Crystalline form of pyrrolopyridine-aniline compounds

Abstract

The present disclosure provides crystalline forms of the compound having formula (I), crystalline forms A, B, C, E, F, and H, each of which is characterized by an X-ray powder diffraction (XRPD) pattern. The present disclosure also provides methods for preparing the crystalline forms, particularly form A. The present disclosure further provides methods of treating various skin disorders using the crystalline forms of the present disclosure or pharmaceutical compositions thereof. TIFF2024503892000054.tif110128

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 139,975, filed on 21 January 2021, which is incorporated in its entirety for all purposes. [Background technology]

[0002] Background of Disclosure Neurofibromatosis type 1 (NF1) occurs in approximately 1 in 3,500 births and is one of the most common autosomal dominant monogenic disorders affecting neurological function in humans. Clinically, NF1 is characterized by the presence of benign peripheral nerve tumors called neurofibromas, which involve Schwann cells with biallele mutations in the NF1 gene, as well as the presence of other neoplastic and non-neoplastic signs. (See Jousma et al. Pediatr. Blood Cancer 62: 1709-1716, 2015 (Non-patent Literature 1)). NF1 is associated with several skin disorders, including cutaneous neurofibromas; plexiform neurofibromas; café-au-lait spots; and axillary and groin blemishes. Cutaneous neurofibromas occur in over 95% of NF1 patients and can appear anywhere on the body, causing itching, irritation, infection, physical discomfort, and cosmetic impairment. Furthermore, cutaneous neurofibromas are associated with social isolation and social anxiety.

[0003] NF1 is caused by one or more germline mutations in the NF1 gene, which inactivates the RAS pathway. Since the NF1 gene encodes the Ras-GAP protein, NF1 deficiency results in high Ras-GTP levels. Therefore, NF1 research has focused exclusively on testing inhibitors in the Ras signaling pathway, including the Ras-MAPK cascade. See Jousma et al. Pediatr. Blood Cancer 62: 1709-1716, 2015 (Non-Patent Literature 1). Four separate MAPK cascades have been identified and named according to the MAPK module. See Akinleye et al. Journal of Hematology & Oncology 6:27, 2013 (Non-Patent Literature 2). MEK proteins belong to a family of enzymes upstream of specific MAPK targets in each of the four MAP kinase signaling pathways. Two of these MEK proteins, MEK1 and MEK2, are closely related to and involved in this signaling pathway cascade. MEK1 and MEK2 inhibitors have been shown to effectively inhibit MEK signaling downstream of Ras, thus providing a rationale for targeting MEK in the treatment of NF1. See Rice et al. Medicinal Chemistry Letters 3:416-421, 2012 (Non-Patent Literature 3).

[0004] Currently available MEK inhibitors are designed to exhibit oral bioavailability with respect to systemic delivery and are associated with serious side effects including decreased left ventricular ejection fraction, elevated creatine phosphokinase, interstitial pneumonia, renal failure, diarrhea, infection, urticaria, and maculopapular rash, all of which are dose-limiting or necessitate permanent discontinuation. Furthermore, clinical trials have demonstrated side effects with long-term high-dose administration of MEK inhibitors. See Huang et al. J. Ocul. Pharmacol. Ther. 25:519-530, 2009 (Non-Patent Literature 4). For example, the MEK inhibitor PD0325901, currently in clinical trials, has shown neurological side effects including ataxia, confusion, and syncope. In addition, several other side effects have been observed with respect to systemic exposure to MEK inhibitors, including acneiform rash, elevated CPK, nausea, vomiting, diarrhea, abdominal pain, and fatigue. Therefore, there is a need for MEK-inhibiting therapies to treat NF1-related cutaneous neurofibromas and limit these severe side effects.

[0005] In many cases, benign skin tumors of the vascular, keratinocyte, and melanocyte compartments occur at birth or in childhood. These lesions, referred to in this application as “birthmarks,” can cause cosmetic concerns, disfigurement, and social anxiety. In some cases, these lesions may predispose an individual to functional impairment or future malignancy. These birthmarks may be sporadic or may occur as part of an underlying neurocutaneous syndrome.

[0006] Examples of vascular nevi include port-wine stains / capillary malformations, hemangiomas, lobular hemangiomas, arterial vascular malformations, lymphatic malformations, vascular malformations, hemangiomas, and other hemangiomas. Keratinic nevi refer to keratinic epidermal nevi and sebaceous nevi. Examples of pigmented nevi (commonly known as moles) include congenital nevi, lentigo multifocals (which can occur in syndromes such as LEOPARD), freckles, and flat nevi.

[0007] Neurocutaneous syndromes, also known as birthmarks, such as port-wine stains, are associated with congenital low-flow vascular malformations (capillary malformations) in the skin, which, if left untreated, can lead to hypertrophy and nodule formation (Minkis, K. et al, Lasers Surg Med. (2009) 41(6): pp423-426 (Non-patent Literature 5)). Laser treatment is usually used to treat port-wine stains, but in many cases, they do not completely disappear. Epidermal nevi are common skin mosaic disorders and are subdivided into keratocyte nevi and organ nevi. Sebaceous nevi (NS) are an example of organ nevi. Immunolabeling of NS has been reported to be accompanied by increased phosphorylated ERK staining (Aslam, A, et al., Clinical and Experimental Dermatology (2014) 39: pp 1-6 (Non-patent Literature 6)). Non-organic keratocyte epidermal nevi (KEN) are benign, congenital hyperpigmented skin lesions. Epidermal nevi, accompanied by localized epidermal thickening, are present at birth or become visible in childhood. Other skin disorders that can occur in childhood birthmarks include nevus cell nevi, lobular hemangiomas, congenital nevi, freckles, lentigo multifocals (which can occur in multiple syndromes, including LEOPARD syndrome), microangiomas, nevus latum, arteriovenous malformations, lymphatic malformations, and congenital pigmented nevi. Lentigo with mutations that activate the RAS / MAPK pathway can occur in childhood (in syndromes such as LEOPARD syndrome) or be acquired in adulthood. In some cases, birthmarks are not suitable for surgical excision and / or laser treatment. In some cases, if left untreated, birthmarks may progress to lesions and / or proliferative skin conditions.

[0008] Modification of the ERK / MEK pathway may have a therapeutic effect on birthmarks. RAS mutations have been reported in mosaic RAS disease, i.e., non-organ kenia and sebaceous nevi (Farschtschi S, et al., BMC Medical Genetics. (2015); 16: pp 6 (Non-patent Literature 7); and Sun, BK et. Al, Journal of Investigative Dermatology, (2013); 3: pp824-827 (Non-patent Literature 8)). Therefore, inhibition of Ras signaling pathways, including the Ras-MAPK cascade, may be useful in treating birthmarks.

[0009] Four distinct MAPK cascades were identified and named according to the MAPK module. (See Akinleye et al. Journal of Hematology & Oncology 6:27, 2013 (Non-Patent Literature 2)). MEK proteins belong to a family of enzymes upstream of specific MAPK targets in each of the four MAP kinase signaling pathways. Two of these MEK proteins, MEK1 and MEK2, are closely related to and involved in this signaling pathway cascade. MEK1 and MEK2 inhibitors have been shown to effectively inhibit MEK signaling downstream of Ras (Rice et al. Medicinal Chemistry Letters 3:416-421, 2012 (Non-Patent Literature 3)), thus providing a rationale for targeting MEK in the treatment of birthmarks.

