XVIII. [Figure 15B] Figure 15B shows the DSC and TGA corresponding to crystalline form XVIII. [Figure 16A] Figure 16A shows the XRPD corresponding to crystalline form XIX. [Figure 16B] Figure 16B shows the DSC and TGA corresponding to crystalline form XIX. [Figure 17A] Figure 17A shows the XRPD corresponding to crystalline form XX. [Figure 17B] Figure 17B shows the DSC and TGA corresponding to crystalline form XX. [Figure 18A] Figure 18A shows the XRPD corresponding to crystalline form XXI. [Figure 18B] Figure 18B shows the DSC and TGA corresponding to crystalline form XXI. [Figure 19A] Figure 19A shows the XRPD corresponding to crystalline form XXII. [Figure 19B] Figure 19B shows the DSC and TGA corresponding to crystalline form XXII. [Figure 20A] Figure 20A shows the XRPD corresponding to crystalline form XXIII. <00001​Figure 20B shows DSC and TGA corresponding to crystal morphology XXIII. [Figure 21A] Figure 21A shows the XRPD corresponding to crystal morphology XXIV. [Figure 21B] Figure 21B shows DSC and TGA corresponding to crystal morphology XXIV. [Figure 22A] Figure 22A shows the XRPD corresponding to amorphous mildametinib. [Figure 22B] Figure 22B shows the DSC and TGA corresponding to amorphous mildametinib. [Overview of the Initiative]

[0007] Crystalline form and amorphous solid This disclosure features compositions and methods useful for treating disorders involving abnormal MEK1 or MEK2 activity, such as cancer, tumors, or rasopathy disorders such as neurofibromatosis type 1, in subjects requiring such treatment. In some embodiments, this disclosure features novel polymorphic forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and methods for producing them using contaminated forms, such as a pure form IV substantially free of form I.

[0008] In some embodiments, the present disclosure features a novel method for synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. In some embodiments, the method for synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein is useful for producing pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide.

[0009] In some embodiments, the methods and compositions described herein are useful for treating patients who have difficulty swallowing whole capsules or tablets, for example, pediatric patients, or patients with dysphagia, for example, patients with esophageal cancer, Parkinson's disease, amyotrophic lateral sclerosis, stroke, achalasia, or esophageal stricture.

[0010] In some embodiments, the present disclosure provides a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I), [ka] These are selected from the following group: a) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4±0.2, 17.5±0.2, and 22.8±0.2 degrees 2θ; b) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2, and 21.2±0.2 degrees 2θ; c) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at 5.3±0.2, 10.6±0.2, and 16.1±0.2 degrees; d) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at 5.4±0.2, 10.7±0.2, and 18.7±0.2 degrees; e) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2, and 22.2±0.2 degrees 2θ; f) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 10.6±0.2, 19.6±0.2, and 24.8±0.2 degrees 2θ; g) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 5.5±0.2, 6.9±0.2, and 10.1±0.2 degrees at 2θ; h) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 10.1±0.2, 17.3±0.2, and 22.6±0.2 degrees 2θ; i) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2, and 14.6±0.2 degrees 2θ; j) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 4.6±0.2, 23.4±0.2, and 25.2±0.2 degrees 2θ; Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 5.5±0.2, 14.7±0.2, and 20.9±0.2 degrees 2θ; l) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at 6.0±0.2, 17.1±0.2, and 20.6±0.2 degrees; Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 5.9±0.2, 10.1±0.2, and 15.5±0.2 degrees 2θ; n) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at 4.6±0.2, 10.7±0.2, and 15.9±0.2 degrees; o) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having 2θ peaks at 10.2±0.2, 11.6±0.2, and 20.0±0.2 degrees; Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at p)7.8±0.2, 14.0±0.2, and 17.1±0.2 degrees; q) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2, and 16.7±0.2 degrees at 2θ; The crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2, and 29.1±0.2 degrees at 2θ; The crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having 2θ peaks at 5.4±0.2, 9.7±0.2, and 10.7±0.2 degrees; and The crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2, and 23.0±0.2 degrees 2θ.

[0011] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4±0.2, 17.5±0.2, and 22.8±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 2A.

[0012] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 2.7% by weight from approximately 35°C to approximately 100°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 77°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 95°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 77°C and a second endothermic initiation at approximately 95°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 2B, and / or b) a DSC profile substantially as shown in Figure 2B.

[0013] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form V.

[0014] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2, and 21.2±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 3A.

[0015] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 2.4% by weight from approximately 25°C to approximately 125°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 41°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 70°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 109°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 41°C and endothermic initiation at approximately 70°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 41°C and endothermic initiation at approximately 109°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 70°C and an endothermic initiation at approximately 109°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 41°C, a second endothermic initiation at approximately 70°C, and a third endothermic initiation at approximately 109°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 3B, and / or b) a DSC profile substantially as shown in Figure 3B.

[0016] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form VI.

[0017] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2, and 16.1±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 4A.

[0018] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 5.2% by weight from approximately 40°C to approximately 120°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 85°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic event at approximately 110°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 85°C and a second endothermic event at approximately 110°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 4B, and / or b) a DSC profile substantially as shown in Figure 4B.

[0019] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form VII.

[0020] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2, and 18.7±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2, 18.7±0.2, and 23.9±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 5A.

[0021] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 3.3% by weight from approximately 40°C to approximately 112°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 81°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 110°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 81°C and a second endothermic initiation at approximately 110°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 5B, and / or b) a DSC profile substantially as shown in Figure 5B.

[0022] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form VIII.

[0023] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2, and 22.2±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 6A.

[0024] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 4.6% by weight from approximately 28°C to approximately 128°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 84°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 107°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 84°C and endothermic initiation at approximately 107°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 84°C and endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 107°C and an endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 84°C, a second endothermic initiation at approximately 107°C, and a third endothermic initiation at approximately 114°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 6B, and / or b) a DSC profile substantially as shown in Figure 6B.

[0025] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form IX.

[0026] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.6±0.2, 19.6±0.2, and 24.8±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 10.6±0.2, 19.6±0.2, and 24.8±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 7A.

[0027] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 2.9 wt% from about 40°C to about 115°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at about 89°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 7B, and / or b) a DSC profile substantially as shown in Figure 7B.

[0028] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form X.

[0029] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2, and 10.1±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2, 10.1±0.2, and 19.2±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 8A.

[0030] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 40°C to approximately 175°C, with a loss of approximately 7.6% by weight. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 69°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 104°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 69°C and a second endothermic initiation at approximately 104°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 8B, and / or b) a DSC profile substantially as shown in Figure 8B.

[0031] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XI.

[0032] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2, and 22.6±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 9A.

[0033] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 8.5% by weight from approximately 40°C to approximately 160°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 72°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 109°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 72°C and a second endothermic initiation at approximately 109°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 9B, and / or b) a DSC profile substantially as shown in Figure 9B.

[0034] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XII.

[0035] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2, and 14.6±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 10A.

[0036] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 3.1% by weight from approximately 20°C to approximately 100°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 55°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 109°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 55°C and a second endothermic initiation at approximately 109°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 10B, and / or b) a DSC profile substantially as shown in Figure 10B.

[0037] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XIII.

[0038] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2, and 25.2±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2, 25.2±0.2, and 30.6±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 11A.

[0039] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 0.15 wt% from about 40°C to about 150°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at about 111°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 11B, and / or b) a DSC profile substantially as shown in Figure 11B.

[0040] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XIV.

[0041] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2, and 20.9±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2, 20.9±0.2, and 26.6±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 12A.

[0042] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 3.8 wt% from about 40°C to about 150°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with endothermic initiation at about 104°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 12B, and / or b) a DSC profile substantially as shown in Figure 12B.

[0043] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XV.

[0044] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.0±0.2, 17.1±0.2, and 20.6±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 13A.

[0045] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 2.1% by weight from approximately 40°C to approximately 150°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 74°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 74°C and endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 74°C and endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 102°C and an endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 74°C, a second endothermic initiation at approximately 102°C, and a third endothermic initiation at approximately 114°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 13B, and / or b) a DSC profile substantially as shown in Figure 13B.

[0046] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XVI.

[0047] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2, and 15.5±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 14A.

[0048] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 2.7 wt% from about 40°C to about 100°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with endothermic initiation at about 89°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 14B, and / or b) a DSC profile substantially as shown in Figure 14B.

[0049] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XVII.

[0050] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2, and 15.9±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2, 15.9±0.2, and 19.6±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 15A.

[0051] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 1.6% by weight from about 30°C to about 150°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at about 83°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 15B, and / or b) a DSC profile substantially as shown in Figure 15B.

[0052] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XVIII.

[0053] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2, and 20.0±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 16A.

[0054] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 1.85% by weight from approximately 23°C to approximately 92°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 69°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 98°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 115°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 69°C and endothermic initiation at approximately 98°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 69°C and endothermic initiation at approximately 115°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 98°C and an endothermic initiation at approximately 115°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 69°C, a second endothermic initiation at approximately 98°C, and a third endothermic initiation at approximately 115°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 16B, and / or b) a DSC profile substantially as shown in Figure 16B.

[0055] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XIX.

[0056] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2, and 17.1±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 17A.

[0057] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 2.6% by weight from approximately 29°C to approximately 126°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 77°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 92°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 110°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 77°C and endothermic initiation at approximately 92°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 77°C and endothermic initiation at approximately 110°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 92°C and an endothermic initiation at approximately 110°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 77°C, a second endothermic initiation at approximately 92°C, and a third endothermic initiation at approximately 110°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 17B, and / or b) a DSC profile substantially as shown in Figure 17B.

[0058] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XX.

[0059] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2, and 16.7±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2, 16.7±0.2, and 17.7±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 18A.

[0060] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 30°C to approximately 110°C, with a loss of approximately 14.1% by weight. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 52°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 90°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 52°C and a second endothermic initiation at approximately 90°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 18B, and / or b) a DSC profile substantially as shown in Figure 18B.

[0061] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XXI.

[0062] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2, and 29.1±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 19A.

[0063] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 13.8% by weight from approximately 26°C to approximately 135°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 65°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 89°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 65°C and endothermic initiation at approximately 89°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 65°C and endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 89°C and an endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 65°C, a second endothermic initiation at approximately 89°C, and a third endothermic initiation at approximately 102°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 19B, and / or b) a DSC profile substantially as shown in Figure 19B.

[0064] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XXII.

[0065] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4±0.2, 9.7±0.2, and 10.7±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 20A.

[0066] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 4.4% by weight from approximately 27°C to approximately 137°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 81°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 101°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 81°C and a second endothermic initiation at approximately 101°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 20B, and / or b) a DSC profile substantially as shown in Figure 20B.

[0067] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XXIII.

[0068] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2, and 23.0±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 21A.

[0069] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 1.2% by weight from about 30°C to about 119°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at about 104°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 21B, and / or b) a DSC profile substantially as shown in Figure 21B.

[0070] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XXIV.

[0071] In some embodiments, the present disclosure provides an amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I). [ka]

[0072] In some embodiments, the amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 22A.

[0073] In some embodiments, the amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 22B, and / or b) a DSC profile substantially as shown in Figure 22B.

[0074] In some embodiments, the XRPD pattern is configured such that (a) on the incident beam side: a variable divergence slit (irradiation length of 10 mm), a 0.04 rad solar slit, a fixed anti-scattering slit (0.50°), and a 10 mm beam mask, and (b) on the diffracting beam side: a variable anti-scattering slit (observed length of 10 mm) and a 0.04 rad solar slit, using Ni-filtered CuKα (45 kV / 40 mA) emission with an X'CELERATOR® Real Time Multi-Strip detector and a step size of 0.03°²θ, PANALYTICAL® X'Pert The samples are generated using a Pro diffractometer or using a BRUKER® D8® ADVANCE® system with a LYNXEYE® detector, configured (a) on the incident beam side as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° solar slit, beam knife, and (b) on the diffracted beam side as follows: anti-scattering slit (8 mm) and 2.5° solar slit, with CuKα (40 kV / 40 mA) emission and a step size of 0.03°2θ, and the samples are mounted flat on a zero-background Si wafer. In some embodiments, the DSC patterns are generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature rise rate of approximately 15°C / min.

[0075] Pharmaceutical composition In some embodiments, the present disclosure aims to provide a pharmaceutical composition (e.g., a capsule, tablet, powder, granule, minitablet, or pellet) comprising the crystalline or amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, and one or more pharmaceutically acceptable carriers.

[0076] In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is in solid dosage form. In some embodiments, the pharmaceutical composition is in the form of capsules, tablets (e.g., dispersible tablets or orally dispersible tablets), powders (e.g., dispersible powders), granules (e.g., dispersible granules), minitablets (e.g., dispersible minitablets), or pellets (e.g., dispersible pellets). In some embodiments, the pharmaceutical composition is in the form of tablets (e.g., dispersible tablets or orally dispersible tablets) or capsules.

[0077] In some embodiments, the pharmaceutical composition is a capsule. In some embodiments, the capsule contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the capsule are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, (d) 0 wt / wt% to about 5 wt / wt% of one or more lubricants, and (e) a gelatin capsule enclosing components (a) to (d). In some embodiments, the capsule contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the capsule are as follows: (a) about 0.25 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, (d) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants, and (e) a gelatin capsule enclosing components (a) to (d).

[0078] In some embodiments, the capsule contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the capsule are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, (d) 0 wt / wt% to about 5 wt / wt% of one or more lubricants, and (e) a gelatin capsule enclosing components (a) to (d). In some embodiments, the capsule contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the capsule are as follows: (a) about 0.25 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, (d) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants, and (e) a gelatin capsule enclosing components (a) to (d).

[0079] In some embodiments, the capsule contains about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the capsule are as follows: (a) about 2.5 wt / wt% to about 7.0 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, and (d) a gelatin capsule enclosing components (a) to (c). In some embodiments, the capsule contains about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the capsule are as follows: (a) about 2.5 wt / wt% to about 7.0 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, and (d) a gelatin capsule enclosing components (a) to (c).

[0080] In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the tablet contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the components of the tablet being: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, and (d) 0 wt / wt% to about 5 wt / wt% of one or more lubricants. In some embodiments, the tablet contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the components of the tablet being as follows: (a) about 0.25 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, and (d) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants.

[0081] In some embodiments, the tablet contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the components of the tablet being: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, and (d) 0 wt / wt% to about 5 wt / wt% of one or more lubricants. In some embodiments, the tablet contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the components of the tablet being as follows: (a) about 0.25 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, and (d) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants.

[0082] In some embodiments, the tablet contains about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the components of the tablet being: (a) about 2.5 wt / wt% to about 7.0 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, and (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants. In some embodiments, the tablet contains about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the components of the tablet being: (a) about 2.5 wt / wt% to about 7.0 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous solid form, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, and (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants.

[0083] In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is dispersible orally.

[0084] In some embodiments, the pharmaceutical composition is in the form of tablets, powders, granules, minitablets, or pellets (also called beads).

[0085] In some embodiments, the pharmaceutical composition is a powder. In some embodiments, the pharmaceutical composition is a dispersible powder. In some embodiments, the capsule or sachet contains a dispersible powder.

[0086] In some embodiments, the pharmaceutical composition is in the form of granules. In some embodiments, the granules are dispersible granules. In some embodiments, the capsule or sachet contains dispersible granules.