[0010] Currently available MEK pathway inhibitors are designed to exhibit oral bioavailability with respect to systemic delivery, but are associated with one or more serious adverse events, including decreased left ventricular ejection fraction, elevated creatine phosphokinase, interstitial pneumonia, renal failure, diarrhea, infection, urticaria, and maculopapular rash, all of which are dose-limiting or necessitate permanent discontinuation. Furthermore, clinical trials have shown one or more adverse events with long-term high-dose administration of MEK inhibitors (Huang et al. J. Ocul. Pharmacol. Ther. 25:519-530, 2009 (Non-Patent Literature 4)). For example, the clinically tested MEK inhibitor PD0325901 showed one or more neurological adverse events, including ataxia, confusion, and syncope. In addition, several other adverse events have been observed with respect to systemic exposure to MEK inhibitors, including acneiform rash, elevated CPK, nausea, vomiting, diarrhea, abdominal pain, and fatigue. Therefore, there is a need for therapeutic agents that treat bruising and limit one or more side effects associated with systemic exposure to MEK / ERK pathway inhibitors.

[0011] The compound of formula (I) was first disclosed in WO 2018 / 213810 (Patent Document 1) as a MEK inhibitor for the treatment of skin diseases or related skin disorders. However, the crystalline form of the compound of formula (I) is unknown. Therefore, in the development of drug formulations for the treatment of MEK inhibitor-responsive or MEK-mediated skin disorders, and skin disorders such as birthmarks, there is a need to develop a stable crystalline form of the compound that can be stored as a pharmaceutically active ingredient (API). [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] WO 2018 / 213810 [Non-patent literature]

[0013] [Non-Patent Document 1] Jousma et al. Pediatr. Blood Cancer 62: 1709-1716, 2015

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Summary of the Invention

[0014] Summary of the Disclosure In a first aspect, the present disclosure provides a crystalline form of a compound having formula (I), which is any one of crystalline forms A, B, C, E, F, and H, each of which is characterized by the X-ray powder diffraction (XRPD) pattern described herein. TIFF0007879134000001.tif43128

[0015] In some embodiments, the disclosure provides a crystalline form A of a compound of formula (I) characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.3, 8.0, 18.3, 18.5, and 24.3°2θ (±0.2°2θ).

[0016] In a second aspect, the Disclosure provides pharmaceutical compositions prepared by a method comprising combining a crystalline form of a compound of formula (I), each of which is one of crystalline forms A, B, C, E, F, and H as defined and described herein, with one or more pharmaceutically acceptable carriers. In some embodiments, the Disclosure provides pharmaceutical compositions prepared by a method comprising combining crystalline form A of a compound of formula (I) as defined and described herein with one or more pharmaceutically acceptable excipients.

[0017] In a third aspect, the Disclosure provides a method for treating a skin disorder. The method includes the step of treating a skin disorder by administering a crystalline form of a compound of formula (I), which is one of crystalline forms A, B, C, E, F, and H, each of which is defined and described herein, or a pharmaceutically acceptable composition thereof. In some embodiments, the Disclosure provides a method for treating a skin disorder, which includes the step of administering crystalline form A of a compound of formula (I), each of which is defined and described herein, or a pharmaceutically acceptable composition thereof.

[0018] In the fourth aspect, this disclosure relates to a method for preparing crystalline form A as described herein, a) A step of forming a first mixture containing the compound of formula (I) and tetrahydrofuran (THF) at a first temperature of approximately 50°C to approximately 65°C; b) A step of cooling the first mixture to a second temperature of approximately 35°C to approximately 45°C; c) Adding one or more seed crystals of crystal form A before step d) or during step d) to form a second mixture; d) Adding methyl tert-butyl ether (MTBE) to form a third mixture; e) A step of cooling the third mixture to a third temperature of about 25°C or below in order to form a fourth mixture containing precipitates; and f) To obtain crystalline form A, the process includes the step of isolating the precipitate from the fourth mixture, The present invention provides a method in which steps c) and d) are each maintained at a second temperature.