[0087] In some embodiments, the pharmaceutical composition is in the form of a mini-tablet. In some embodiments, the mini-tablet is a dispersible mini-tablet. In some embodiments, the capsule or sachet contains a dispersible mini-tablet.

[0088] In some embodiments, the pharmaceutical composition is in the form of pellets. In some embodiments, the pellets are dispersible pellets. In some embodiments, the capsules or sachets contain dispersible pellets.

[0089] In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the tablet is a dispersible tablet. In some embodiments, the tablet is an orally dispersible tablet.

[0090] In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet contains about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the pharmaceutical composition are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy) Xypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0091] In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet contains about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the pharmaceutical composition are as follows: (a) about 0.2 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b) roxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 75% to about 98% by weight, (d) one or more disintegrants in an amount of about 3% to about 8% by weight, (e) one or more flavoring agents in an amount of 0% to about 5% by weight, (e) one or more sweeteners in an amount of 0% to about 5% by weight, and (f) one or more lubricants in an amount of 0% to about 5% by weight.

[0092] In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet contains about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the components of the pharmaceutical composition are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxy (b) propoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 85% by weight to about 95% by weight, (d) one or more disintegrants in an amount of about 3.5% by weight to about 6% by weight, (e) one or more flavorings in an amount of 0% by weight to about 2.5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 2% by weight, and (f) one or more lubricants in an amount of about 0.5% by weight to about 2% by weight.

[0093] In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet contains about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. In some embodiments, a pharmaceutical composition contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet contains about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. In some embodiments, a pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet contains about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide.

[0094] In some embodiments, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate. In some embodiments, at least one of the diluents is microcrystalline cellulose.

[0095] In some embodiments, at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and alginic acid. In some embodiments, at least one of the disintegrants is croscarmellose sodium.

[0096] In some embodiments, at least one of the flavorings is selected from the group consisting of natural or synthetic flavors, including but not limited to grape flavor, bubblegum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor. In some embodiments, at least one of the flavorings is grape flavor.

[0097] In some embodiments, at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some embodiments, at least one of the sweeteners is sucralose.

[0098] In some embodiments, at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc. In some embodiments, at least one of the lubricants is magnesium stearate.

[0099] Treatment method In some embodiments, the present disclosure provides a method for treating a tumor, cancer, or rasopathy disorder, comprising administering a pharmaceutical composition described herein (e.g., a capsule, tablet, powder, granules, minitablet, or pellet) to a subject in need of such treatment.

[0100] In some embodiments, the present disclosure provides the use of the pharmaceutical compositions described herein (e.g., capsules, tablets, powders, granules, minitablets, or pellets) for the manufacture of pharmaceuticals for the treatment of tumors, cancer, or rasopathy disorders.

[0101] In some embodiments, the tumor is a neurofibroma. In some embodiments, the tumor is a neurofibroma associated with neurofibromatosis type 1. In some embodiments, the tumor is selected from the group consisting of cutaneous neurofibromas, plexiform neurofibromas, optic tract gliomas, low-grade gliomas, high-grade gliomas, or malignant peripheral nerve sheath tumors. In some embodiments, the tumor is a plexiform neurofibroma.

[0102] In some aspects, subjects are diagnosed with rasopathy, selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardiac-facial-cutaneous syndrome, Costello syndrome, Regius syndrome, Noonan syndrome, and Noonan syndrome with lentigo multiplica.

[0103] In some embodiments, cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial carcinoma, uterine tumor, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer, and serous carcinoma of the peritoneum. In some embodiments, leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. In some embodiments, lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, small lymphocytic lymphoma, and Waldenström macroglobulinemia. In some embodiments, lung cancer is selected from the group consisting of lung adenocarcinoma, squamous cell non-small cell lung cancer, non-squamous cell non-small cell lung cancer, and small cell lung cancer.

[0104] In some embodiments, the subjects have mutations or other abnormalities in one or more genes that cause the acquisition or loss of function characteristic of a particular cancer, and the mutations or other abnormalities in one or more genes are mutations or other abnormalities in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0105] In some embodiments, individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are administered as two or more capsules, two or more tablets (e.g., dispersible tablets), two or more doses of powder (e.g., dispersible powder), two or more doses of granules (e.g., dispersible granules), two or more doses of minitablets (e.g., dispersible minitablets), two or more doses of pellets (e.g., dispersible pellets), or a combination thereof.

[0106] In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, and the pharmaceutical composition is dispersed in a beverage liquid before being administered to a subject. For example, a dose of 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide may be administered as two dispersible tablets—one containing 2 mg and the other containing 1 mg—or as three dispersible tablets, each containing 1 mg. As another example, a 1.5 mg dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide may be administered as a dispersible dosage form containing 1 mg in one dispersible tablet and 0.5 mg in separate units of dispersible powder, or as three units of dispersible powder, each containing 0.5 mg.

[0107] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 6 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

[0108] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is approximately 0.1 mg to approximately 20 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is approximately 0.5 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is approximately 1 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is approximately 2 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is approximately 4 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is approximately 6 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is approximately 8 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered at approximately 20 mg.

[0109] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily.

[0110] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 0.1 mg to approximately 10 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 0.5 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 1 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 2 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 3 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 4 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 10 mg each.

[0111] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily in doses ranging from approximately 0.1 mg to approximately 20 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily in doses ranging from approximately 0.5 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 1 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 2 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 4 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 8 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 10 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 20 mg.

[0112] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 6 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 4 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

[0113] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) 21 days in which the total daily dose is administered, and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) 21 consecutive days in which the total daily dose is administered, followed by (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered.

[0114] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) three 7-day periods, each comprising (i) five days in which the total daily dose is administered and (ii) two days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered, and (b) seven days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) three 7-day periods, each comprising (i) five consecutive days in which the total daily dose is administered and (ii) two consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered, followed by (b) seven consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered.

[0115] In some embodiments, the 28-day administration cycle is repeated up to a total of 24 consecutive 28-day administration cycles.

[0116] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle, including 28 days in which the total daily dose is administered.

[0117] In some aspects, the subjects experience dysphagia. In some aspects, the subjects experience dysphagia caused by one or more of the following: neurological disorders, muscle weakness, developmental disorders, stroke, trauma, anatomical defects, cancer, cancer treatment, allergic reactions, dementia, memory loss, or cognitive decline.

[0118] In some aspects, the target population is children.

[0119] Preparation method for N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and essentially pure form IV A novel method for producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I), [ka] A method is disclosed herein, as shown in Scheme I below, which involves reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent which is 1-propylphosphonic anhydride ("T3P") to obtain 901 acetonide. Scheme 1 [ka]

[0120] In some embodiments, T3P is in a solution. In some embodiments, T3P is provided as a solution in ethyl acetate.

[0121] In some embodiments, a method for producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I) in an essentially pure form IV comprises (a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent, T3P, to obtain 901 acetonide, and (b) treating 901 acetonide with an acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, as shown in Scheme II below. Scheme II [ka]

[0122] In some embodiments, the synthesis of the essentially pure crystalline form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I) involves the reaction described according to scheme III. Scheme III [ka]

[0123] In some embodiments, the synthesis of the essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I) is shown below in scheme IV. Scheme IV [ka]

[0124] In some embodiments, the methods provided herein provide a crystalline composition which is essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and contains ≤0.2% of the dimeric impurity PF-00191189. [ka]

[0125] In some embodiments, the crystalline composition contains about 0.05% to about 0.19% by weight of the dimerized impurity PF-00191189. In some embodiments, the crystalline composition does not contain any detectable amount of the dimerized impurity PF-00191189.

[0126] definition To facilitate understanding of the disclosures contained herein, several terms are defined below.

[0127] In general, the technical terms used herein, as well as the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein, are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.

[0128] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include multiple referents unless the context clearly indicates otherwise. The terms “a” (or “an”), as well as “one or more” and “at least one,” may be used interchangeably herein. In certain embodiments, the terms “a” or “an” mean “single.” In other embodiments, the terms “a” or “an” include “two or more” or “multiple.”

[0129] Furthermore, as used herein, “and / or” should be interpreted as the specific disclosure of each of the two specified features or components, with or without others. Accordingly, the term “and / or” as used in phrases such as “A and / or B” is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0130] The terms "mildametinib" and "PD-0325901" refer to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide.

[0131] The term "subject" refers to animals including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein to refer to mammalian subjects, such as human subjects.

[0132] The term "children" refers to human subjects under 21 years of age at the time of treatment. The term "children" can be further divided into various subgroups, including neonates (from birth to 28 days old), infants (from 29 days old to under 2 years old), children (2 years old to under 12 years old), and adolescents (12 years old to 21 years old (up to their 22nd birthday, excluding their 22nd birthday)). See, for example, Berhman RE, Kliegman R, Arvin AM, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WBSaunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In particular, young children, including newborns, infants, and toddlers, may have difficulty swallowing the entire capsule or tablet.

[0133] As used herein, the term “dispersible” refers to a composition (e.g., tablets, powders, granules, minitablets, or pellets (also known as “beads”)) that disintegrates and / or dissolves with or without stirring or temperature changes when combined with water or another beverage liquid (e.g., a non-aqueous beverage) or with the subject’s own saliva when placed in the subject’s mouth. In some embodiments, a dispersible composition disintegrates or dissolves within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute after being combined with water or another beverage liquid. Such disintegration or dissolution does not need to be complete. For example, a dispersible tablet may dissolve almost completely, but some undissolved particulate matter may remain.

[0134] The term "oral dispersible" refers to a composition that, when administered orally, can dissolve or disintegrate in the mouth of the subject (i.e., in the saliva of the subject) without requiring it to first dissolve or disintegrate in a separate container.

[0135] As used herein, the terms “treat,” “treated,” and “treating” mean both therapeutic measures and preventive or protective measures aimed at preventing or slowing (mitigating) an undesirable physiological condition, disorder, or disease, or obtaining a beneficial or desired clinical outcome. Therefore, those requiring treatment include those already diagnosed with or suspected of having a disorder. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, whether detectable or undetectable; reduction of the severity of a condition, disorder, or disease; stabilization (i.e., non-worsening) of a condition, disorder, or disease; delay or slowing of the onset of progression of a condition, disorder, or disease; improvement or remission (partial or complete) of the condition, disorder, or disease; improvement of at least one measurable physical parameter not necessarily identifiable by the patient; or enhancement or improvement of a condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes extending survival compared to the predicted survival without treatment. The term “therapeutically effective dose” means an amount of a compound that, when administered, is sufficient to prevent or, to some extent, alleviate the onset of one or more symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective dose” also refers to an amount of a compound that is sufficient to elicit a biological or medical response in a cell, tissue, system, animal, or human being being sought by a researcher, veterinarian, physician, or clinician.

[0136] In certain embodiments, a subject is considered to have successfully “treated” the tumor if the patient exhibits one or more of the following: reduction in tumor size; relief of one or more symptoms associated with a particular tumor; reduction in tumor volume; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), reduction in progressive disease (PD), increased time to progression (TTP), or any combination thereof. In some embodiments, it may be determined whether an effective dose of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR) using nationally or internationally accepted criteria for treatment outcomes in a given tumor.

[0137] In certain embodiments, a patient is considered to have successfully “treated” cancer, e.g., lung cancer or ovarian cancer, in accordance with the methods disclosed herein, if the patient exhibits one or more of the following: a reduction or complete absence of cancer cells; relief of one or more symptoms associated with a particular cancer; a reduction in morbidity and mortality; an improvement in quality of life; an increase in progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), a complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a reduction in progressive disease (PD), an increase in time to progression (TTP), or any combination thereof. In some embodiments, it may be determined whether an effective dose of mirdametinib meets any of these specific endpoints (e.g., CR, PFS, PR) using nationally or internationally accepted criteria for treatment outcomes in a given cancer.

[0138] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid excipient, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical preparation, is suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and is commensurate with a reasonable benefit-risk ratio. Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005, Handbook of Pharmaceutical Excipients, 5 th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005, and Handbook of Pharmaceutical Additives, 3 rdSee Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference). Examples of excipients include anti-adhesion agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, fragrances, aromas, flow accelerators (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending agents or dispersants, sweeteners, and water hydrates. Examples of excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, calcium sulfate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0139] The term "pharmaceutical composition," as used herein, refers to a composition containing a compound described herein, formulated with one or more pharmaceutically acceptable excipients (carriers), which may be manufactured or marketed with the approval of a government regulatory body as part of a therapeutic regimen for the treatment of diseases in mammals. Pharmaceutical compositions may be formulated for oral administration, for example, in unit dosage forms (e.g., tablets (e.g., dispersible tablets), powders (e.g., dispersible powders), capsules, granules, minitablets, pellets, caplets, gel caps, or syrups).

[0140] The terms “about” or “approximately” mean that a particular value is within a tolerance range determined by those skilled in the art, which depends in part on how that value is measured or determined. In some embodiments, the terms “about” or “approximately” mean within 1, 2, 3, or 4 standard deviations. In some embodiments, the terms “about” or “approximately” mean a quantity, level, value, number, frequency, percentage, dimension, size, volume, weight, or length that varies by about 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% relative to a reference quantity, level, value, number, frequency, percentage, dimension, size, volume, weight, or length.

[0141] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation containing a compound as described herein) to a subject or system. Administration to animal subjects (e.g., humans) may be by any suitable route, such as those described herein.

[0142] The term "solvate" refers to a compound or salt thereof provided herein, further comprising a stoichiometric or non-stoichiometric amount of a solvent bonded by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. When the solvent contains ethanol, the compound may be an ethanol solvate.

[0143] As used herein, the term "crystalline" refers to a solid form consisting of an ordered arrangement of structural units. Different crystalline forms of the same compound, or their salts, hydrates, or solvates, arise from different molecular packing in the solid state, which results in different crystal symmetries and / or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. For example, Remington's Pharmaceutical Sciences, 18 th ed.,Mack Publishing,Easton PA,173(1990);The United States Pharmacopeia,23 rd See ed., 1843–1844 (1995) (incorporated herein by reference).

[0144] Crystal morphology is generally characterized by powder X-ray diffraction (XRPD). The XRPD pattern of reflections (peaks, typically represented by 2°θ) is generally considered a fingerprint of a particular crystal morphology. The relative intensity of XRPD peaks can vary widely, particularly depending on the sample preparation technique, crystal size distribution, filters, sample mounting procedure, and the specific instrument used. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or setting of the instrument. In some cases, depending on the type or setting of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystal morphology, any particular peak in the XRPD pattern may appear as singlet, doublet, triplet, quadruplet, or multiplet. In some cases, any particular peak in XRPD may appear as symmetrical or asymmetrical shapes, for example, with shoulders. Furthermore, changes in the instrument and other factors may affect the 2θ value. Those skilled in the art who understand these variations can use XRPD, as well as other known physicochemical techniques, to identify or confirm features or properties that define a particular crystal morphology.

[0145] The term "anhydrous" applied to compounds refers to a crystalline form in which the compound does not contain structural water within its crystal lattice.

[0146] As used herein, the term “essentially pure” with respect to Form IV means that a composition containing Form IV does not contain any detectable amount of another polymorphic form (e.g., Form I or Form II), as determined by observing a detectable difference in the XRPD and / or DSC patterns between a single Form IV crystal and a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. However, “essentially pure” Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide may contain impurities, but are not limited to, such as synthetic reactants or by-products generated during chemical synthesis.

[0147] As used herein, the term “abnormal” as applied to a gene refers to a mutation, chromosome loss or fusion, epigenetic chemical modification, or other event that alters the sequence, expression level, or treated mRNA sequence associated with the wild-type gene.

[0148] Wherever the language “comprising” is used in this specification to describe an aspect, it is understood that other similar aspects are also provided that are described in terms of “consisting of” and / or “consisting essentially of.”

[0149] Details of one or more embodiments are described below. Other features, purposes, and advantages will become apparent from the specification and claims. [Modes for carrying out the invention]

[0150] Novel crystalline and amorphous solid forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are described herein. Pharmaceutical compositions (e.g., capsules, tablets, dispersible and non-dispersible dosage forms) and methods for treating patients requiring therapeutic administration of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are also described herein. Furthermore, a novel method for producing a pure composition of crystalline form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is described herein.

[0151] Crystalline form and amorphous solid This disclosure relates in part to a novel crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. As with all pharmaceutical compounds and compositions, the chemical and physical properties of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are important in its commercial development. These properties include, but are not limited to, (1) packing properties such as molar volume, bulk density and hygroscopicity; (2) thermodynamic properties such as melting temperature, vapor pressure and solubility; (3) kinetic properties such as dissolution rate and stability (including stability under ambient conditions, particularly with respect to moisture and under storage conditions); (4) surface properties such as surface area, wettability, interfacial tension and shape; (5) mechanical properties such as hardness, tensile strength, compressibility, handling, flow and blendability; and (6) filtration properties. These properties may, for example, affect the processing and storage of compounds and pharmaceutical compositions containing those compounds.

[0152] In some embodiments, the present disclosure provides a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I), [ka] These are selected from the following group: a) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4±0.2, 17.5±0.2, and 22.8±0.2 degrees 2θ; b) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2, and 21.2±0.2 degrees 2θ; c) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at 5.3±0.2, 10.6±0.2, and 16.1±0.2 degrees; d) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at 5.4±0.2, 10.7±0.2, and 18.7±0.2 degrees; e) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2, and 22.2±0.2 degrees 2θ; f) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 10.6±0.2, 19.6±0.2, and 24.8±0.2 degrees 2θ; g) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 5.5±0.2, 6.9±0.2, and 10.1±0.2 degrees at 2θ; h) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 10.1±0.2, 17.3±0.2, and 22.6±0.2 degrees 2θ; i) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2, and 14.6±0.2 degrees 2θ; j) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 4.6±0.2, 23.4±0.2, and 25.2±0.2 degrees 2θ; Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 5.5±0.2, 14.7±0.2, and 20.9±0.2 degrees 2θ; l) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at 6.0±0.2, 17.1±0.2, and 20.6±0.2 degrees; Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with peaks at 5.9±0.2, 10.1±0.2, and 15.5±0.2 degrees 2θ; n) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at 4.6±0.2, 10.7±0.2, and 15.9±0.2 degrees; o) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having 2θ peaks at 10.2±0.2, 11.6±0.2, and 20.0±0.2 degrees; Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern with 2θ peaks at p)7.8±0.2, 14.0±0.2, and 17.1±0.2 degrees; q) Crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2, and 16.7±0.2 degrees at 2θ; The crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2, and 29.1±0.2 degrees at 2θ; The crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide characterized by an XRPD pattern having 2θ peaks at 5.4±0.2, 9.7±0.2, and 10.7±0.2 degrees; and The crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2, and 23.0±0.2 degrees 2θ.

[0153] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4±0.2, 17.5±0.2, and 22.8±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 2A.

[0154] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 2.7% by weight from approximately 35°C to approximately 100°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 77°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 95°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 77°C and a second endothermic initiation at approximately 95°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 2B, and / or b) a DSC profile substantially as shown in Figure 2B.

[0155] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form V.

[0156] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9±0.2, 7.2±0.2, and 21.2±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 3A.

[0157] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 2.4% by weight from approximately 25°C to approximately 125°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 41°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 70°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 109°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 41°C and endothermic initiation at approximately 70°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 41°C and endothermic initiation at approximately 109°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 70°C and an endothermic initiation at approximately 109°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 41°C, a second endothermic initiation at approximately 70°C, and a third endothermic initiation at approximately 109°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 3B, and / or b) a DSC profile substantially as shown in Figure 3B.

[0158] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form VI.

[0159] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.3±0.2, 10.6±0.2, and 16.1±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 4A.

[0160] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 5.2% by weight from approximately 40°C to approximately 120°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 85°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic event at approximately 110°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 85°C and a second endothermic event at approximately 110°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 4B, and / or b) a DSC profile substantially as shown in Figure 4B.

[0161] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form VII.

[0162] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2, and 18.7±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4±0.2, 10.7±0.2, 18.7±0.2, and 23.9±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 5A.

[0163] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 3.3% by weight from approximately 40°C to approximately 112°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 81°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 110°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 81°C and a second endothermic initiation at approximately 110°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 5B, and / or b) a DSC profile substantially as shown in Figure 5B.

[0164] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form VIII.

[0165] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.7±0.2, 13.5±0.2, and 22.2±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 6A.

[0166] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 4.6% by weight from approximately 28°C to approximately 128°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 84°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 107°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 84°C and endothermic initiation at approximately 107°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 84°C and endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 107°C and an endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 84°C, a second endothermic initiation at approximately 107°C, and a third endothermic initiation at approximately 114°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 6B, and / or b) a DSC profile substantially as shown in Figure 6B.

[0167] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form IX.

[0168] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.6±0.2, 19.6±0.2, and 24.8±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 10.6±0.2, 19.6±0.2, and 24.8±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 7A.

[0169] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 2.9 wt% from about 40°C to about 115°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at about 89°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 7B, and / or b) a DSC profile substantially as shown in Figure 7B.

[0170] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form X.

[0171] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2, and 10.1±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 6.9±0.2, 10.1±0.2, and 19.2±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 8A.

[0172] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 40°C to approximately 175°C, with a loss of approximately 7.6% by weight. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 69°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 104°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 69°C and a second endothermic initiation at approximately 104°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 8B, and / or b) a DSC profile substantially as shown in Figure 8B.

[0173] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XI.

[0174] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.1±0.2, 17.3±0.2, and 22.6±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 9A.

[0175] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 8.5% by weight from approximately 40°C to approximately 160°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 72°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 109°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 72°C and a second endothermic initiation at approximately 109°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 9B, and / or b) a DSC profile substantially as shown in Figure 9B.

[0176] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XII.

[0177] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 5.1±0.2, and 14.6±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 10A.

[0178] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 3.1% by weight from approximately 20°C to approximately 100°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 55°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 109°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 55°C and a second endothermic initiation at approximately 109°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 10B, and / or b) a DSC profile substantially as shown in Figure 10B.

[0179] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XIII.

[0180] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2, and 25.2±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 23.4±0.2, 25.2±0.2, and 30.6±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 11A.

[0181] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 0.15 wt% from about 40°C to about 150°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at about 111°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 11B, and / or b) a DSC profile substantially as shown in Figure 11B.

[0182] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XIV.

[0183] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2, and 20.9±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 14.7±0.2, 20.9±0.2, and 26.6±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 12A.

[0184] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 3.8 wt% from about 40°C to about 150°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with endothermic initiation at about 104°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 12B, and / or b) a DSC profile substantially as shown in Figure 12B.

[0185] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XV.

[0186] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.0±0.2, 17.1±0.2, and 20.6±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 13A.

[0187] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 2.1% by weight from approximately 40°C to approximately 150°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 74°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 74°C and endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 74°C and endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 102°C and an endothermic initiation at approximately 114°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 74°C, a second endothermic initiation at approximately 102°C, and a third endothermic initiation at approximately 114°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 13B, and / or b) a DSC profile substantially as shown in Figure 13B.

[0188] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XVI.

[0189] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9±0.2, 10.1±0.2, and 15.5±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 14A.

[0190] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 2.7 wt% from about 40°C to about 100°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with endothermic initiation at about 89°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 14B, and / or b) a DSC profile substantially as shown in Figure 14B.

[0191] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XVII.

[0192] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2, and 15.9±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6±0.2, 10.7±0.2, 15.9±0.2, and 19.6±0.2 degrees 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 15A.

[0193] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 1.6% by weight from about 30°C to about 150°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at about 83°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 15B, and / or b) a DSC profile substantially as shown in Figure 15B.

[0194] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XVIII.

[0195] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.2±0.2, 11.6±0.2, and 20.0±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 16A.

[0196] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 1.85% by weight from approximately 23°C to approximately 92°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 69°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 98°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 115°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 69°C and endothermic initiation at approximately 98°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 69°C and endothermic initiation at approximately 115°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 98°C and an endothermic initiation at approximately 115°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 69°C, a second endothermic initiation at approximately 98°C, and a third endothermic initiation at approximately 115°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 16B, and / or b) a DSC profile substantially as shown in Figure 16B.

[0197] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XIX.

[0198] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.8±0.2, 14.0±0.2, and 17.1±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 17A.

[0199] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 2.6% by weight from approximately 29°C to approximately 126°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 77°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 92°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 110°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 77°C and endothermic initiation at approximately 92°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 77°C and endothermic initiation at approximately 110°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 92°C and an endothermic initiation at approximately 110°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 77°C, a second endothermic initiation at approximately 92°C, and a third endothermic initiation at approximately 110°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 17B, and / or b) a DSC profile substantially as shown in Figure 17B.

[0200] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XX.

[0201] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2, and 16.7±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5±0.2, 8.2±0.2, 16.7±0.2, and 17.7±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 18A.

[0202] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 30°C to approximately 110°C, with a loss of approximately 14.1% by weight. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 52°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at approximately 90°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 52°C and a second endothermic initiation at approximately 90°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 18B, and / or b) a DSC profile substantially as shown in Figure 18B.

[0203] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XXI.

[0204] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2±0.2, 21.7±0.2, and 29.1±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 19A.

[0205] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 13.8% by weight from approximately 26°C to approximately 135°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 65°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 89°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 65°C and endothermic initiation at approximately 89°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 65°C and endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with an endothermic initiation at approximately 89°C and an endothermic initiation at approximately 102°C. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 65°C, a second endothermic initiation at approximately 89°C, and a third endothermic initiation at approximately 102°C.In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 19B, and / or b) a DSC profile substantially as shown in Figure 19B.

[0206] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XXII.

[0207] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4±0.2, 9.7±0.2, and 10.7±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 20A.

[0208] In some embodiments, TGA shows that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost at approximately 4.4% by weight from approximately 27°C to approximately 137°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 81°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with endothermic initiation at approximately 101°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide exhibits a DSC thermogram with a first endothermic initiation at approximately 81°C and a second endothermic initiation at approximately 101°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 20B, and / or b) a DSC profile substantially as shown in Figure 20B.

[0209] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XXIII.

[0210] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2±0.2, 20.6±0.2, and 23.0±0.2 degrees at 2θ. In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 21A.

[0211] In some embodiments, the TGA indicates that the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is lost by about 1.2% by weight from about 30°C to about 119°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide shows a DSC thermogram with an endothermic initiation at about 104°C. In some embodiments, the crystalline morphology of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 21B, and / or b) a DSC profile substantially as shown in Figure 21B.

[0212] In some embodiments, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is form XXIV.

[0213] In some embodiments, the present disclosure provides an amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I). [ka]

[0214] In some embodiments, the amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is substantially characterized by an XRPD pattern as shown in Figure 22A.

[0215] In some embodiments, the amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is characterized by a) a TGA profile substantially as shown in Figure 22B, and / or b) a DSC profile substantially as shown in Figure 22B.

[0216] In some embodiments, the XRPD pattern is configured such that (a) on the incident beam side: a variable divergence slit (irradiation length of 10 mm), a 0.04 rad solar slit, a fixed anti-scattering slit (0.50°), and a 10 mm beam mask, and (b) on the diffracting beam side: a variable anti-scattering slit (observed length of 10 mm) and a 0.04 rad solar slit, using Ni-filtered CuKα (45 kV / 40 mA) emission with an X'CELERATOR® Real Time Multi-Strip detector and a step size of 0.03°²θ, PANALYTICAL® X'Pert The samples are generated using a Pro diffractometer or using a BRUKER® D8® ADVANCE® system with a LYNXEYE® detector, configured (a) on the incident beam side as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5° solar slit, beam knife, and (b) on the diffracted beam side as follows: anti-scattering slit (8 mm) and 2.5° solar slit, with CuKα (40 kV / 40 mA) emission and a step size of 0.03°2θ, and the samples are mounted flat on a zero-background Si wafer. In some embodiments, the DSC patterns are generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a temperature rise rate of approximately 15°C / min.

[0217] Pharmaceutical composition In some embodiments, the Disclosure provides a pharmaceutical composition comprising a crystalline or amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, and one or more pharmaceutically acceptable carriers.

[0218] In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total less than 10% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total less than 9% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total less than 8% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total less than 7% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total less than 6% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total less than 5% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total less than 4% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total amounts of less than 3% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total amounts of less than 2% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total amounts of less than 1% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total amounts of less than 0.5% by weight. In some embodiments, the desired crystalline or amorphous solid contains one or more other crystalline forms and / or amorphous solids in total amounts of less than 0.4% by weight. In some embodiments, the desired crystalline or amorphous solid is essentially a pure other crystalline form and / or amorphous solid.

[0219] In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is in solid dosage form. In some embodiments, the pharmaceutical composition is in the form of capsules, tablets (e.g., dispersible tablets), powders (e.g., dispersible powders), granules (e.g., dispersible granules), minitablets (e.g., dispersible minitablets), or pellets (e.g., dispersible pellets). In some embodiments, the pharmaceutical composition (e.g., dispersible tablets, dispersible powders, dispersible granules, dispersible minitablets, or dispersible pellets) further comprises one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition is for oral administration. In some embodiments, the pharmaceutical composition is orally dispersible.

[0220] In some embodiments, the beverage liquid is water, milk, or juice (e.g., orange juice or apple juice). In some embodiments, the beverage liquid is water. In some embodiments, the beverage liquid is juice.

[0221] In some embodiments, the pharmaceutical composition is in the form of tablets, powders, granules, minitablets, or pellets.

[0222] In some embodiments, the pharmaceutical composition is a powder. In some embodiments, the powder is a dispersible powder. In some embodiments, the capsule or sachet contains a dispersible powder.

[0223] In some embodiments, the pharmaceutical composition is in the form of granules. In some embodiments, the granules are dispersible granules. In some embodiments, the capsule or sachet contains dispersible granules.

[0224] In some embodiments, the pharmaceutical composition is in the form of a mini-tablet. In some embodiments, the mini-tablet is a dispersible mini-tablet. In some embodiments, the capsule or sachet contains a dispersible mini-tablet.

[0225] In some embodiments, the pharmaceutical composition is in the form of pellets. In some embodiments, the pellets are dispersible pellets. In some embodiments, the capsules or sachets contain dispersible pellets.