[0019] In the fifth aspect, this disclosure relates to a method for preparing crystalline form A as described herein, a) A step of forming a third slurry containing a compound having formula (I), tetrahydrofuran (THF), and methyl tert-butyl ether (MTBE); b) Adding one or more seed crystals of crystal form A to form a fourth slurry; c) A step of stirring the fourth slurry to form a fifth slurry; and d) The process includes a step of isolating a precipitate from a fifth slurry in order to obtain crystalline form A, The present invention provides a method comprising: one or more seed crystals of crystalline form A present in an amount of at least about 5% by weight of the compound of formula (I); and steps a) to c) each being maintained at a temperature of about 40°C to about 50°C. [Invention 1001] Equation (I): TIFF0007879134000002.tif43128 A crystalline form A of a compound having, Crystal form A is characterized by an X-ray powder diffraction (XRPD) pattern that includes peaks at 5.3, 8.0, 18.3, 18.5, and 24.3°²θ (±0.2°²θ). [Invention 1002] Crystal form A of the present invention 1001, wherein the X-ray powder diffraction pattern further includes peaks at 13.1, 20.5, 20.7, 21.7, and 24.0°²θ (±0.2°²θ). [Invention 1003] Crystal form A of the present invention 1001 or 1002, wherein the X-ray powder diffraction pattern further includes peaks at 9.6, 16.0, 16.6, 19.3, and 21.4°²θ (±0.2°²θ). [Invention 1004] Crystal form A of the present invention 1001, whose X-ray powder diffraction pattern substantially matches that of Figure 1. [Invention 1005] Crystalline form A of any of the invention 1001 to 1004, substantially free from other crystalline or amorphous forms of the compound having formula (I). [Invention 1006] Crystal form A of any of the invention 1001 to 1005, further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at approximately 189.9°C. [Invention 1007] Crystal form A of the present invention 1006, wherein the endothermic peak has an onset temperature of approximately 187.1°C. [Invention 1008] Crystalline form A of the present invention 1006, whose DSC thermogram substantially matches that of Figure 2. [Invention 1009] Crystal form A of any of the present invention 1001 to 1008, further characterized by a weight loss of approximately 0.1% to 1% when heated to approximately 100°C, as measured by thermogravimetric analysis (TGA). [Invention 1010] Crystal form A of the present invention 1009, wherein the weight loss when heated from approximately 40°C to approximately 100°C, as measured by thermogravimetric analysis, is approximately 0.3%. [Invention 1011] Crystal form A of any of the invention 1001 to 1008, further characterized by a thermogravimetric analysis (TGA) thermogram that substantially matches Figure 3. [Invention 1012] Crystal form A of any of the invention 1001 to 1011, further characterized by a weight increase of approximately 1.1% after undergoing a dynamic water vapor adsorption cycle at 25°C with relative humidity (RH) of approximately 5% to 95%. [Invention 1013] Crystal form A of any of the invention 1001 to 1011, further characterized by a weight reduction of approximately 1.2% after undergoing a dynamic water vapor desorption cycle at 25°C with a relative humidity (RH) of approximately 95% to approximately 5%. [Invention 1014] Crystal form A of any of the invention 1001 to 1011, having a dynamic water vapor adsorption profile substantially as shown in Figure 4. [Invention 1015] Crystal form A of any of the present invention 1001 to 1014, which is anhydrous. [Invention 1016] A step of combining any crystalline form A of the present invention 1001 to 1015 with one or more pharmaceutically acceptable excipients. A pharmaceutical composition prepared by a method comprising [a certain substance]. [Invention 1017] A pharmaceutical composition according to the present invention 1016, which is a topical preparation. [Invention 1018] The pharmaceutical composition of the present invention 1017, wherein the topical preparation is a ointment, lotion, spray, ointment, cream, gel, or patch. [Invention 1019] A method for treating a skin disorder, comprising the step of administering any crystalline form A of the present invention 1001 to 1015 or any pharmaceutical composition of the present invention 1016 to 1018. [Invention 1020] The method of the present invention 1019, wherein the skin disorder is a MEK inhibitor-responsive skin disorder or a MEK-mediated skin disorder. [Invention 1021] The method of the present invention 1020, wherein the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is selected from the group consisting of neurofibromatosis type 1, cutaneous neurofibroma, subcutaneous neurofibroma, superficial plexiform neurofibroma, and cutaneous RAS disease. [Invention 1022] The method of the present invention 1021, wherein the cutaneous RAS disease is selected from the group consisting of psoriasis, keratoacanthoma (KA), keratosis, papilloma, Noonan syndrome (NS), cardiac-facial-cutaneous syndrome (CFC), Costello syndrome (facial-cutaneous-skeletal syndrome or FCS syndrome), ectophthalmic syndrome, café-au-lait spots, and lentigo multiflora syndrome (formerly known as leopard syndrome). [Invention 1023] The method of the present invention 1019, wherein the skin disorder is a birthmark. [Invention 1024] The method of the present invention 1023, wherein the birthmark is selected from the group consisting of port-wine stain / capillary malformation, nevus cell nevus, dysplastic nevus, capillary hemangioma, epidermal nevus, sebaceous nevus, flat nevus, arteriovenous malformation, lymphatic malformation, and congenital pigmented nevus. [Invention 1025] A method of the present invention 1023 or 1024, wherein the bruising is related to the activation of p-ERK. [Invention 1026] The method of the present invention 1024 or 1025, wherein the birthmark associated with p-ERK activation is selected from the group consisting of epidermal nevi, sebaceous nevi, flat nevi, arteriovenous malformations, capillary malformations / port-wine stains, congenital pigmented nevi, and lymphatic malformations. [Invention 1027] The method of the present invention 1019, wherein the skin disorder is skin cancer. [Invention 1028] The method of the present invention 1027, wherein the skin cancer is cutaneous squamous cell carcinoma. [Invention 1029] The method of the present invention 1027, wherein the skin cancer is MEK inhibitor-responsive or MEK-mediated cutaneous squamous cell carcinoma. [Invention 1030] The method of the present invention 1028 or 1029, wherein cutaneous squamous cell carcinoma is associated with p-ERK activation. [Invention 1031] If the pharmaceutical composition is a topical formulation, any method of the present invention 1019 to 1030 wherein the topical formulation is administered topically. [Invention 1032] The method of the present invention 1031, wherein the topical formulation is administered as a ointment, lotion, spray, ointment, cream, gel, or patch. [Invention 1033] A method for preparing any of the crystal forms A of the present invention 1001 to 1015, a) Equation (I): TIFF0007879134000003.tif43128 A first mixture comprising a compound having and tetrahydrofuran (THF) is formed at a first temperature of approximately 50°C to approximately 65°C; b) A step of cooling the first mixture to a second temperature of approximately 35°C to approximately 45°C; c) Adding one or more seed crystals of crystal form A before step d) or during step d) to form a second mixture; d) Adding methyl tert-butyl ether (MTBE) to form a third mixture; e) A step of cooling the third mixture to a third temperature of about 25°C or below in order to form a fourth mixture containing precipitates; and f) To obtain crystalline form A, the process includes the step of isolating the precipitate from the fourth mixture, A method wherein steps c) and d) are each maintained at a second temperature. [Invention 1034] The method of the present invention 1033, wherein the compound of formula (I) has a purity of approximately 90% to approximately 99%, or approximately 95% to approximately 99%. [Invention 1035] The method of the present invention 1033 or 1034, wherein the compound of formula (I) is present in the first mixture in an amount of about 50 g / L to about 150 g / L, about 75 g / L to about 125 g / L, about 90 g / L to about 110 g / L, or about 100 g / L. [Invention 1036] Any method according to invention 1033 to 1035, wherein the volume ratio of THF to MTBE is approximately 1:2. [Invention 1037] Any method 1033 to 1036 of the present invention, wherein one or more seed crystals of crystal form A are added before step d). [Invention 1038] The method according to any of the invention 1033 to 1037, wherein the second mixture is further stirred for about 20 to 120 minutes before step d); and step d) is carried out over about 1 to 3 hours while maintaining the second temperature. [Invention 1039] Any method according to invention 1033 to 1038, wherein the first mixture is a solution; and the second mixture and / or the third mixture are each a slurry. [Invention 1040] The method according to any of the invention 1033 to 1039, wherein step e) is carried out for approximately 1 to 3 hours; and the fourth mixture is further stirred for approximately 1 to 24 hours while maintaining the third temperature. [Invention 1041] A method according to any of the present invention 1033 to 1040, wherein the first temperature is approximately 55°C to 65°C; the second temperature is approximately 40°C; and the third temperature is approximately 20°C. [Invention 1042] A method of the present invention, any of items 1033 to 1040, wherein the precipitate is isolated by filtration and dried to obtain crystalline form A. [Invention 1043] A method for preparing any of the crystal forms A of the present invention 1001 to 1015, a) Equation (I): TIFF0007879134000004.tif43128 A step of forming a third slurry containing a compound having, tetrahydrofuran (THF), and methyl tert-butyl ether (MTBE); b) Adding one or more seed crystals of crystal form A to form a fourth slurry; c) A step of stirring the fourth slurry to form a fifth slurry; and d) The process includes a step of isolating a precipitate from a fifth slurry in order to obtain crystalline form A, A method comprising: one or more seed crystals of crystal form A present in an amount of at least about 5% by weight of the compound of formula (I); and steps a) to c) each being maintained at a temperature of about 40°C to about 50°C. [Invention 1044] The method of the present invention 1043, wherein the compound of formula (I) has a purity of approximately 90% to approximately 99%, or approximately 95% to approximately 99%. [Invention 1045] The method of the present invention 1043 or 1044, wherein the compound of formula (I) is present in the third slurry in an amount of about 20 g / L to about 50 g / L, about 25 g / L to about 40 g / L, about 30 g / L to about 35 g / L, or about 33 g / L. [Invention 1046] A method according to any of the present invention 1043 to 1045, wherein the volume ratio of THF to MTBE is approximately 1:2. [Invention 1047] Any method 1043 to 1046 of the present invention, wherein one or more seed crystals of crystalline form A are present in an amount of about 5% to about 20% by weight, about 5% to about 10% by weight, or about 5% by weight of the compound of formula (I). [Invention 1048] The method according to any of the invention 1043 to 1047, wherein step c) is performed over approximately 1 to 2 days, and steps a) to c) are each maintained at a temperature of approximately 45°C. [Brief explanation of the drawing]