[0226] In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the tablet is a dispersible tablet. In some embodiments, the dispersible tablet is an orally dispersible tablet.

[0227] In some embodiments, the pharmaceutical composition comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms. In some embodiments, the pharmaceutical composition contains about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms. In some embodiments, the pharmaceutical composition contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms. In some embodiments, the pharmaceutical composition contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms. In some embodiments, the pharmaceutical composition comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms. In some embodiments, the pharmaceutical composition comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms. In some embodiments, the pharmaceutical composition comprises about 5 mg of a crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide.

[0228] In some embodiments, the pharmaceutical composition comprises about 0.1 wt / w% to about 7 wt / w% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms. In some embodiments, the pharmaceutical composition comprises about 0.1 wt / w% to about 5 wt / w% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms.In some embodiments, the pharmaceutical composition is approximately 0.1% by weight, approximately 0.2% by weight, approximately 0.3% by weight, approximately 0.4% by weight, approximately 0.5% by weight, approximately 0.6% by weight, approximately 0.7% by weight, approximately 0.8% by weight, approximately 0.9% by weight, approximately 1% by weight, approximately 1.1% by weight, approximately 1.2% by weight, approximately 1.3% by weight, approximately 1.4% by weight, approximately 1.5% by weight, approximately 1.6% by weight, approximately 1.7% by weight, approximately 1.8% by weight, and approximately 1% by weight. .9 wt / wt%, about 2 wt / wt%, about 2.1 wt / wt%, about 2.2 wt / wt%, about 2.3 wt / wt%, about 2.4 wt / wt%, about 2.5 wt / wt%, about 2.6 wt / wt%, about 2.7 wt / wt%, about 2.8 wt / wt%, about 2 .9 wt / wt%, about 3 wt / wt%, about 3.1 wt / wt%, about 3.2 wt / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3 .9 wt / wt%, about 4 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4. 9 wt / wt%, about 5 wt / wt%, about 5.1 wt / wt%, about 5.2 wt / wt%, about 5.3 wt / wt%, about 5.4 wt / wt%, about 5.5 wt / wt%, about 5.6 wt / wt%, about 5.7 wt / wt%, about 5.8 wt / wt%, about 5. The composition comprises one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in amounts of 9 wt / weight, approximately 6 wt / weight, approximately 6.1 wt / weight, approximately 6.2 wt / weight, approximately 6.3 wt / weight, approximately 6.4 wt / weight, approximately 6.5 wt / weight, approximately 6.6 wt / weight, approximately 6.7 wt / weight, approximately 6.8 wt / weight, approximately 6.9 wt / weight, or approximately 7 wt / weight. In some embodiments, the pharmaceutical composition comprises one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in amounts of approximately 0.5 wt / weight.In some embodiments, the pharmaceutical composition comprises about 0.8 wt / wt% of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide.

[0229] In some embodiments, the pharmaceutical composition comprises one or more diluents. In some embodiments, the pharmaceutical composition comprises one or more diluents in an amount of about 50% by weight to about 98% by weight. In some embodiments, the pharmaceutical composition comprises one or more diluents in an amount of about 70% by weight to about 98% by weight. In some embodiments, the pharmaceutical composition comprises one or more diluents in an amount of about 85% by weight to about 95% by weight. In such embodiments, the pharmaceutical composition is approximately 50% by weight, approximately 51% by weight, approximately 52% by weight, approximately 53% by weight, approximately 54% by weight, approximately 55% by weight, approximately 56% by weight, approximately 57% by weight, approximately 58% by weight, approximately 59% by weight, approximately 60% by weight, approximately 61% by weight, approximately 62% by weight, approximately 63% by weight, approximately 64% by weight, approximately 65% ​​by weight, approximately 66% by weight, approximately 67% by weight, approximately 68% by weight, approximately 69% by weight, approximately 70% by weight, approximately 71% by weight, approximately 72% by weight, approximately 73% by weight, and approximately 74% by weight. The composition comprises one or more diluents in weight / weight%, approximately 75 weight / weight%, approximately 76 weight / weight%, approximately 77 weight / weight%, approximately 78 weight / weight%, approximately 79 weight / weight%, approximately 80 weight / weight%, approximately 81 weight / weight%, approximately 82 weight / weight%, approximately 83 weight / weight%, approximately 84 weight / weight, approximately 85 weight / weight%, approximately 86 weight / weight%, approximately 87 weight / weight, approximately 88 weight / weight%, approximately 89 weight / weight, approximately 90 weight / weight%, approximately 91 weight / weight%, approximately 92 weight / weight, approximately 93 weight / weight%, approximately 94 weight / weight, approximately 95 weight / weight%, approximately 96 weight / weight%, approximately 97 weight / weight, or approximately 98 weight / weight. In such embodiments, the pharmaceutical composition comprises one or more diluents in weight of approximately 90 weight / weight. In some embodiments, the pharmaceutical composition comprises one or more diluents in an amount of about 93% by weight.

[0230] In some embodiments, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate. In some embodiments, at least one of the diluents is microcrystalline cellulose.

[0231] In some embodiments, the pharmaceutical composition contains about 50% by weight to about 98% by weight of microcrystalline cellulose. In some embodiments, the pharmaceutical composition contains about 70% by weight to about 95% by weight of microcrystalline cellulose. In some embodiments, the pharmaceutical composition contains about 85% by weight to about 95% by weight of microcrystalline cellulose. In such embodiments, the pharmaceutical composition is approximately 50% by weight, approximately 51% by weight, approximately 52% by weight, approximately 53% by weight, approximately 54% by weight, approximately 55% by weight, approximately 56% by weight, approximately 57% by weight, approximately 58% by weight, approximately 59% by weight, approximately 60% by weight, approximately 61% by weight, approximately 62% by weight, approximately 63% by weight, approximately 64% by weight, approximately 65% ​​by weight, approximately 66% by weight, approximately 67% by weight, approximately 68% by weight, approximately 69% by weight, approximately 70% by weight, approximately 71% by weight, approximately 72% by weight, approximately 73% by weight, and approximately 74% by weight. The composition comprises microcrystalline cellulose in weight / weight%, approximately 75 weight / weight%, approximately 76 weight / weight%, approximately 77 weight / weight%, approximately 78 weight / weight%, approximately 79 weight / weight%, approximately 80 weight / weight%, approximately 81 weight / weight%, approximately 82 weight / weight%, approximately 83 weight / weight%, approximately 84 weight / weight, approximately 85 weight / weight%, approximately 86 weight / weight%, approximately 87 weight / weight, approximately 88 weight / weight%, approximately 89 weight / weight, approximately 90 weight / weight%, approximately 91 weight / weight%, approximately 92 weight / weight, approximately 93 weight / weight%, approximately 94 weight / weight, approximately 95 weight / weight%, approximately 96 weight / weight%, approximately 97 weight / weight, or approximately 98 weight / weight%. In such embodiments, the pharmaceutical composition comprises approximately 90 weight / weight% microcrystalline cellulose. In some embodiments, the pharmaceutical composition contains about 93% by weight of microcrystalline cellulose.

[0232] In some embodiments, the pharmaceutical composition contains one or more disintegrants in amounts of about 1 wt / kg to about 10 wt / kg. In some embodiments, the pharmaceutical composition contains one or more disintegrants in amounts of about 3.5 wt / kg to about 6 wt / kg. In some embodiments, the pharmaceutical composition contains about 1.0 wt / kg, about 1.1 wt / kg, about 1.2 wt / kg, about 1.3 wt / kg, about 1.4 wt / kg, about 1.5 wt / kg, about 1.6 wt / kg, about 1.7 wt / kg, about 1.8 wt / kg, about 1.9 wt / kg, about 2.0 wt / kg, about 2.1 wt / kg, about 2.2 wt / kg, about 2.3 wt / kg, about 2.4 wt / kg, about 2.5 wt / kg, about 2.6 wt / kg, about 2.7 wt / kg, about 2.8 wt / kg %, about 2.9 wt / wt%, about 3.0 wt / wt%, about 3.1 wt / wt%, about 3.2 wt / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, About 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4. 9 wt / wt%, about 5.0 wt / wt%, about 5.1 wt / wt%, about 5.2 wt / wt%, about 5.3 wt / wt%, about 5.4 wt / wt%, about 5.5 wt / wt%, about 5.6 wt / wt%, about 5.7 wt / wt%, about 5.8 wt / wt%, about 5.9 wt / wt%, about 6.0 wt / wt%, about 6.1 wt / wt%, about 6.2 wt / wt%, about 6.3 wt / wt%, about 6.4 wt / wt%, about 6.5 wt / wt%, about 6.6 wt / wt%, about 6.7 wt / wt%, about 6.8 wt / wt%, about 6.9 wt / wt %, about 7.0 wt / wt%, about 7.1 wt / wt%, about 7.2 wt / wt%, about 7.3 wt / wt%, about 7.4 wt / wt%, about 7.5 wt / wt%, about 7.6 wt / wt%, about 7.7 wt / wt%, about 7.8 wt / wt%, about 7.9 wt / wt%, About 8.0 wt / wt%, about 8.1 wt / wt%, about 8.2 wt / wt%, about 8.3 wt / wt%, about 8.4 wt / wt%, about 8.5 wt / wt%, about 8.6 wt / wt%, about 8.7 wt / wt%, about 8.8 wt / wt%, about 8.9 wt / wt%, about 9.It contains one or more disintegrants of 0 wt / wt%, about 9.1 wt / wt%, about 9.2 wt / wt%, about 9.3 wt / wt%, about 9.4 wt / wt%, about 9.5 wt / wt%, about 9.6 wt / wt%, about 9.7 wt / wt%, about 9.8 wt / wt%, about 9.9 wt / wt%, or about 10.0 wt / wt%. In some embodiments, the pharmaceutical composition contains about 5 wt / wt% of one or more disintegrants.

[0233] In some embodiments, at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and alginic acid. In some embodiments, at least one of the disintegrants is croscarmellose sodium. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical composition contains about 1 wt / wt% to about 10 wt / wt% of croscarmellose sodium. In some embodiments, the pharmaceutical composition contains about 3.5 wt / wt% to about 6 wt / wt% of croscarmellose sodium. In some embodiments, the pharmaceutical composition is approximately 1.0 wt / kg, approximately 1.1 wt / kg, approximately 1.2 wt / kg, approximately 1.3 wt / kg, approximately 1.4 wt / kg, approximately 1.5 wt / kg, approximately 1.6 wt / kg, approximately 1.7 wt / kg, approximately 1.8 wt / kg, approximately 1.9 wt / kg, approximately 2.0 wt / kg, approximately 2.1 wt / kg, approximately 2.2 wt / kg, approximately 2.3 wt / kg Amount%, approx. 2.4 wt / wt%, approx. 2.5 wt / wt%, approx. 2.6 wt / wt%, approx. 2.7 wt / wt%, approx. 2.8 wt / wt%, approx. 2.9 wt / wt%, approx. 3.0 wt / wt%, approx. 3.1 wt. Amount / wt%, about 3.2 wt / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3 .9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt %, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4.9 wt / wt%, about 5 wt / wt%, about 5.1 wt / wt%, about 5.2 wt / wt%, about 5.3 wt / wt%, about 5.4 wt / wt 5.5 wt / wt%, about 5.6 wt / wt%, about 5.7 wt / wt%, about 5.8 wt / wt%, about 5.9 wt / wt%, about 6.0 wt / wt%, about 6.1 wt / wt%, about 6.2 wt. / wt%, about 6.3 wt / wt%, about 6.4 wt / wt%, about 6.5 wt / wt%, about 6.6 wt / wt%, about 6.7 wt / wt%, about 6.8 wt / wt%, about 6.9 wt / wt%, about 7.0 wt / wt%, about 7.1 wt / wt%, about 7.2 wt / wt%, about 7.3 wt / wt%, about 7.4 wt / wt%, about 7.5 wt / wt%, about 7.6 wt / wt%, about 7.7 wt / wt%, about 7.8 wt Amount / wt%, about 7.9 wt / wt%, about 8.0 wt / wt%, about 8.1 wt / wt%, about 8.2 wt / wt%, about 8.3 wt / wt%, about 8.4 wt / wt%, about 8.5 wt / wt%, about 8.6 wt / wt% The composition contains croscarmellose sodium in amounts of approximately 8.7% by weight, approximately 8.8% by weight, approximately 8.9% by weight, approximately 9.0% by weight, approximately 9.1% by weight, approximately 9.2% by weight, approximately 9.3% by weight, approximately 9.4% by weight, approximately 9.5% by weight, approximately 9.6% by weight, approximately 9.7% by weight, approximately 9.8% by weight, approximately 9.9% by weight, or approximately 10.0% by weight. In some embodiments, the pharmaceutical composition contains approximately 5% by weight of croscarmellose sodium.

[0234] In some embodiments, the pharmaceutical composition comprises from 0 wt / wt% to about 5 wt / wt% of one or more lubricants. In some embodiments, the pharmaceutical composition comprises from about 0.1 wt / wt% to about 5 wt / wt% of one or more lubricants. In some embodiments, the pharmaceutical composition comprises from 0 wt / wt% to about 2 wt / wt% of one or more lubricants. In some embodiments, the pharmaceutical composition comprises from about 0.1 wt / wt% to about 2 wt / wt% of one or more lubricants. In some embodiments, the pharmaceutical composition comprises 0 wt / wt%, about 0.1 wt / wt%, about 0.2 wt / wt%, about 0.3 wt / wt%, about 0.4 wt / wt%, about 0.5 wt / wt%, about 0.6 wt / wt%, about 0.7 wt / wt%, about 0.8 wt / wt%, about 0.9 wt / wt%, about 1 wt / wt%, about 1.1 wt / wt%, about 1.2 wt / wt%, about 1.3 wt / wt%, about 1.4 wt / wt%, about 1.5 wt / wt%, about 1.6 wt / wt%, about 1.7 wt / wt%, about 1.8 wt / wt%, about 1.9 wt / wt%, about 2 wt / wt%, about 2.1 wt / wt%, about 2.2 wt / wt%, about 2.3 wt / wt%, about 2.4 wt / wt%, about 2.5 wt / wt%, about 2.6 wt / wt%, about 2.7 wt / wt%, about 2.8 wt / wt%, about 2.9 wt / wt%, about 3.0 wt / wt%, about 3.1 wt / wt%, about 3.2 wt / wt%, about 3.3 wt / wt%, about 3.4 wt / wt%, about 3.5 wt / wt%, about 3.6 wt / wt%, about 3.7 wt / wt%, about 3.8 wt / wt%, about 3.9 wt / wt%, about 4.0 wt / wt%, about 4.1 wt / wt%, about 4.2 wt / wt%, about 4.3 wt / wt%, about 4.4 wt / wt%, about 4.5 wt / wt%, about 4.6 wt / wt%, about 4.7 wt / wt%, about 4.8 wt / wt%, about 4.9 wt / wt%, or about 5.0 wt / wt% of one or more lubricants. In some embodiments, the pharmaceutical composition comprises about 1 wt / wt% of one or more lubricants.