[0020] [Figure 1] The X-ray powder diffraction (XRPD) pattern of crystal form A is shown. [Figure 2] The differential scanning calorimetry (DSC) thermogram of crystal form A is shown. [Figure 3] The thermogravimetric analysis (TGA) thermogram of crystal form A is shown. [Figure 4] This shows the dynamic water vapor adsorption (DVS) cycle of crystal form A. [Figure 5] The X-ray powder diffraction (XRPD) pattern of crystal form E is shown. [Figure 6]The differential scanning calorimetry (DSC) thermogram of crystal form E is shown. [Figure 7] The thermogravimetric analysis (TGA) thermogram of crystal form E is shown. [Figure 8] The X-ray powder diffraction (XRPD) pattern of crystal form F is shown. [Figure 9] The differential scanning calorimetry (DSC) thermogram of crystal form F is shown. [Figure 10] The thermogravimetric analysis (TGA) thermogram of crystal form F is shown. [Figure 11] The X-ray powder diffraction (XRPD) pattern of crystal form B is shown. [Figure 12] The differential scanning calorimetry (DSC) thermogram of crystal form B is shown. [Figure 13] The thermogravimetric analysis (TGA) thermogram of crystal form B is shown. [Figure 14] This shows the X-ray powder diffraction (XRPD) pattern of crystal form C. [Figure 15A] The 1H NMR spectrum of crystalline form C is shown. Figure 15A shows the full spectrum. [Figure 15B] The 1H NMR spectrum of crystalline form C is shown. Figure 15B shows the expanded aromatic region. [Figure 16] This shows the X-ray powder diffraction (XRPD) pattern of crystalline form H. [Modes for carrying out the invention]

[0021] Detailed explanation of disclosure I. General This disclosure provides crystalline forms of a compound having formula (I), which are crystalline forms A, B, C, E, F, and H. Crystalline forms A, B, C, E, F, and H are each characterized by X-ray powder diffraction (XRPD) patterns. The selected crystalline form is further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic water vapor adsorption (DVS) cycles, and / or water content by Karl Fischer (KF) method. This disclosure also provides methods for preparing crystalline forms, particularly form A. This disclosure further provides methods for treating various skin disorders using the crystalline forms of this disclosure (e.g., form A) or their pharmaceutical compositions.

[0022] II. Definition "Substantially free" means other forms or impurities in amounts of 10% or less, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less.

[0023] "Crystalline form" refers to the solid form of a compound in which its constituent molecules are packed in a repeating pattern of regular arrangement. Crystalline forms can include triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal, and cubic crystal geometries. A crystalline form can include one or more regions, i.e., particles, with distinct crystal boundaries. A crystalline form can include two or more crystal geometries.

[0024] "Amorphous" refers to the solid form of a compound that does not have a clear crystalline structure, that is, it lacks a repeating pattern of regular arrangement of its constituent molecules.

[0025] "Solvate" means a compound or salt thereof provided herein, further comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0026] "Hydrate" means a compound that forms a complex with water molecules. The compounds of this disclosure may form a complex with 1 / 2 water molecules or 1 to 10 water molecules.

[0027] XRPD patterns can be indexed in the absence of a single crystal suitable for structural decipherment [McClurg, Richard B.; Smit, Jared P. X-ray Powder Diffraction Pattern Indexing for Pharmaceutical Applications. Pharm. Tech. Europe, Jan. 2013; and X'Pert High Score Plus 2.2a (2.2.1)]. Indexing is the process of determining the size and shape of a crystalline unit cell based on the peak positions in the diffraction pattern. The term is derived from assigning Miller index labels to individual peaks. XRPD indexing serves several purposes. If all peaks in the pattern are indexed by a single unit cell, this provides strong evidence that the sample contains a single crystalline phase. Based on the indexed solution, the volume of the unit cell can be directly calculated. Furthermore, indexing provides a solid description of the crystalline form and a concise overview of all available peak positions of the phase at a particular thermodynamic state point.

[0028] "Crude product" means a mixture containing the desired compound (e.g., the compound of formula (I)) and at least one other chemical species (e.g., a solvent, a reagent such as an acid or base, a starting material, or a by-product of the reaction that produces the desired compound).

[0029] Unless otherwise specified, "purity %" or "purity area %" (e.g., 95% or 95 area%) means the purity of the compound (e.g., the compound of formula (I)) within the area under the curve (AUC) determined by HPLC or ULC (e.g., the chemical development HPLC or ULC method described herein).

[0030] "First mixture," "second mixture," etc., mean the mixtures described in the embodiments of this disclosure. The mixture naming conventions are used solely for clarity in the steps of the methods described herein and do not need to be in numerical order. Some mixtures may not exist in the selected embodiments of this disclosure described herein. Those skilled in the art will understand the meaning of these mixture naming conventions (e.g., "first mixture," "second mixture") in the context in which the terms are used in the embodiments and claims described herein.

[0031] "First slurry," "second slurry," etc., mean the slurries described in the embodiments of this disclosure. The slurry naming conventions are used solely for clarity in the processes of the methods described herein and do not need to be in numerical order. In selected embodiments of this disclosure described herein, some slurry may not exist. Those skilled in the art will understand the meaning of these slurry naming conventions (e.g., "first slurry," "second slurry") in the context in which the terms are used in the embodiments and claims described herein.

[0032] "First temperature," "second temperature," etc., refer to the temperatures described in the embodiments of this disclosure. The temperature naming conventions are used solely for clarity in the steps of the methods described herein and do not need to be in numerical order. Those skilled in the art will understand the meaning of these temperature naming conventions (e.g., "first temperature," "second temperature") in the context in which the terms are used in the embodiments and claims herein.

[0033] "Alkyl alcohol" refers to an alkyl group having a hydroxyl group bonded to a carbon in the chain, where the alkyl group has a specified number of carbon atoms (i.e., C 1~4 A is defined as a linear or branched saturated aliphatic group (meaning 1 to 4 carbon atoms). For example, C 1~4Examples of alkyl alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and tert-butanol. The alkyl alcohols useful in this disclosure are fully saturated. Those skilled in the art will recognize that other alcohols may be useful in this disclosure.

[0034] "Precipitation" refers to the process of assembling a compound in a solution into a solid form of matter (i.e., a precipitate). The entire compound in the solution, or any part thereof, may precipitate. The solid form of the matter can be amorphous or crystalline.

[0035] "Isolation" means the process of isolating at least a portion of a first substance (e.g., a precipitate) from a mixture containing that substance and at least one further substance. In some cases, the isolated substance substantially does not contain at least one further substance present in the original mixture.

[0036] As used herein, “composition” is intended to encompass products containing predetermined amounts of a given component, and any products obtained directly or indirectly by predetermined combinations of a given component in predetermined amounts. “Pharmacologically acceptable” means that the carrier, diluent, or excipient is necessarily compatible with the other components of the formulation and is not harmful to its recipient.