[0235] In some embodiments, at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc. In some embodiments, at least one of the lubricants is magnesium stearate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the pharmaceutical composition contains 0% by weight to about 5% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition contains about 0.1% by weight to about 5% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition contains 0% by weight to about 2% by weight of magnesium stearate. In some embodiments, the pharmaceutical composition contains about 0.1% by weight to about 2% by weight of magnesium stearate.In some embodiments, the pharmaceutical composition is approximately 0% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, about 2% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, about 2.5% by weight Contains magnesium stearate in amounts of approximately 2.6 wt / kg%, approximately 2.7 wt / kg%, approximately 2.8 wt / kg%, approximately 2.9 wt / kg%, approximately 3.0 wt / kg%, approximately 3.1 wt / kg%, approximately 3.2 wt / kg%, approximately 3.3 wt / kg%, approximately 3.4 wt / kg%, approximately 3.5 wt / kg%, approximately 3.6 wt / kg%, approximately 3.7 wt / kg%, approximately 3.8 wt / kg%, approximately 3.9 wt / kg%, approximately 4.0 wt / kg%, approximately 4.1 wt / kg%, approximately 4.2 wt / kg%, approximately 4.3 wt / kg%, approximately 4.4 wt / kg%, approximately 4.5 wt / kg%, approximately 4.6 wt / kg%, approximately 4.7 wt / kg%, approximately 4.8 wt / kg%, approximately 4.9 wt / kg%, or approximately 5.0 wt / kg%. In some embodiments, the pharmaceutical composition contains 0 wt / wt% magnesium stearate. In some embodiments, the pharmaceutical composition contains about 0.1 wt / wt% magnesium stearate. In some embodiments, the pharmaceutical composition contains about 1 wt / wt% magnesium stearate.

[0236] In some embodiments, the pharmaceutical composition comprises one or more fragrance agents in an amount of 0% by weight to about 5% by weight. In some embodiments, the pharmaceutical composition comprises one or more fragrance agents in an amount of 0% by weight to about 2.5% by weight. In some embodiments, the pharmaceutical composition is 0 weight / weight%, about 0.1 weight / weight%, about 0.2 weight / weight%, about 0.3 weight / weight%, about 0.4 weight / weight%, about 0.5 weight / weight%, about 0.6 weight / weight%, about 0.7 weight / weight%, about 0.8 weight / weight%, about 0.9 weight / weight%, about 1 weight / weight%, about 1.1 weight / weight%, about 1.2 weight / weight%, about 1.3 weight / weight%, about 1.4 weight / weight%, about 1.5 weight / weight%, about 1.6 weight / weight%, about 1.7 weight / weight%, about 1.8 weight / weight%, about 1.9 weight / weight%, about 2 weight / weight%, about 2.1 weight / weight%, about 2.2 weight / weight%, about 2.3 weight / weight%, about 2.4 weight / weight%, about 2.5 weight / weight Contains one or more fragrances in the following proportions: weight %, approximately 2.6 weight / weight%, approximately 2.7 weight / weight%, approximately 2.8 weight / weight%, approximately 2.9 weight / weight%, approximately 3.0 weight / weight%, approximately 3.1 weight / weight%, approximately 3.2 weight / weight%, approximately 3.3 weight / weight%, approximately 3.4 weight / weight%, approximately 3.5 weight / weight%, approximately 3.6 weight / weight%, approximately 3.7 weight / weight%, approximately 3.8 weight / weight%, approximately 3.9 weight / weight%, approximately 4.0 weight / weight%, approximately 4.1 weight / weight%, approximately 4.2 weight / weight%, approximately 4.3 weight / weight%, approximately 4.4 weight / weight%, approximately 4.5 weight / weight%, approximately 4.6 weight / weight%, approximately 4.7 weight / weight%, approximately 4.8 weight / weight%, approximately 4.9 weight / weight%, or approximately 5.0 weight / weight%. In some embodiments, the pharmaceutical composition comprises one or more fragrance agents in an amount of about 2% by weight.

[0237] In some embodiments, at least one of the flavorings is selected from the group consisting of natural or synthetic flavors, including but not limited to grape flavor, bubblegum flavor, caramel flavor, orange flavor, lemon flavor, strawberry flavor, raspberry flavor, mint flavor, peppermint flavor, grapefruit flavor, pineapple flavor, pear flavor, peach flavor, vanilla flavor, banana flavor, or cherry flavor. In some embodiments, at least one of the flavorings is grape flavor. In some embodiments, the pharmaceutical composition contains 0% by weight to about 5.0% by weight of grape flavor. In some embodiments, the pharmaceutical composition contains 0% by weight to about 2.5% by weight of grape flavor. In some embodiments, the pharmaceutical composition is approximately 0% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, about 2% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, and about 2.5% by weight. Contains grape flavoring in amounts of approximately 2.6% by weight, approximately 2.7% by weight, approximately 2.8% by weight, approximately 2.9% by weight, approximately 3.0% by weight, approximately 3.1% by weight, approximately 3.2% by weight, approximately 3.3% by weight, approximately 3.4% by weight, approximately 3.5% by weight, approximately 3.6% by weight, approximately 3.7% by weight, approximately 3.8% by weight, approximately 3.9% by weight, approximately 4.0% by weight, approximately 4.1% by weight, approximately 4.2% by weight, approximately 4.3% by weight, approximately 4.4% by weight, approximately 4.5% by weight, approximately 4.6% by weight, approximately 4.7% by weight, approximately 4.8% by weight, approximately 4.9% by weight, or approximately 5.0% by weight. In some embodiments, the pharmaceutical composition contains about 2 wt / wt% of grape flavoring.

[0238] In some embodiments, the pharmaceutical composition contains one or more sweeteners in an amount of 0% by weight to about 5% by weight. In some embodiments, the pharmaceutical composition contains one or more sweeteners in an amount of 0% by weight to about 2% by weight. In some embodiments, the pharmaceutical composition is 0 weight / weight%, about 0.1 weight / weight%, about 0.2 weight / weight%, about 0.3 weight / weight%, about 0.4 weight / weight%, about 0.5 weight / weight%, about 0.6 weight / weight%, about 0.7 weight / weight%, about 0.8 weight / weight%, about 0.9 weight / weight%, about 1 weight / weight%, about 1.1 weight / weight%, about 1.2 weight / weight%, about 1.3 weight / weight%, about 1.4 weight / weight%, about 1.5 weight / weight%, about 1.6 weight / weight%, about 1.7 weight / weight%, about 1.8 weight / weight%, about 1.9 weight / weight%, about 2 weight / weight%, about 2.1 weight / weight%, about 2.2 weight / weight%, about 2.3 weight / weight%, about 2.4 weight / weight%, about 2.5 weight / weight Contains one or more sweeteners in the following amounts: weight %, approximately 2.6 weight / weight%, approximately 2.7 weight / weight%, approximately 2.8 weight / weight%, approximately 2.9 weight / weight%, approximately 3.0 weight / weight%, approximately 3.1 weight / weight%, approximately 3.2 weight / weight%, approximately 3.3 weight / weight%, approximately 3.4 weight / weight%, approximately 3.5 weight / weight%, approximately 3.6 weight / weight%, approximately 3.7 weight / weight%, approximately 3.8 weight / weight%, approximately 3.9 weight / weight%, approximately 4.0 weight / weight%, approximately 4.1 weight / weight%, approximately 4.2 weight / weight%, approximately 4.3 weight / weight%, approximately 4.4 weight / weight%, approximately 4.5 weight / weight%, approximately 4.6 weight / weight%, approximately 4.7 weight / weight%, approximately 4.8 weight / weight%, approximately 4.9 weight / weight%, or approximately 5.0 weight / weight%. In some embodiments, the pharmaceutical composition comprises one or more sweeteners in an amount of about 1% by weight.

[0239] In some embodiments, at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some embodiments, at least one of the sweeteners is sucralose. In some embodiments, the sweetener is sucralose. In some embodiments, the pharmaceutical composition contains 0% by weight to about 5% by weight of sucralose. In some embodiments, the pharmaceutical composition contains 0% by weight to about 2% by weight of sucralose. In some embodiments, the pharmaceutical composition is approximately 0% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, about 2% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, and about 2.5% by weight. Contains sucralose in amounts of approximately 2.6g / kg%, 2.7g / kg%, 2.8g / kg%, 2.9g / kg%, 3.0g / kg%, 3.1g / kg%, 3.2g / kg%, 3.3g / kg%, 3.4g / kg%, 3.5g / kg%, 3.6g / kg%, 3.7g / kg%, 3.8g / kg%, 3.9g / kg%, 4.0g / kg%, 4.1g / kg%, 4.2g / kg%, 4.3g / kg%, 4.4g / kg%, 4.5g / kg%, 4.6g / kg%, 4.7g / kg%, 4.8g / kg%, 4.9g / kg%, or approximately 5.0g / kg%. In some embodiments, the pharmaceutical composition comprises about 1 wt / wt% sucralose.

[0240] In some embodiments, the pharmaceutical composition is a capsule. In some embodiments, the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms, the components of the capsule being: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, (d) 0 wt / wt% to about 5 wt / wt% of one or more lubricants, and (e) a gelatin capsule enclosing components (a) to (d).

[0241] In some embodiments, the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms, the components of the capsule being: (a) about 0.25 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, (d) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants, and (e) a gelatin capsule encapsulating components (a) to (d).

[0242] In some embodiments, the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms, the components of the capsule being: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, (d) 0 wt / wt% to about 5 wt / wt% of one or more lubricants, and (e) a gelatin capsule encapsulating components (a) to (d).

[0243] In some embodiments, the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms, the components of the capsule being: (a) about 0.25 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, (d) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants, and (e) a gelatin capsule encapsulating components (a) to (d). In some embodiments, the capsule comprises about 3 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, wherein each component of the capsule is as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, (d) 0 wt / wt% to about 5 wt / wt% of one or more lubricants, and (e) a gelatin capsule enclosing components (a) to (d).

[0244] In some embodiments, the capsule comprises about 3 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, the components of the capsule being: (a) about 0.25 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, (d) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants, and (e) a gelatin capsule encapsulating components (a) to (d). In some embodiments, the capsule comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms, wherein each component of the capsule is as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, (d) 0 wt / wt% to about 5 wt / wt% of one or more lubricants, and (e) a gelatin capsule enclosing components (a) to (d).

[0245] In some embodiments, the capsule comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms, the components of the capsule being: (a) about 0.25 wt / wt% to about 1.5 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, (d) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants, and (e) a gelatin capsule enclosing components (a) to (d).

[0246] In some embodiments, the capsule comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms, wherein each component of the capsule is as follows: (a) about 2.5 wt / wt% to about 7.0 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, and (d) a gelatin capsule enclosing components (a) to (c).

[0247] In some embodiments, the capsule comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in one or more crystalline or amorphous forms, the components of the capsule being: (a) about 2.5 wt / wt% to about 7.0 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, and (d) a gelatin capsule enclosing components (a) to (c).

[0248] In some embodiments, the pharmaceutical composition is a tablet (e.g., a dispersible tablet). In some embodiments, the tablet is a dispersible tablet. In some embodiments, the tablet (e.g., a dispersible tablet) comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (c)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0249] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy) -3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0250] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 1 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0251] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0252] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 2 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0253] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0254] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 3 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0255] In some embodiments, tablets (e.g., dispersible tablets) contain the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein at about 3 mg, and the components of the tablets (e.g., dispersible tablets) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, (b) about 85 wt / wt% to about 95 wt / wt% of one or more diluents, (c) about 3.5 wt / wt% to about 6 wt / wt% of one or more disintegrants, (d) 0 wt / wt% to about 2.5 wt / wt% of one or more flavoring agents, (e) 0 wt / wt% to about 2 wt / wt% of one or more sweetening agents, and (f) about 0.5 wt / wt% to about 2 wt / wt% of one or more lubricants.

[0256] In some embodiments, tablets (e.g., dispersible tablets) contain the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein at about 4 mg, and the components of the tablets (e.g., dispersible tablets) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, (b) about 50 wt / wt% to about 98 wt / wt% of one or more diluents, (c) about 1 wt / wt% to about 10 wt / wt% of one or more disintegrants, (d) 0 wt / wt% to about 5 wt / wt% of one or more flavoring agents, (e) 0 wt / wt% to about 5 wt / wt% of one or more sweetening agents, and (f) 0 wt / wt% to about 5 wt / wt% of one or more lubricants.

[0257] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0258] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 5 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0259] In some embodiments, the tablet (e.g., a dispersible tablet) contains about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the tablet (e.g., a dispersible tablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0260] In some embodiments, the tablets (e.g., dispersible tablets) contain about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the pharmaceutical composition is dispersible in a beverage liquid, and the components of the pharmaceutical composition are as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.1 wt / wt% to approximately 7 wt / wt%, (b) one or more diluents in an amount of approximately 50 wt / wt% to approximately 98 wt / wt%, (c) one or more disintegrants in an amount of approximately 1 wt / wt% to approximately 10 wt / wt%, (d) one or more flavoring agents in an amount of 0 wt / wt% to approximately 5 wt / wt%, (e) one or more sweeteners in an amount of 0 wt / wt% to approximately 5 wt / wt%, and (f) one or more lubricants in an amount of 0 wt / wt% to approximately 5 wt / wt%.

[0261] In some embodiments, the tablets (e.g., dispersible tablets) contain about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the pharmaceutical composition is dispersible in a beverage liquid, and the components of the pharmaceutical composition are as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.5 wt / w% to approximately 1.2 wt / w%; (b) one or more diluents in an amount of approximately 85 wt / w% to approximately 95 wt / w%; (c) one or more disintegrants in an amount of approximately 3.5 wt / w% to approximately 6 wt / w%; (d) one or more flavoring agents in an amount of 0 wt / w% to approximately 2.5 wt / w%; (e) one or more sweeteners in an amount of 0 wt / w% to approximately 2 wt / w%; and (f) one or more lubricants in an amount of approximately 0.5 wt / w% to approximately 2 wt / w%.

[0262] In some embodiments, the tablets (e.g., dispersible tablets) are dissolved in a beverage before administration. In some embodiments, the beverage is water, milk, or juice (e.g., orange juice or apple juice). In some embodiments, the beverage is water. In some embodiments, the beverage is juice. In some embodiments, the tablets are orally dispersible in the subject's saliva.

[0263] In some embodiments, the pharmaceutical composition is in powder form (e.g., dispersible powder). In some embodiments, the powder (e.g., dispersible powder) is a dispersible powder. In some embodiments, the capsule or sachet contains the dispersible powder. In some embodiments, the powder (e.g., dispersible powder) contains about 0.5 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, and the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (c)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0264] In some embodiments, the powder (e.g., dispersible powder) comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy) -3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0265] In some embodiments, the powder (e.g., dispersible powder) comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0266] In some embodiments, the powder (e.g., dispersible powder) comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0267] In some embodiments, the powder (e.g., dispersible powder) comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0268] In some embodiments, the powder (e.g., dispersible powder) comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0269] In some embodiments, the powder (e.g., dispersible powder) comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0270] In some embodiments, the powder (e.g., dispersible powder) comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0271] In some embodiments, the powder (e.g., dispersible powder) comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0272] In some embodiments, the powder (e.g., dispersible powder) comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0273] In some embodiments, the powder (e.g., dispersible powder) comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0274] In some embodiments, the powder (e.g., dispersible powder) comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the powder (e.g., dispersible powder) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0275] In some embodiments, the powder (e.g., a dispersible powder) contains about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the pharmaceutical composition is dispersible in a beverage liquid, and the components of the pharmaceutical composition are as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.1 wt / wt% to approximately 7 wt / wt%, (b) one or more diluents in an amount of approximately 50 wt / wt% to approximately 98 wt / wt%, (c) one or more disintegrants in an amount of approximately 1 wt / wt% to approximately 10 wt / wt%, (d) one or more flavoring agents in an amount of 0 wt / wt% to approximately 5 wt / wt%, (e) one or more sweeteners in an amount of 0 wt / wt% to approximately 5 wt / wt%, and (f) one or more lubricants in an amount of 0 wt / wt% to approximately 5 wt / wt%.

[0276] In some embodiments, the powder (e.g., a dispersible powder) contains about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the pharmaceutical composition is dispersible in a beverage liquid, and the components of the pharmaceutical composition are as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.5 wt / w% to approximately 1.2 wt / w%; (b) one or more diluents in an amount of approximately 85 wt / w% to approximately 95 wt / w%; (c) one or more disintegrants in an amount of approximately 3.5 wt / w% to approximately 6 wt / w%; (d) one or more flavoring agents in an amount of 0 wt / w% to approximately 2.5 wt / w%; (e) one or more sweeteners in an amount of 0 wt / w% to approximately 2 wt / w%; and (f) one or more lubricants in an amount of approximately 0.5 wt / w% to approximately 2 wt / w%.

[0277] In some embodiments, the powder (e.g., a dispersible powder) is dissolved in a beverage before administration. In some embodiments, the beverage is water, milk, or juice (e.g., orange juice or apple juice). In some embodiments, the beverage is water. In some embodiments, the beverage is juice. In some embodiments, the powder is orally dispersible in the saliva of the subject.

[0278] In some embodiments, the pharmaceutical composition is in the form of granules (e.g., dispersible granules). In some embodiments, the granules (e.g., dispersible granules) are dispersible granules. In some embodiments, the capsule or sachet contains dispersible granules. In some embodiments, the granules (e.g., dispersible granules) contain about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (c)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0279] In some embodiments, the granules (e.g., dispersible granules) comprise about 0.5 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy) -3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0280] In some embodiments, the granules (e.g., dispersible granules) comprise about 1 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, the components of which the granules (e.g., dispersible granules) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0281] In some embodiments, the granules (e.g., dispersible granules) comprise about 1 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0282] In some embodiments, the granules (e.g., dispersible granules) comprise about 2 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0283] In some embodiments, the granules (e.g., dispersible granules) comprise about 2 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0284] In some embodiments, the granules (e.g., dispersible granules) comprise about 3 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, the components of which the granules (e.g., dispersible granules) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0285] In some embodiments, the granules (e.g., dispersible granules) comprise about 3 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0286] In some embodiments, the granules (e.g., dispersible granules) comprise about 4 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0287] In some embodiments, the granules (e.g., dispersible granules) comprise about 4 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0288] In some embodiments, the granules (e.g., dispersible granules) comprise about 5 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, the components of which the granules (e.g., dispersible granules) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy (b)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0289] In some embodiments, the granules (e.g., dispersible granules) comprise about 5 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the granules (e.g., dispersible granules) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0290] In some embodiments, the granules (e.g., dispersible granules) contain about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the pharmaceutical composition is dispersible in a beverage liquid, and the components of the pharmaceutical composition are as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.1 wt / wt% to approximately 7 wt / wt%, (b) one or more diluents in an amount of approximately 50 wt / wt% to approximately 98 wt / wt%, (c) one or more disintegrants in an amount of approximately 1 wt / wt% to approximately 10 wt / wt%, (d) one or more flavoring agents in an amount of 0 wt / wt% to approximately 5 wt / wt%, (e) one or more sweeteners in an amount of 0 wt / wt% to approximately 5 wt / wt%, and (f) one or more lubricants in an amount of 0 wt / wt% to approximately 5 wt / wt%.

[0291] In some embodiments, the granules (e.g., dispersible granules) contain about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the pharmaceutical composition is dispersible in a beverage liquid, and the components of the pharmaceutical composition are as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.5 wt / w% to approximately 1.2 wt / w%; (b) one or more diluents in an amount of approximately 85 wt / w% to approximately 95 wt / w%; (c) one or more disintegrants in an amount of approximately 3.5 wt / w% to approximately 6 wt / w%; (d) one or more flavoring agents in an amount of 0 wt / w% to approximately 2.5 wt / w%; (e) one or more sweeteners in an amount of 0 wt / w% to approximately 2 wt / w%; and (f) one or more lubricants in an amount of approximately 0.5 wt / w% to approximately 2 wt / w%.

[0292] In some embodiments, the granules (e.g., dispersible granules) are dissolved in a beverage before administration. In some embodiments, the beverage is water, milk, or juice (e.g., orange juice or apple juice). In some embodiments, the beverage is water. In some embodiments, the beverage is juice. In some embodiments, the granules are orally dispersible in the saliva of the subject.

[0293] In some embodiments, the pharmaceutical composition is in the form of a minitablet (e.g., a dispersible minitablet). In some embodiments, the minitablet is a dispersible minitablet. In some embodiments, the minitablet (e.g., a dispersible minitablet) contains about 0.5 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3- (b) dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0294] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in crystalline or amorphous form, the components of which the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy) (b) droxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 85% by weight to about 95% by weight, (d) one or more disintegrants in an amount of about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 2.5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 2% by weight, and (f) one or more lubricants in an amount of about 0.5% by weight to about 2% by weight.

[0295] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy) (Hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0296] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (roxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0297] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy) (Hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0298] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 2 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (roxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0299] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy) (Hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0300] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 3 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (roxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0301] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 4 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy) (Hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0302] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 4 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (roxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0303] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy) (Hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in an amount of about 50% by weight to about 98% by weight, (c) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0304] In some embodiments, a minitablet (e.g., a dispersible minitablet) contains about 5 mg of the crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide described herein, and the components of the minitablet (e.g., a dispersible minitablet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (roxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0305] In some embodiments, the mini-tablets (e.g., dispersible mini-tablets) contain about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the pharmaceutical composition is dispersible in a beverage liquid, with the components of the pharmaceutical composition being as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.1 wt / wt% to approximately 7 wt / wt%, (b) one or more diluents in an amount of approximately 50 wt / wt% to approximately 98 wt / wt%, (c) one or more disintegrants in an amount of approximately 1 wt / wt% to approximately 10 wt / wt%, (d) one or more flavoring agents in an amount of 0 wt / wt% to approximately 5 wt / wt%, (e) one or more sweeteners in an amount of 0 wt / wt% to approximately 5 wt / wt%, and (f) one or more lubricants in an amount of 0 wt / wt% to approximately 5 wt / wt%.

[0306] In some embodiments, the mini-tablets (e.g., dispersible mini-tablets) contain about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, and the pharmaceutical composition is dispersible in a beverage liquid, with the components of the pharmaceutical composition being as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.5 wt / w% to approximately 1.2 wt / w%; (b) one or more diluents in an amount of approximately 85 wt / w% to approximately 95 wt / w%; (c) one or more disintegrants in an amount of approximately 3.5 wt / w% to approximately 6 wt / w%; (d) one or more flavoring agents in an amount of 0 wt / w% to approximately 2.5 wt / w%; (e) one or more sweeteners in an amount of 0 wt / w% to approximately 2 wt / w%; and (f) one or more lubricants in an amount of approximately 0.5 wt / w% to approximately 2 wt / w%.

[0307] In some embodiments, the mini-tablets (e.g., dispersible mini-tablets) are dissolved in a beverage before administration. In some embodiments, the beverage is water, milk, or juice (e.g., orange juice or apple juice). In some embodiments, the beverage is water. In some embodiments, the beverage is juice. In some embodiments, the mini-tablets are orally dispersible in the subject's saliva.

[0308] In some embodiments, the pharmaceutical composition is in the form of pellets (e.g., dispersible pellets). In some embodiments, the pellets are dispersible pellets. In some embodiments, the pellets (e.g., dispersible pellets) contain about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the pellets (e.g., dispersible pellets) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy) (b) propoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 50% by weight to about 98% by weight, (d) one or more disintegrants in an amount of about 1% by weight to about 10% by weight, (d) one or more flavoring agents in an amount of 0% by weight to about 5% by weight, (e) one or more sweeteners in an amount of 0% by weight to about 5% by weight, and (f) one or more lubricants in an amount of 0% by weight to about 5% by weight.

[0309] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy) (b)(2-fluoro-4-iodophenylamino)-benzamide, (c) one or more diluents in an amount of about 85% to about 95% by weight, (d) one or more disintegrants in an amount of about 3.5% to about 6% by weight, (e) one or more flavorings in an amount of 0% to about 2.5% by weight, (f) one or more lubricants in an amount of about 0.5% to about 2% by weight.

[0310] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy Ropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 50% by weight to about 98% by weight, (c) one or more disintegrants in about 1% by weight to about 10% by weight, (d) one or more flavoring agents in 0% by weight to about 5% by weight, (e) one or more sweeteners in 0% by weight to about 5% by weight, and (f) one or more lubricants in 0% by weight to about 5% by weight.

[0311] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (xy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0312] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy Ropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 50% by weight to about 98% by weight, (c) one or more disintegrants in about 1% by weight to about 10% by weight, (d) one or more flavoring agents in 0% by weight to about 5% by weight, (e) one or more sweeteners in 0% by weight to about 5% by weight, and (f) one or more lubricants in 0% by weight to about 5% by weight.

[0313] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (xy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0314] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy Ropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 50% by weight to about 98% by weight, (c) one or more disintegrants in about 1% by weight to about 10% by weight, (d) one or more flavoring agents in 0% by weight to about 5% by weight, (e) one or more sweeteners in 0% by weight to about 5% by weight, and (f) one or more lubricants in 0% by weight to about 5% by weight.

[0315] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, wherein the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (xy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0316] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy Ropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 50% by weight to about 98% by weight, (c) one or more disintegrants in about 1% by weight to about 10% by weight, (d) one or more flavoring agents in 0% by weight to about 5% by weight, (e) one or more sweeteners in 0% by weight to about 5% by weight, and (f) one or more lubricants in 0% by weight to about 5% by weight.

[0317] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (xy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0318] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.1 wt / wt% to about 7 wt / wt% of N-((R)-2,3-dihydroxypropoxy Ropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 50% by weight to about 98% by weight, (c) one or more disintegrants in about 1% by weight to about 10% by weight, (d) one or more flavoring agents in 0% by weight to about 5% by weight, (e) one or more sweeteners in 0% by weight to about 5% by weight, and (f) one or more lubricants in 0% by weight to about 5% by weight.

[0319] In some embodiments, the pellet (e.g., a dispersible pellet) comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide as described herein, in crystalline or amorphous form, and the components of the pellet (e.g., a dispersible pellet) are as follows: (a) about 0.5 wt / wt% to about 1.2 wt / wt% of N-((R)-2,3-dihydroxypropoxy (xy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, (b) one or more diluents in about 85% by weight to about 95% by weight, (c) one or more disintegrants in about 3.5% by weight to about 6% by weight, (d) one or more flavoring agents in 0% by weight to about 2.5% by weight, (e) one or more sweeteners in 0% by weight to about 2% by weight, and (f) one or more lubricants in about 0.5% by weight to about 2% by weight.

[0320] In some embodiments, the pellet (e.g., a dispersible pellet) contains about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the pharmaceutical composition is dispersible in a beverage liquid, and the components of the pharmaceutical composition are as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.1 wt / wt% to approximately 7 wt / wt%, (b) one or more diluents in an amount of approximately 50 wt / wt% to approximately 98 wt / wt%, (c) one or more disintegrants in an amount of approximately 1 wt / wt% to approximately 10 wt / wt%, (d) one or more flavoring agents in an amount of 0 wt / wt% to approximately 5 wt / wt%, (e) one or more sweeteners in an amount of 0 wt / wt% to approximately 5 wt / wt%, and (f) one or more lubricants in an amount of 0 wt / wt% to approximately 5 wt / wt%.

[0321] In some embodiments, the pellet (e.g., a dispersible pellet) contains about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, the pharmaceutical composition is dispersible in a beverage liquid, and the components of the pharmaceutical composition are as follows: (a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide in an amount of approximately 0.5 wt / w% to approximately 1.2 wt / w%; (b) one or more diluents in an amount of approximately 85 wt / w% to approximately 95 wt / w%; (c) one or more disintegrants in an amount of approximately 3.5 wt / w% to approximately 6 wt / w%; (d) one or more flavoring agents in an amount of 0 wt / w% to approximately 2.5 wt / w%; (e) one or more sweeteners in an amount of 0 wt / w% to approximately 2 wt / w%; and (f) one or more lubricants in an amount of approximately 0.5 wt / w% to approximately 2 wt / w%.

[0322] In some embodiments, the pellets (e.g., dispersible pellets) are dissolved in a drinking liquid before administration. In some embodiments, the drinking liquid is water, milk, or juice (e.g., orange juice or apple juice). In some embodiments, the drinking liquid is water. In some embodiments, the drinking liquid is juice. In some embodiments, the pellets are orally dispersible in the saliva of the subject.

[0323] Treatment method In some embodiments, the present disclosure provides a method for treating a tumor, cancer, or rasopathy disorder, comprising administering a pharmaceutical composition described herein to a subject in need of such treatment.

[0324] In some embodiments, the tumor is a neurofibroma. In some embodiments, the tumor is a neurofibroma associated with neurofibromatosis type 1. In some embodiments, the tumor is selected from the group consisting of cutaneous neurofibromas, plexiform neurofibromas, optic tract gliomas, low-grade gliomas, high-grade gliomas, or malignant peripheral nerve sheath tumors. In some embodiments, the tumor is a plexiform neurofibroma.

[0325] In some aspects, subjects are diagnosed with rasopathy, selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardiac-facial-cutaneous syndrome, Costello syndrome, Regius syndrome, Noonan syndrome, and Noonan syndrome with lentigo multiplica.

[0326] In some embodiments, cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial carcinoma, uterine tumor, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer, and serous carcinoma of the peritoneum. In some embodiments, leukemia is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. In some embodiments, lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal large B-cell lymphoma, small lymphocytic lymphoma, and Waldenström macroglobulinemia. In some embodiments, lung cancer is selected from the group consisting of lung adenocarcinoma, squamous cell non-small cell lung cancer, non-squamous cell non-small cell lung cancer, and small cell lung cancer.

[0327] In some embodiments, the subjects have mutations or other abnormalities in one or more genes that cause the acquisition or loss of function characteristic of a particular cancer, and the mutations or other abnormalities in one or more genes are mutations or other abnormalities in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.

[0328] In some embodiments, individual doses of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are administered as two or more capsules, tablets (e.g., dispersible tablets), powders (e.g., dispersible powders), granules (e.g., dispersible granules), minitablets (e.g., dispersible minitablets), pellets (e.g., dispersible pellets), or combinations thereof. For example, a 3 mg dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide may be administered as two capsules—one containing 2 mg and the other containing 1 mg—or as three capsules, each containing 1 mg. As another example, a 1.5 mg dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide may be administered as a dispersible dosage form containing 1 mg in one dispersible tablet and 0.5 mg in separate units of dispersible powder, or as three units of dispersible powder, each containing 0.5 mg.