[0037] "Pharmacologically acceptable excipients" means substances that assist in the administration of an active agent to a target and its absorption by that target. Useful pharmaceutically acceptable excipients in this disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorants. Useful pharmaceutically acceptable excipients in this disclosure for transdermal / topical delivery include, but are not limited to, accelerators, solubilizers, antioxidants, plasticizers, thickeners, polymers, and pressure-sensitive adhesives. Those skilled in the art will recognize that other pharmaceutically acceptable excipients may be useful in this disclosure.

[0038] "Inhibition," "to inhibit," and "inhibitor" mean a compound or method of inhibiting a particular action or function.

[0039] "Administration" means oral administration, suppository administration, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, subcutaneous administration, subarachnoid administration, or implantation of a slow-release device, such as a mini osmotic pump.

[0040] "To treat," "to treat," and "treatment" mean any evidence relating to the successful treatment or remission of an injury, condition, or state, including any objective or subjective parameters such as reduction; improvement; reduction of symptoms or increased patient tolerance to the injury, condition, or state; slowing the rate of degeneration or decline; reducing the debilitation of the final degenerative point; or improving the patient's physical or mental health. Treatment or remission of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0041] "Patient" or "Subject" means an organism that is suffering from or susceptible to a disease or condition treatable by the administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is human.

[0042] "Therapeutic dose" means the amount of compound or pharmaceutical composition that is useful to treat or induce remission of an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The exact amount depends on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0043] "Approximately" means a range of values ​​including a given value that would be considered to be substantially similar to the given value by those skilled in the art. In some embodiments, the term "approximately" means within the range of standard deviations using measurements generally accepted in the art. In some embodiments, "approximately" means a range of ±10% of the given value. In some embodiments, "approximately" means the given value.

[0044] III. Crystal Form In the first aspect, the present disclosure provides crystalline forms of compounds having formula (I), each of which is one of crystalline forms A, B, C, E, F, and H, each characterized by an X-ray powder diffraction (XRPD) pattern described herein. TIFF0007879134000005.tif43128

[0045] Methods for acquiring XRPD data are known in the art, and any of these methods can be used to characterize the crystalline form of the compound of formula (I). For example, the X-ray powder diffraction pattern described herein can be prepared using the Cu Kα1 line.

[0046] In some embodiments, the crystalline forms described herein are further characterized by differential scanning calorimetry (DSC) thermograms. In some embodiments, DSC thermograms are recorded using a sample weight of approximately 1–2 mg subjected to temperatures in the range of 30°C–350°C with a gradient of 10°C / min.

[0047] In some embodiments, the crystalline forms described herein are further characterized by thermogravimetric analysis (TGA). In some embodiments, a TGA thermogram is recorded using a sample weight of approximately 2–10 mg subjected to temperatures in the range of 30°C–300°C with a gradient of 10°C / min.

[0048] In some embodiments, the crystalline forms described herein are further characterized by water content measured by the Karl Fischer (KF) method.

[0049] In some embodiments, the crystalline forms described herein are 1 It is further characterized by nuclear magnetic resonance spectra such as 1H NMR spectra. In some embodiments, 1 1H NMR is recorded using a Bruker Avance-AV 400MHz probe with a 5mm PABBO BB-1H / D.

[0050] III-1. Crystal Form A In one embodiment, the disclosure provides a crystalline form A of a compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.3, 8.0, 18.3, 18.5, and 24.3°²θ (±0.2°²θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 13.1, 20.5, 20.7, 21.7, and 24.0°²θ (±0.2°²θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 9.6, 16.0, 16.6, 19.3, and 21.4°²θ (±0.2°²θ). In some embodiments, crystal form A is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.3, 8.0, 13.1, 18.3, 18.5, 20.5, 20.7, 21.7, 24.0, and 24.3°2θ (±0.2°2θ) (i.e., the first 10 peaks ranked according to relative peak intensity %). In some embodiments, crystal form A is characterized by an X-ray powder diffraction (XRPD) pattern containing 3, 4, 5, or more peaks listed in Table 2A or Table 2B. In some embodiments, crystal form A is characterized by an X-ray powder diffraction (XRPD) pattern containing at least 5 peaks listed in Table 2A or Table 2B.

[0051] In some embodiments, crystalline form A of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially consistent with that in Figure 1.

[0052] In some embodiments, crystalline form A substantially does not include other crystalline or amorphous forms of the compound having formula (I).

[0053] In some embodiments, crystal form A is further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at approximately 189.9°C. In some embodiments, crystal form A is further characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of approximately 187.1°C and an endothermic peak at approximately 189.9°C.

[0054] In some embodiments, crystal form A is further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 2.

[0055] In some embodiments, crystal form A is further characterized by a weight loss of approximately 0.1% to approximately 1% when heated to approximately 100°C, as measured by thermogravimetric analysis (TGA). In some embodiments, crystal form A is further characterized by a weight loss of approximately 0.3% when heated from approximately 50°C to approximately 100°C, as measured by thermogravimetric analysis (TGA).

[0056] In some embodiments, crystal form A is further characterized by a thermogravimetric analysis (TGA) thermogram that substantially matches that of Figure 3.

[0057] In some embodiments, crystalline form A is further characterized by a weight increase of approximately 1.1% after undergoing a dynamic water vapor adsorption cycle at 25°C with a relative humidity (RH) of approximately 5% to approximately 95%. In some embodiments, crystalline form A is further characterized by a weight decrease of approximately 1.2% after undergoing a dynamic water vapor desorption cycle at 25°C with a relative humidity (RH) of approximately 95% to approximately 5%. In some embodiments, crystalline form A is further characterized by a weight increase of approximately 1.1% after undergoing a dynamic water vapor adsorption cycle at 25°C with a relative humidity (RH) of approximately 5% to approximately 95%; and further characterized by a weight decrease of approximately 1.2% after undergoing a dynamic water vapor desorption cycle at 25°C with a relative humidity (RH) of approximately 95% to approximately 5%.

[0058] In some embodiments, crystalline form A further features a dynamic water vapor adsorption profile that substantially coincides with that of Figure 4.

[0059] In some embodiments, crystalline form A is further characterized by a water content of approximately 0.1% to approximately 0.5% by weight, as measured by the Karl Fischer (KF) method. In some embodiments, crystalline form A is further characterized by a water content of approximately 0.35% by weight, as measured by the Karl Fischer (KF) method.

[0060] In some embodiments, crystalline form A is anhydrous. In some embodiments, crystalline form A is anhydrous, and the water content measured by the Karl Fischer (KF) method is approximately 0.1% to approximately 0.5% by weight. In some embodiments, crystalline form A is anhydrous, and the water content measured by the Karl Fischer (KF) method is approximately 0.35% by weight.

[0061] In some embodiments, crystal form A is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 1; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 2. In some embodiments, crystal form A is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 1; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 2; further characterized by a thermogravimetric analysis (TGA) thermogram substantially consistent with Figure 3. In some embodiments, crystal form A is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 1; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 2; further characterized by a thermogravimetric analysis (TGA) thermogram substantially consistent with Figure 3; and further characterized by a dynamic water vapor adsorption profile substantially consistent with Figure 4. In some embodiments, crystal form A is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 1; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 2; further characterized by a thermogravimetric analysis (TGA) thermogram substantially consistent with Figure 3; and further characterized by a water content of approximately 0.1% to approximately 0.5% by weight as measured by the Karl Fischer (KF) method.