[0329] In some embodiments, if N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered more than twice a day, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide may be divided so that the patient receives a different dose with each administration. For example, if the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is 2 mg administered twice daily, the patient may receive 0.5 mg in the morning (e.g., as one 0.5 mg tablet (e.g., a dispersible tablet)) and 1.5 mg in the evening (e.g., as one 0.5 mg dose of powder (e.g., a dispersible powder) and one 1 mg capsule).

[0330] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is provided in an amount of about 0.1 mg to about 20 mg per dose of the pharmaceutical composition described herein. In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of approximately 0.1 mg, approximately 0.2 mg, approximately 0.3 mg, approximately 0.4 mg, approximately 0.5 mg, approximately 0.6 mg, approximately 0.7 mg, approximately 0.8 mg, approximately 0.9 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 6 mg, approximately 7 mg, approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, approximately 15 mg, approximately 16 mg, approximately 17 mg, approximately 18 mg, approximately 19 mg, or approximately 20 mg per dose. In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of about 0.5 mg per dose. In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of about 1 mg per dose. In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of about 2 mg per dose. In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of approximately 3 mg per dose. In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of approximately 4 mg per dose.In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of approximately 5 mg per dose. In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of approximately 10 mg per dose. In some embodiments, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide are provided in amounts of approximately 20 mg per dose.

[0331] In some embodiments, a pharmaceutical composition comprising one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once, twice, three times, or four times daily. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily.

[0332] In some embodiments, the Disclosure provides a method for treating a tumor, cancer, or rasopathy disorder, comprising administering a pharmaceutical composition described herein to a patient in need of such treatment, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is approximately 0.1 mg to approximately 10 mg, administered twice daily.

[0333] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered via the pharmaceutical compositions described herein, and N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is provided in a total daily dose not exceeding 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 20 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 15 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 12 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 10 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 8 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 6 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 4 mg.In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 2 mg. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a total daily dose not exceeding 1 mg.

[0334] In some embodiments, the present disclosure provides a method for treating a tumor, cancer, or rasopathy disorder, comprising administering a pharmaceutical composition described herein to a patient in need of such treatment, wherein the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily in doses ranging from about 0.1 mg to about 20 mg, respectively.

[0335] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily in doses ranging from approximately 0.1 mg to approximately 20 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily in doses of approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 0.5 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 1 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 2 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 3 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 4 mg.In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 5 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 6 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 7 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 8 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 9 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 10 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 11 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 12 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 13 mg.In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 14 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 15 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 16 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 17 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 18 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 19 mg. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered once daily at a dose of approximately 20 mg.

[0336] In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily in doses of approximately 0.1 mg to approximately 10 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily in doses of approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, respectively. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily in doses of approximately 0.25 mg, respectively. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 0.5 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 1 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 2 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 3 mg each.In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 4 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 5 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 6 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 7 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 8 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 9 mg each. In some embodiments, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered twice daily at doses of approximately 10 mg each.

[0337] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) 21 days in which the total daily dose is administered, and (b) 7 days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) 21 consecutive days in which the total daily dose is administered, followed by (b) 7 consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered.

[0338] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) three 7-day periods, each comprising (i) five days in which the total daily dose is administered and (ii) two days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered, and (b) seven days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered. In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle comprising: (a) three 7-day periods, each comprising (i) five consecutive days in which the total daily dose is administered and (ii) two consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered, followed by (b) seven consecutive days in which N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is not administered.

[0339] In some embodiments, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide is administered in a 28-day administration cycle, including 28 days in which the total daily dose is administered.

[0340] In some embodiments, the 28-day administration cycle is repeated up to a total of 24 consecutive 28-day administration cycles.

[0341] In some embodiments, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablet, or dispersible pellet, which is dispersed in a drinking liquid (e.g., water or juice (e.g., orange juice or apple juice)) before being administered to a subject.

[0342] In some embodiments, the composition is an orally dispersible dosage form (e.g., a dispersible tablet, a dispersible powder, dispersible granules, a dispersible minitablet, or a dispersible pellet) that is administered to the subject without first dissolving the dosage form in a separate container.

[0343] In some aspects, the subjects experience dysphagia. In some aspects, the subjects experience dysphagia caused by one or more of the following: neurological disorders, muscle weakness, developmental disorders, stroke, trauma, anatomical defects, cancer, cancer treatment, allergic reactions, dementia, memory loss, or cognitive decline. In some aspects, the subjects are diagnosed with autism spectrum disorder. In some aspects, the subjects are diagnosed with craniofacial disorders. In some aspects, the subjects are diagnosed with myasthenia gravis. In some aspects, the subjects are diagnosed with tardive dyskinesia.

[0344] In some embodiments, the target audience is children. In some embodiments, the target audience is under 18, under 17, under 16, under 15, under 14, under 13, under 12, under 11, under 10, under 9, under 8, under 7, under 6, under 5, under 4, under 3, under 2, or under 1 year old. In some embodiments, the target audience is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 years old. In some embodiments, the target audience is under 13 years old. In some embodiments, the target audience is under 12 years old. In some embodiments, the target audience is under 11 years old. In some embodiments, the target audience is under 10 years old. In some embodiments, the target audience is under 9 years old. In some embodiments, the target audience is under 8 years old. In some cases, the target age is under 7 years old. In some cases, the target age is under 6 years old. In some cases, the target age is under 5 years old. In some cases, the target age is under 4 years old. In some cases, the target age is under 3 years old. In some cases, the target age is under 2 years old. In some cases, the target age is under 1 year old. In some cases, the target age is approximately 2 to 18 years old. In some cases, the target age is approximately 3 to 17 years old. In some cases, the target age is approximately 4 to 16 years old. In some cases, the target age is approximately 5 to 15 years old. In some cases, the target age is approximately 6 to 14 years old. In some cases, the target age is approximately 7 to 13 years old. In some cases, the target age is approximately 8 to 12 years old.

[0345] In some cases, the target group is elderly. In some cases, the target group is over 30, over 35, over 40, over 45, over 50, over 55, over 60, over 65, over 70, over 75, over 80, over 85, over 90, over 95, or over 100. In some cases, the target group is over 50. In some cases, the target group is over 60. In some cases, the target group is over 70. In some cases, the target group is over 80. In some cases, the target group is over 90. In some cases, the target group is over 100.

[0346] In some embodiments, the present disclosure provides the use of the pharmaceutical compositions described herein for the manufacture of pharmaceuticals for the treatment of cancer, tumors, or rasopathy disorders.

[0347] Preparation method for N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and essentially pure form IV A novel method for producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I), [ka] A method is disclosed herein, as shown in Scheme I below, which involves reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent which is 1-propylphosphonic anhydride ("T3P") to obtain 901 acetonide. Scheme 1 [ka]

[0348] In some embodiments, T3P is in a solution. In some embodiments, T3P is provided as a solution in ethyl acetate.

[0349] In some embodiments, a method for producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I) in an essentially pure form IV comprises (a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent, T3P, to obtain 901 acetonide, and (b) treating 901 acetonide with an acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, as shown in Scheme II below. Scheme II [ka]

[0350] In some embodiments, the synthesis of the essentially pure crystalline form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I) involves the reaction described according to scheme III. Scheme III [ka]

[0351] In some embodiments, the synthesis of the essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I) is shown below in scheme IV. Scheme IV [ka]

[0352] In some embodiments, a method for preparing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide yields a crystalline composition that is essentially a pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide.

[0353] In some embodiments, the crystalline composition of form IV, which is essentially pure, contains ≤0.2% of the dimeric impurity PF-00191189. [ka]

[0354] In some embodiments, the essentially pure form IV crystalline composition contains about 0.05% to about 0.19% by weight of the dimerized impurity PF-00191189. In some embodiments, the essentially pure form IV crystalline composition contains about 0.05% to about 0.15% by weight of the dimerized impurity PF-00191189. In some embodiments, the essentially pure form IV crystalline composition contains about 0.05% to about 0.10% by weight of the dimerized impurity PF-00191189. In some embodiments, the essentially pure form IV crystalline composition does not contain any detectable amount of the dimerized impurity PF-00191189.

[0355] In some embodiments, the amount of the dimeric impurity PF-00191189 is determined using high-performance liquid chromatography ("HPLC"). In some embodiments, reversed-phase liquid chromatography using a 275 nm ultraviolet detector is used. [Examples]

[0356] Abbreviations and acronyms [Table 1-1] [Table 1-2]

[0357] Example 1: Generation of a seed crystal of morphology IV Step 1: Preparation of "side chain," PD-0337792 14.4 kg of alcohol (99.4% chemical purity, 99.6% optical purity, with an excess of enantiomers) was converted to a 9.7 wt / wt% PD-0337792 (IPGA) solution of 97.5 kg in toluene (overall yield approximately 60%). Triflate activation was carried out in a 200 L reactor by maintaining the temperature below -20°C during the addition of anhydrous triflric acid. The resulting activated alcohol was then transferred to a 400 L reactor containing solid N-hydroxyphthalimide (NHP), and the reaction was completed at ambient temperature. Final base deprotection was carried out by adding aqueous ammonia (approximately 28% solution, 5 equivalents, 34 kg). After the reaction was complete, water was removed from the toluene by distillation, and the resulting solid byproduct was filtered to obtain the product solution.

[0358] Step 2: Preparation of PD-0315209 This process theoretically yielded 21.4 kg (99.4 wt / wt% assay) at 80% concentration using lithium amide base (5 kg, 3.2 equivalents) from the starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 equivalent) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 equivalents). The reaction was initiated by adding 5% of the total TFBA and FIA solution to the lithium amide slurry at 50°C. This reaction showed a minimum initiation period of approximately 10 minutes, observed by color change and slight exothermic reaction. The remaining TFBA / FIA solution in THF was slowly added through a pressure vessel within 1 hour, while maintaining the reaction temperature within 45-55°C. No significant pressure increases (due to ammonia gas release) were observed throughout the operation.

[0359] Step 3: Preparation of PD-0325901 To mitigate potential gas generation, modifications were made to the CDI packing. Two equal portions of CDI were added to solid FIPFA (via a shot loader) before and after solvent addition. The timing between the two additions of solid CDI (4.6 kg each) should not exceed 30 minutes. The two intermediate filter cakes were then dissolved in ethanol. Excess ethanol was distilled and replaced with approximately 5% vol / vol ethanol in toluene before recrystallization of PD-0325901. Laboratory studies suggested that crystallization from toluene and acetonitrile, as well as recrystallization from ethanol in toluene, could not reduce the impurities essential for polymorph conversion. The presence of dimer impurities (PF-00191189) at levels above 0.2% is known to result in the formation of undesirable polymorphs. [ka]

[0360] Crude crystallization from the final reaction mixture reduced the dimeric impurity PF-00191189 to approximately 1.9%, and subsequent recrystallization further reduced it to approximately 0.4%. As a result, undesirable polymorphs were produced. The DSC pattern showed two different melting points: approximately 80°C (low melt form II) and approximately 117°C (form I). Also, during processing, the solid crystallized at a much lower temperature than expected (actually approximately 10°C, expected to be approximately 40°C). The unsuccessful recrystallization is presumed to be due to changes in solvent composition resulting from incomplete drying of the crude product. When the crude product was approximately 28 kg (theoretically 26 kg), drying of the crude wet cake before ethanol dissolution was stopped after approximately 36 hours.

[0361] Polymorphic transformation Approximately 7.4 kg of PD-0325901 (mixed polymorph) from the final EtOH / water crystallization and the precipitate from the previous EtOH / toluene filtrate were subjected to polymorph conversion. Both products were dried separately by filtration to a certain weight, and each was dissolved in EtOH. The combined EtOH solution was analyzed by HPLC to obtain an estimated 16.4 kg of PD-0325901. Recrystallization was initiated after removing EtOH by vacuum distillation and adjusting the solvent composition to approximately 5% EtOH in toluene at 65°C (i.e., EtOH was added dropwise at 65°C until complete solid dissolution).

[0362] To ensure satisfactory results, a slow cooling lamp was used to 5°C for 4 hours, followed by 12 hours of stirring. The resulting slurry was filtered and again completely dried in the filter until a constant weight was achieved (approximately 3 days). The purified solid showed 99.8% pure PD-0325901 and no detectable levels of the dimeric impurity PF-00191189.

[0363] The dried solid (15.4 kg) was redissolved in exactly 4 volumes of EtOH (62 L) from the filter, transferred to a reactor, and precipitated by slowly adding water (308 L) at 30-35°C (approximately 3 hours). The mixture was then cooled to 20°C and stirred for 12 hours. DSC analysis of the slurry sample taken after 2 hours showed that the solid was completely in morph IV (the desired polymorph).

[0364] Using 21.4 kg of PD-0315209, 9.7 kg of CDI (1.05 equivalents), and 91 kg of a toluene solution of 9.7% PD-0337792 (1.1 equivalents), 12.74 kg of PD-0325901 was obtained (assay 99.4%, 100% form IV, yield approximately 48%).

[0365] Example 2: Assay / Impurity and Identification of PD-0325901 PD-0325901 is separated from process impurities and degradation products by reversed-phase liquid chromatography with UV detection at 275 nm. Identification of PD-0325901 is performed by obtaining either infrared or proton NMR spectra in addition to HPLC retention time. For purity assessment, process impurities and degradation products are identified by their characteristic relative retention times and quantified by area normalization.

[0366] Chromatography conditions: Agilent Zorbax SB C18, 5 μm, 4.6 × 250 mm (or equivalent), flow rate 1.0 mL / min, column temperature 30°C, detector wavelength 275 nm, diluent 50 / 50 acetonitrile / water, mobile phase A 0.1% trifluoroacetic acid (TFA) in water, mobile phase B methanol, and the following gradient conditions. Assays are determined against a reference standard and reported on an anhydrous, solvent-free basis. Quantification of specified and unspecified impurities is reported as area percentage. Total impurities are the sum of all impurities present above the reporting threshold of 0.05%. [Table 2]

[0367] Example 3: Improved process for preparing Form IV As described in Example 1, the synthetic method for producing mildametinib as form IV produced form IV containing the dimeric impurity PF-00191189, and a further step was required to convert the product into essentially pure form IV, which does not have the undesirable polymorphs of forms I and II. Therefore, there was a need to develop a method for producing essentially pure form IV without additional processing steps.