[0062] III-2. Crystal Form E In one embodiment, the disclosure provides a crystalline form E of a compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 18.0, 18.3, 20.1, 20.4, and 23.5°²θ (±0.2°²θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 7.3, 15.1, 21.2, 22.8, and 24.4°²θ (±0.2°²θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 18.5, 21.9, 24.6, and 25.8°²θ (±0.2°²θ). In some embodiments, crystal form E is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 7.3, 15.1, 18.0, 18.3, 20.1, 20.4, 21.2, 22.8, 23.5, and 24.4°2θ (±0.2°2θ) (i.e., the first 10 peaks ranked according to relative peak intensity %). In some embodiments, crystal form E is characterized by an X-ray powder diffraction (XRPD) pattern containing 3, 4, 5, or more peaks listed in Table 4A or Table 4B. In some embodiments, crystal form E is characterized by an X-ray powder diffraction (XRPD) pattern containing at least 5 peaks listed in Table 4A or Table 4B.

[0063] In some embodiments, the crystalline form E of the compound having formula (I) is characterized by an X-ray powder diffraction pattern that substantially matches that of Figure 5.

[0064] In some embodiments, crystalline form E substantially does not include other crystalline or amorphous forms of the compound having formula (I).

[0065] In some embodiments, crystal form E is further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at approximately 190.2°C. In some embodiments, crystal form E is further characterized by a differential scanning calorimetry (DSC) thermogram including an onset temperature of approximately 188.0°C and an endothermic peak at approximately 190.2°C.

[0066] In some embodiments, crystal form E is further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 6.

[0067] In some embodiments, crystalline form E is further characterized by a weight loss of approximately 0.3% upon heating from approximately 39°C to approximately 180°C, as measured by thermogravimetric analysis (TGA).

[0068] In some embodiments, crystal form E is further characterized by a thermogravimetric analysis (TGA) thermogram that substantially matches that of Figure 7.

[0069] In some embodiments, crystal form E is the anhydrous form.

[0070] In some embodiments, crystal form E is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 5; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 6. In some embodiments, crystal form E is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 5; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 6; further characterized by a thermogravimetric analysis (TGA) thermogram substantially consistent with Figure 7.

[0071] III-3. Crystal form F In one embodiment, the disclosure provides a crystalline form F of a compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 12.1, 17.8, 19.3, 22.1, and 23.3°²θ (±0.2°²θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 18.9, 19.2, 19.5, 21.1, and 22.4°²θ (±0.2°²θ). In some embodiments, crystalline form F is characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 12.1, 17.8, 18.9, 19.2, 19.3, 19.5, 21.1, 22.1, 22.4, and 23.3°²θ (±0.2°²θ) (i.e., the first 10 peaks ranked according to relative peak intensity %). In some embodiments, crystal form F is characterized by an X-ray powder diffraction (XRPD) pattern containing one, two, three, four, five, or more peaks listed in Table 6A or Table 6B. In some embodiments, crystal form F is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks listed in Table 6A or Table 6B.

[0072] In some embodiments, the crystalline form F of the compound having formula (I) is characterized by an X-ray powder diffraction pattern that substantially coincides with that in Figure 8.

[0073] In some embodiments, crystalline form F substantially does not include other crystalline or amorphous forms of the compound having formula (I).

[0074] In some embodiments, crystal form F is further characterized by a differential scanning calorimetry (DSC) thermogram including one or more endothermic peaks at approximately 162.7°C and 187.5°C. In some embodiments, crystal form F is further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at a starting temperature of approximately 158.9°C and approximately 162.7°C. In some embodiments, crystal form F is further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at a starting temperature of approximately 185.3°C and approximately 187.5°C.

[0075] In some embodiments, crystal form F is further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 9.

[0076] In some embodiments, crystalline form F is further characterized by a weight loss of approximately 0.4% upon heating from approximately 50°C to approximately 180°C, as measured by thermogravimetric analysis (TGA).

[0077] In some embodiments, crystal form F is further characterized by a thermogravimetric analysis (TGA) thermogram that substantially matches that of Figure 10.

[0078] In some embodiments, the crystalline form F is the anhydrous form.

[0079] In some embodiments, crystalline form F is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 8; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 9. In some embodiments, crystalline form F is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 8; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 9; further characterized by a thermogravimetric analysis (TGA) thermogram substantially consistent with Figure 10.

[0080] III-4. Crystal form B In one embodiment, the disclosure provides a crystalline form B of a compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.1, 15.1, 17.3, 17.8, and 23.8°2θ (±0.2°2θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 14.8, 16.5, 20.8, 25.0, and 28.5°2θ (±0.2°2θ). In some embodiments, crystalline form B is characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.1, 14.8, 15.1, 16.5, 17.3, 17.8, 20.8, 23.8, 25.0, and 28.5°2θ (±0.2°2θ) (i.e., the first 10 peaks ranked according to relative peak intensity %). In some embodiments, crystal form B is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, five, or more peaks listed in Table 8A or Table 8B. In some embodiments, crystal form B is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks listed in Table 8A or Table 8B.

[0081] In some embodiments, crystalline form B of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially consistent with that in Figure 11.

[0082] In some embodiments, crystalline form B substantially does not include other crystalline or amorphous forms of the compound having formula (I).

[0083] In some embodiments, crystal form B is further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at approximately 95.4°C. In some embodiments, crystal form B is further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at an onset temperature of approximately 80.0°C and approximately 95.4°C. In some embodiments, the differential scanning calorimetry (DSC) thermogram further includes one or more endothermic peaks at approximately 151.1°C, approximately 170.3°C, and 185.3°C.

[0084] In some embodiments, crystal form B is further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 12.

[0085] In some embodiments, crystalline form B is further characterized by a weight loss of approximately 3.4% upon heating from approximately 80°C to approximately 145°C, as measured by thermogravimetric analysis (TGA).

[0086] In some embodiments, crystal form B is further characterized by a thermogravimetric analysis (TGA) thermogram that substantially matches that of Figure 13.

[0087] In some embodiments, crystal form B is hydrated. In some embodiments, crystal form B is monohydrated.

[0088] In some embodiments, crystal form B is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 11; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 12. In some embodiments, crystal form B is characterized by an X-ray powder diffraction pattern substantially consistent with Figure 11; further characterized by a differential scanning calorimetry (DSC) thermogram substantially consistent with Figure 12; further characterized by a thermogravimetric analysis (TGA) thermogram substantially consistent with Figure 13.

[0089] III-5. Crystal form C In one embodiment, the disclosure provides a crystalline form C of a compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 14.4, 17.4, 19.1, 19.4, and 22.3°2θ (±0.2°2θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 6.9, 11.7, 23.7, 24.9, and 25.1°2θ (±0.2°2θ). In some embodiments, crystalline form C is characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 6.9, 11.7, 14.4, 17.4, 19.1, 19.4, 22.3, 23.7, 24.9, and 25.1°2θ (±0.2°2θ) (i.e., the first 10 peaks ranked according to relative peak intensity %). In some embodiments, crystal form C is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, five, or more peaks listed in Table 10A or Table 10B. In some embodiments, crystal form C is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks listed in Table 10A or Table 10B.

[0090] In some embodiments, the crystalline form C of the compound having formula (I) is characterized by an X-ray powder diffraction pattern that substantially matches that of Figure 14.

[0091] In some embodiments, crystalline form C substantially does not include other crystalline or amorphous forms of the compound having formula (I).

[0092] In some embodiments, the crystal form C is shown in Figures 15A and 15B. 1 Further features include the 1H NMR spectrum.

[0093] In some embodiments, crystalline form C is the solvated form. In some embodiments, crystalline form C is the chloroform solvated form. In some embodiments, crystalline form C is the chloroform solvated form; the molar ratio of the chloroform-paired compound (I), determined by the crystal volume by X-ray powder diffraction (XRPD), is 1:1 or less. In some embodiments, crystalline form C is the chloroform solvated form; as shown in Figures 15A and 15B. 1The molar ratio of compound (I) to chloroform, as determined by 1H NMR spectroscopy, is approximately 0.4:1.

[0094] In some embodiments, crystal form C is characterized by an X-ray powder diffraction pattern substantially consistent with that of Figure 14; shown in Figures 15A and 15B. 1 Further features include the 1H NMR spectrum.

[0095] III-6. Crystal form H In one embodiment, the disclosure provides a crystalline form H of a compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.1, 17.3, 18.7, 23.4, and 25.6°²θ (±0.2°²θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 14.3, 16.5, 18.1, 21.02, and 22.5°²θ (±0.2°²θ). In some embodiments, the X-ray powder diffraction pattern further includes peaks at 15.8, 16.3, 18.9, and 19.6°²θ (±0.2°²θ). In some embodiments, crystalline form H is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 5.1, 14.3, 16.5, 17.3, 18.1, 18.7, 21.02, 22.5, 23.4, and 25.6°2θ (±0.2°2θ) (i.e., the first 10 peaks ranked according to relative peak intensity %). In some embodiments, crystalline form H is characterized by an X-ray powder diffraction (XRPD) pattern containing 3, 4, 5, or more peaks listed in Table 12A or Table 12B. In some embodiments, crystalline form H is characterized by an X-ray powder diffraction (XRPD) pattern containing at least 5 peaks listed in Table 12A or Table 12B.

[0096] In some embodiments, the crystalline form H of the compound having formula (I) is characterized by an X-ray powder diffraction pattern that substantially matches that of Figure 16.

[0097] In some embodiments, crystalline form H substantially does not include other crystalline or amorphous forms of the compound having formula (I).

[0098] In some embodiments, crystalline form H is the solvated form. In some embodiments, crystalline form H is the methanol solvated form. In some embodiments, crystalline form H is the methanol solvated form; the molar ratio of the methanol-paired compound of formula (I), as determined by the crystal volume by X-ray powder diffraction (XRPD), is 1:1 or less.

[0099] IV. Method for preparing crystal form A In one aspect, this disclosure provides a method (hereinafter referred to as the first method) for preparing the crystalline form A described herein by a crystallization method. The first method is a) Equation (I): A first mixture comprising a compound having TIFF0007879134000006.tif43128 and tetrahydrofuran (THF), formed at a first temperature of approximately 50°C to approximately 65°C; b) A step of cooling the first mixture to a second temperature of approximately 35°C to approximately 45°C; c) Adding one or more seed crystals of crystal form A before step d) or during step d) to form a second mixture; d) Adding methyl tert-butyl ether (MTBE) to form a third mixture; e) A step of cooling the third mixture to a third temperature of about 25°C or below in order to form a fourth mixture containing precipitates; and f) To obtain crystalline form A, the process includes the step of isolating the precipitate from the fourth mixture, Here, steps c) and d) are maintained at a second temperature.

[0100] With respect to the first method, the compound of formula (I) may be in any form (e.g., crystalline or amorphous). In some embodiments, the compound of formula (I) is in a crystalline form (e.g., forms A, E, F, B, C, and H as described herein). In some embodiments, the compound of formula (I) is in form A, form E, form F, form B, form C, form H, or a combination thereof. In some embodiments, the compound of formula (I) is in form A, provided that the compound of formula (I) in form A has a purity of less than about 99%. In some embodiments, the compound of formula (I) is in a crystalline form other than form A. In some embodiments, the compound of formula (I) is amorphous.

[0101] With respect to the first method, in some embodiments, the compound of formula (I) has a purity of at least about 90%. In some embodiments, the compound of formula (I) has a purity of about 90% to about 99%. In some embodiments, the compound of formula (I) has a purity of about 95% to about 99%. In some embodiments, the compound of formula (I) has a purity of about 96% to about 99%, about 97% to about 99%, or about 98% to about 99%. In some embodiments, the compound of formula (I) has a purity of about 96%. In some embodiments, the compound of formula (I) has a purity of about 97%. In some embodiments, the compound of formula (I) has a purity of about 98%. In some embodiments, the compound of formula (I) has a purity of about 99%.

[0102] With respect to the first method, in some embodiments, the compound of formula (I) is present in the first mixture in amounts of about 50 g / L to about 150 g / L, about 75 g / L to about 125 g / L, about 90 g / L to about 110 g / L, or about 100 g / L. In some embodiments, the compound of formula (I) is present in the first mixture in amounts of about 75 g / L to about 125 g / L. In some embodiments, the compound of formula (I) is present in the first mixture in amounts of about 90 g / L to about 110 g / L. In some embodiments, the compound of formula (I) is present in the first mixture in amounts of about 100 g / L.

[0103] With respect to the first method, in some embodiments, the volume ratio of THF to MTBE is approximately 1:4 to approximately 2:1. In some embodiments, the volume ratio of THF to MTBE is approximately 1:3 to approximately 1:1. In some embodiments, the volume ratio of THF to MTBE is approximately 1:2.

[0104] With respect to the first method, in some embodiments, one or more seed crystals of crystal form A are added before step d) to form a second mixture. In some embodiments, one or more seed crystals of crystal form A are added during step d) to form a third mixture. In some embodiments, about 1 / 5 of the total amount of MTBE by volume (e.g., 4 volumes out of 20 volumes of MTBE) are added, and then one or more seed crystals of crystal form A are added in step d). In some embodiments, about 2 / 5 of the total amount of MTBE by volume (e.g., 8 volumes out of 20 volumes of MTBE) are added, and then one or more seed crystals of crystal form A are added in step d).

[0105] With respect to the first method, in some embodiments, one or more seed crystals of crystal form A are added in an amount of about 0.5% to about 2% by weight of the compound of formula (I). In some embodiments, one or more seed crystals of crystal form A are added in an amount of about 1% to about 1.5% by weight of the compound of formula (I). In some embodiments, the one or more seed crystals of crystal form A are of form A of Example 2, characterized according to Table 1.

[0106] With respect to the first method, in some embodiments, the first mixture is a solution. In some embodiments, the first mixture is a solution that is substantially free of solids. In some embodiments, the second mixture and / or the third mixture are slurries, respectively. In some embodiments, the second mixture is the first slurry. In some embodiments, the third mixture is the second slurry.