[0368] Mildametinib manufacturing process This pathway is a convergent four-step synthesis with a total of six chemical steps, using the proposed starting materials (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (SGA), 2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-iodoaniline (FIA), and N-hydroxyphthalimide (NHP). The final step (step 4) provides the essentially pure form IV of mildametinib. Scheme for the preparation of mildametinib: [ka]

[0369] Step 1 (Preparation of PD-0337792 (IPGA)): A clean, dry 100-gallon reactor was packed with toluene (139.3 kg, 8 vols) and (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (SGA; 20.0 kg, 1.0 equivalent). Triethylamine (18.8 kg, 1.22 equivalents) was then packed into the reactor. The contents of the reactor were stirred and cooled to -10±10°C. Trifluoromethanesulfonic anhydride (43.5 kg, 1.02 equivalents) was added to a clean 50-L round-bottom flask under nitrogen and then cooled to ≤10°C. The cooled trifluoromethanesulfonic anhydride was slowly transferred to the 100-gallon reactor while maintaining the internal temperature at -10±10°C. The reaction mixture was stirred at -10±10°C for 30 minutes. TLC monitoring of the reaction indicated that the conversion was complete. Anhydrous toluene (99.8 kg, 5.75 vol) was packed into the reactor while maintaining the internal temperature at -10 ± 10°C, followed by N-hydroxyphthalimide (26.4 kg, 1.07 equivalents). The contents were heated to 20 ± 5°C and then stirred at this temperature for at least 5 hours until the triflate intermediate was no longer detectable by TLC. The reaction mixture was divided into two equal parts. Each toluene solution was quenched with USP purified water (66 kg, 6.7 vol). The toluene solutions were then washed twice with USP purified water (66 kg, 6.7 vol).

[0370] The toluene solution was recombined in a 100-gallon reactor. The organic solution was treated with a 28% ammonium hydroxide solution (41.5 kg, 7.8 equivalents). The contents were heated to 35 ± 5°C and then stirred for at least 12 hours ("NLT"). After the reaction was complete, the lower aqueous phase was removed. The toluene solution was dried by azeotropic distillation of toluene. The toluene solution was then concentrated to the minimum stirring volume. The concentrated solution was filtered to remove the solid by-product. The cake was washed with toluene and the filtrates were combined. The assay of the toluene solution showed the presence of 8.6 kg (36.7% yield) of PD-0337792 (IPGA).

[0371] Step 2 (Preparation of PD-0315209): A clean, dry 100-gallon reactor was purged with nitrogen and then packed with lithium amide (LiNH2, 8.8 kg, 3.4 equivalents), followed by tetrahydrofuran (THF, 56.8 kg, 3.2 vols). The mixture was cooled to 10 ± 10°C, then an additional THF (15.1 kg, 0.85 vols) was packed into the reactor, followed by a solution of 2,3,4-trifluorobenzoic acid (TFBA, 20.0 kg, 1.0 equivalent) in THF (26.4 kg, 1.15 vols). The reaction mixture was heated to 50°C NMT ("below"). A solution of 2-fluoro-4-iodoaniline (FIA, 27.5 kg, 1.02 equivalents) in THF (17.8 kg, 1 vol) was gradually added to the reactor while stirring for 1 hour between additions, maintaining a batch temperature of NMT 50°C. After the addition was complete, the reaction mixture was stirred for a further 3 hours at 50±10°C. Once the reaction was complete, the mixture was cooled to NMT 10°C and then quenched with USP purified water (120.3 kg, 6 vol). The reaction mixture was distilled to approximately 30 gallons, and then methyl t-butyl ether (MTBE, 118.6 kg, 8 vol) was added. The MTBE solution was then quenched to pH=7 with 2M hydrochloric acid solution (89.5 kg). The aqueous phase was then removed. The MTBE solution was filtered through Celite, washed twice with 5% brine (104.1 kg, 5.2 vol.), and then washed with 1 M hydrochloric acid (77.4 kg). The MTBE solution was replaced with toluene, and then the volume was adjusted to approximately 50 gallons. This mixture was heated to 75±5°C for 1 hour, then cooled to 20±5°C and stirred for 1 hour. The product was filtered, washed with toluene (68.1 kg, approximately 4 vol.), and then dried under vacuum at 40°C to obtain 25.2 kg of PD-0315209 (56.4% yield).

[0372] Step 3 (Preparation of crude PD-0325901): A clean, dry 100-gallon reactor was purged with nitrogen and then packed with PD-0315209 (18.0 kg, 1 equivalent) and THF (113.0 kg, 7 volumes). The mixture was cooled to 5±5°C. N,N-diisopropylethylamine (15.1 kg, 2.55 equivalents) was packed while maintaining an NMT temperature of 25°C. The mixture was cooled to 5±5°C and then stirred for 10 minutes. PD-0337792 solution in toluene (total 121.7 kg, 1.3 equivalents) was packed into the reactor at 5±5°C, followed by packing with 50% T3P in ethyl acetate (42.0 kg, 1.45 equivalents). The reaction mixture was stirred at 10±5°C for 3 hours under NLT. To complete the coupling reaction, additional N,N-diisopropylethylamine (1.9 kg, 0.3 equivalents) and 50% T3P were added to ethyl acetate (4.1 kg, 0.15 equivalents). The reaction mixture was back-quenched in 5% sodium hydroxide solution (50 kg) and washed with 5% brine (55.4 kg). The organic solution was concentrated, and the solvent was replaced with toluene. Acetonitrile (43.0 kg, 2.4 vols) was added to the reactor, followed by 2M hydrochloric acid (117.6 kg, 5.1 equivalents). The mixture was stirred at 25±5°C until the reaction was complete after 16 hours. The bottom aqueous phase was removed, and the reaction mixture was washed with 5% brine (75.2 kg). The organic phase was concentrated, and the solvent was replaced with toluene to the appropriate volume. The mixture was then heated to 75±5°C for 30 minutes, and then slowly cooled to 20°C. The solid was filtered and then washed with toluene (31.1 kg, 1.7 vol).

[0373] The crude solid was returned to a 100-gallon reactor, followed by the addition of 5% ethanol in toluene (170.0 kg). The mixture was heated to 75±5°C for 60 minutes to obtain a solution, which was then slowly cooled to 20°C. The solid was filtered and then washed twice with toluene (31 kg, 1.7 vol). The wet cake was dried under vacuum at 45°C to obtain 8.2 kg of crude PD-0325901 (37.1% yield).

[0374] Step 4 (Preparation of essentially pure form IV mildametinib): A clean, dry 100-gallon reactor was purged with nitrogen and then packed with USP purified water (164.1 kg, 20 vols), followed by ethanol (200 proof, 20.8 kg, 3.25 vols). The solution was heated to 35 ± 5°C. In a separate vessel, crude PD-0325901 (8.1 kg, 1 equivalent) was dissolved in ethanol (200 proof, 40.5 kg, 6.3 vols). A portion of this solution (14.4 kg) was added to the 100-gallon reactor over 60 minutes. Seed of PD-0325901 form IV prepared in Example 1 (82.6 g, 1 wt%) was added to the reactor to facilitate precipitation. The remaining crude PD-0325901 / ethanol solution (34.3 kg) was added to the reactor over 90 minutes while stirring the mixture at 35±5°C. The contents of the reactor were stirred at 35±5°C for 5.5 hours, and then slowly cooled to 20°C. The solid was then filtered, washed with USP purified water (16.5 kg, 2 volumes), and dried under vacuum at 45°C for 16 hours. The dried solid was screened through a 10-mesh sieve to obtain 5.7 kg of PD-0325901 form IV (70.4% yield).

[0375] Figure 1A shows the XRPD patterns for the essentially pure morph IV used herein. Figure 1B shows the TGA and DSC analyses for the essentially pure morph IV used herein.

[0376] Example 4: Approximate kinetic solubility The solubility of mildametinib prepared according to Example 3 was evaluated in 30 different solvents. Solubility was visually estimated at room temperature (RT; approximately 23°C) by administering a small aliquot of the solvent to a fixed amount of solid (approximately 10 mg) until the dissolution point or maximum volume (1.8 mL) was reached. Samples containing undissolved solid at RT were heated at 40°C for 1 hour, and dissolution was visually evaluated. The solubility data are shown in Table 1 below. [Table 3]

[0377] Example 5: Comprehensive crystal morphology screening Approximately 450 crystallization experiments were conducted using mildametinib prepared in Example 3, and novel polymorphs and solvates / hydrates of mildametinib were identified. The crystallization method and solid form of the input materials are described here.

[0378] Crystallization mode The screening study used four main types of crystallization modes. Slurry equilibrium: ○Isothermal heating at 5, 25, and 50°C for 48-72 hours ○ 48-hour thermal cycle at 40-5°C (1 hour) Rapid and controlled cooling of mildametinib clarification solution: ○The temperature was controlled to cool from 50°C to 5°C at a rate of 0.1°C / min, held for 1 hour for every 5°C increment, then held at 5°C for 5 days, followed by holding at -20°C (for the remaining solution) for 6-9 days. ○ Rapidly cool from 50°C to -20°C at an uncontrollable rate, then maintain at -20°C for 4 to 14 days. Rapid and slow evaporation of mildametinib clarification solution: ○Slow evaporation for up to 30 days under ambient conditions ○Rapid evaporation for up to 3 days under reduced pressure at ambient temperature Addition of a poor solvent to saturated and clarified mildametinib solution at room temperature: ○ Rapid addition of poor solvent and stirring at ambient temperature for up to 11 days. [Table 4-1] [Table 4-2]

[0379] Example 6: Preparation and experimentation of amorphous materials Amorphous mildametinib was prepared on a 100 mg scale by rapid evaporation under reduced pressure (using a Genevac® vacuum centrifuge) of 100 mg / mL solutions of mildametinib in methanol and THF (A-1 and A-2, respectively).

[0380] Mildametinib solutions (100 mg / mL) were prepared in methanol and THF. Each solution was divided into three equal parts and used for 1) evaluation of open stability in RT, 2) evaluation of closed stability in RT, and 3) evaluation of closed stability at -20°C. Observation after rapid evaporation revealed that the methanol-derived sample was mostly a dry, glassy material, while the THF-derived sample was mostly a sticky, dark amber gum.

[0381] PXRD analysis of all six samples (three from both methanol and THF) after rapid evaporation showed an amorphous state. Other analyses (e.g., PLM, TGA-IR, DSC) were performed on one sample from each solvent. Following the initial analysis, one sample from each solvent was stored at RT in an open vial, at RT in a capped vial, and at -20°C in a capped vial.

[0382] PXRD and PLM analysis after 1 day showed no crystallization in A-1a (open at RT) and A-1b (capped at RT) from methanol. A-1c (capped at -20°C) was not analyzed.

[0383] PXRD and PLM analysis after 1 day showed crystallization to morphology IV in A-2a (open at RT) from THF. A-2b (capped at RT) and A-2c (capped at -20°C) were not analyzed.

[0384] Amorphous mildametinib (A-1) was successfully prepared on a 100 mg scale by rapid evaporation under reduced pressure from a methanol solution. This method was used to prepare vials containing the amorphous material for use as input material for slurry maturation experiments in a screen. [Table 5]

[0385] Characterization of amorphous materials (A-1) PXRD and PLM analyses indicated that the material was amorphous. DSC analysis showed no endothermic melting up to 200°C, consistent with the amorphous phase. TGA-IR analysis showed a loss of approximately 1.3 wt% of water and methanol during heating from 26°C to 200°C. Amorphous mildametinib was physically stable in both open and closed vials for at least 24 hours at RT.

[0386] Example 7: Results of crystal form screening The crystal structure screen consisted of approximately 450 crystallization experiments covering crystalline and amorphous input materials, as well as various crystallization modes, solvents, and temperatures.

[0387] Four hydrates (labeled morphs VI, XIII, XIX, and XX) were observed and appear to be novel morphs. Water activity experiments between the unsolvated morph IV and the two stable hydrates (morphs VI and XIX) showed that morph IV was more stable than hydrates morphs VI and XIX, with a water activity (aw) of 0.6–0.99.

[0388] The 15 solvates observed (indicated as forms V, VII-XII, XV-XVIII, and XXI-XXIV) included process-related toluene (form V), toluene / MIBK (form VIII), and unstable toluene (form IX) solvates.

[0389] A mildametinib / process solvent conversion study involving stirring toluene solvate (Form V) in 1.1 / 0.5 (vol / vol) water / ethanol at RT, varying the amount of added toluene, showed that controlling the toluene level entering the final crystallization stage may be important if the crude mildametinib from toluene / ethanol is a pure toluene solvate. However, monitoring the toluene level in crude mildametinib may not be as important if the crude API is Form IV, which mainly contains a smaller amount of toluene solvate. Summary of Slurry Maturation and Evaporation Screening Results [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 7] Summary of Cooling and Solvent-Poor Solvent Screening Results [Table 8-1] [Table 8-2] [Table 8-3] [Table 9]

[0390] Example 8: Description of the obtained crystalline form of mildametinib The following sections describe and outline the physical properties of each observed crystalline form of mildametinib.

[0391] Transient unsolvated form XIV Characterization data for Form XIV, a transient non-solvated form very similar to Form IV, are presented in Figures 12A and 12B. PXRD and PLM analyses indicate the material is crystalline. DSC analysis shows a single sharp endothermic reaction starting at approximately 111°C (ΔH = 85.6 J / g). TGA-IR analysis shows a loss of approximately 0.15 wt% by 150°C, indicating a non-solvated form. Form XIV was found to convert to Form IV within 4 days under ambient conditions. Form XIV was not scaled up for further study (e.g., relative stability testing).

[0392] Toluene solvate form V Characterization data for form V, a process-related toluene solvate, are presented in Figures 3A and 3B. PXRD and PLM analyses indicate the material is crystalline. DSC analysis shows two overlapping endothermic reactions starting at approximately 77°C (ΔH=44.3 J / g) and approximately 95°C (ΔH=33.2 J / g). TGA-IR analysis shows a loss of approximately 2.7 wt% (0.15 equivalents) of toluene when heated to 100°C and a total loss of approximately 4.7 wt% (0.26 equivalents) of toluene when heated to 185°C, indi...

Claims

1. A method for producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I), 【Chemistry 1】 The method described above includes reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with the coupling reagent 1-propylphosphonic anhydride (T3P) to obtain 901 acetonide, as shown in Scheme 1. Scheme 1 【Chemistry 2】

2. The method according to claim 1, wherein the method for producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I) is As shown in Scheme II, (a) Reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent which is 1-propylphosphonic anhydride (T3P) to obtain 901 acetonide, (b) A method comprising treating 901 acetonide with an acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. Scheme II 【Transformation 3】

3. The method according to claim 1, wherein the method for producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide of formula (I) is 【Chemistry 4】 According to Scheme III, (i) Reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent to obtain 901 acetonide, (ii) A method comprising treating 901 acetonide with an acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide. Scheme III 【Transformation 5】

4. A pharmaceutical composition for the treatment of neurofibromas associated with neurofibromatosis type 1, comprising a crystalline composition which is essentially pure form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, wherein the crystalline composition contains ≤0.2% of dimeric impurities PF-00191189 【Transformation 6】 The pharmaceutical composition containing the above.

5. The pharmaceutical composition according to claim 4, wherein the crystalline composition does not contain form I or form II of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide, which is detectable by XRPD and / or DSC.

6. The pharmaceutical composition according to claim 4 or 5 for treating plexiform neurofibromas associated with neurofibromatosis type 1.

7. The pharmaceutical composition according to any one of claims 4 to 6, wherein the crystalline composition contains about 0.05% to about 0.19% by weight of the dimerized impurity PF-00191189.

8. The pharmaceutical composition according to any one of claims 4 to 6, wherein the crystalline composition does not contain a detectable amount of the dimeric impurity PF-00191189.

9. A pharmaceutical composition according to any one of claims 4 to 8, which is a tablet.

10. A pharmaceutical composition according to any one of claims 4 to 8, which is a capsule.

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