[0107] With respect to the first method, in some embodiments, the second mixture is further stirred for about 20 to 120 minutes before step d) while maintaining the second temperature. In some embodiments, the second mixture is further stirred for about 20 to 60 minutes before step d) while maintaining the second temperature. In some embodiments, the second mixture is further stirred for about 30 minutes before step d) while maintaining the temperature at about 40°C.

[0108] With respect to the first method, in some embodiments, step d) is carried out over approximately 1 to 3 hours while maintaining the temperature at the second temperature. In some embodiments, step d) is carried out over approximately 1.5 hours while maintaining the temperature at approximately 40°C.

[0109] With respect to the first method, in some embodiments, the cooling in step e) is carried out over approximately 1 to 3 hours. In some embodiments, the cooling in step e) is carried out over approximately 2 hours.

[0110] With respect to the first method, in some embodiments, the fourth mixture is further stirred for about 1 to 24 hours while being maintained at the third temperature. In some embodiments, the fourth mixture is further stirred for about 1 to 24 hours while being maintained at about 20°C. In some embodiments, the fourth mixture is further stirred for about 1 hour while being maintained at about 20°C.

[0111] With respect to the first method, in some embodiments, the first temperature is approximately 55°C to 65°C. In some embodiments, the first temperature is approximately 60°C to 65°C. In some embodiments, the first temperature is approximately 55°C to 60°C. In some embodiments, the first temperature is approximately 55°C. In some embodiments, the second temperature is approximately 40°C. In some embodiments, the third temperature is approximately 20°C.

[0112] In another aspect, this disclosure provides a method (hereinafter referred to as the second method) for preparing crystalline form A described herein by slurry-to-slurry. The second method is a) Equation (I): A step of forming a third slurry containing a compound having TIFF0007879134000007.tif43128, tetrahydrofuran (THF), and methyl tert-butyl ether (MTBE); b) Adding one or more seed crystals of crystal form A to form a fourth slurry; c) A step of stirring the fourth slurry to form a fifth slurry; and d) The process includes a step of isolating a precipitate from a fifth slurry in order to obtain crystalline form A, Here, one or more seed crystals of crystalline form A are present in an amount of at least about 5% by weight of the compound of formula (I); steps a) to c) are each maintained at a temperature of about 40°C to about 50°C.

[0113] With respect to the second method, the compound of formula (I) may be in any form (e.g., crystalline or amorphous). In some embodiments, the compound of formula (I) is in crystalline form (e.g., forms A, E, F, B, C, and H as described herein). In some embodiments, the compound of formula (I) is in form A, form E, form F, form B, form C, form H, or a combination thereof. In some embodiments, the compound of formula (I) is in form A, provided that the compound of formula (I) in form A has a purity of less than about 99%. In some embodiments, the compound of formula (I) is in a crystalline form other than form A. In some embodiments, the compound of formula (I) is amorphous.

[0114] With respect to the second method, in some embodiments, the compound of formula (I) has a purity of at least about 90%. In some embodiments, the compound of formula (I) has a purity of about 90% to about 99%. In some embodiments, the compound of formula (I) has a purity of about 95% to about 99%. In some embodiments, the compound of formula (I) has a purity of about 96% to about 99%, about 97% to about 99%, or about 98% to about 99%. In some embodiments, the compound of formula (I) has a purity of about 96%. In some embodiments, the compound of formula (I) has a purity of about 97%. In some embodiments, the compound of formula (I) has a purity of about 98%. In some embodiments, the compound of formula (I) has a purity of about 99%.

[0115] With respect to the second method, in some embodiments, the compound of formula (I) is present in the third slurry in amounts of about 20 g / L to about 50 g / L, about 25 g / L to about 40 g / L, about 30 g / L to about 35 g / L, or about 33 g / L. In some embodiments, the compound of formula (I) is present in the third slurry in amounts of about 25 g / L to about 40 g / L. In some embodiments, the compound of formula (I) is present in the third slurry in amounts of about 30 g / L to about 35 g / L. In some embodiments, the compound of formula (I) is present in the third slurry in amounts of about 33 g / L.

[0116] With respect to the second method, in some embodiments, the volume ratio of THF to MTBE in the third slurry is approximately 1:4 to approximately 2:1. In some embodiments, the volume ratio of THF to MTBE in the third slurry is approximately 1:3 to approximately 1:1. In some embodiments, the volume ratio of THF to MTBE in the third slurry is approximately 1:2.

[0117] With respect to the second method, in some embodiments, one or more seed crystals of crystal form A are present in an amount of about 5% to about 20% by weight of the compound of formula (I). In some embodiments, one or more seed crystals of crystal form A are present in an amount of about 5% by weight of the compound of formula (I). In some embodiments, one or more seed crystals of crystal form A are present in an amount of about 10% by weight of the compound of formula (I).

[0118] Regarding the second method, in some embodiments, the stirring step c) is carried out over approximately 1 to 5 days. In some embodiments, the stirring step c) is carried out over approximately 1 to 2 days. In some embodiments, the stirring step c) is carried out over approximately 1.5 days.

[0119] Regarding the second method, in some embodiments, steps a) to c) are each maintained at a temperature of approximately 45°C.

[0120] With respect to the second method, in some embodiments, after step c), the fifth slurry is further cooled to a temperature of approximately 25°C or below and stirred for about 1 to 24 hours while maintaining the temperature at approximately 25°C or below. In some embodiments, the fifth slurry is further cooled to approximately 20°C over about 1 to 3 hours; and stirred for about 1 to 24 hours while maintaining the temperature at approximately 20°C. In some embodiments, the fifth slurry is further cooled to approximately 20°C over about 2 hours; and stirred for about 1 hour while maintaining the temperature at approximately 20°C.

[0121] In general, crystalline form A of the compound of formula (I) can be isolated by common methods (e.g., filtration and drying). With respect to both the first and second methods described above, in some embodiments, the precipitate is isolated by filtration. In some embodiments, the isolated precipitate is further dried to obtain crystalline form A. In some embodiments, the isolated precipitate is further dried by heating (e.g., 45°C) to obtain crystalline form A. In some embodiments, the isolated precipitate is further dried by heating (e.g., 45°C) for several days (e.g., 1-2 days) to obtain crystalline form A.

[0122] With respect to both the first and second methods, in some embodiments, the crystalline form A of the isolated compound of formula (I) has a purity of at least about 99%. In some embodiments, the crystalline form A of the isolated compound of formula (I) has a purity of at least about 99.5%. In some embodiments, the crystalline form A of the isolated compound of formula (I) has a purity of about 99.9%.

[0123] Crystalline form A of the compound of formula (I), prepared by both the first and second methods described herein, can be characterized according to Section III-1. In some embodiments, crystalline form A of the compound of formula (I), prepared by both the first and second methods described herein, has an X-ray powder diffraction pattern substantially consistent with that of Figure 1.

[0124] V. Composition In another aspect, the present disclosure provides pharmaceutical compositions prepared by a method comprising combining a crystalline form of a compound of formula (I), each of which is one of crystalline forms A, B, C, E, F, and H as defined and described herein, with one or more pharmaceutically acceptable carriers. In some embodiments, the crystalline form is form A as defined and described herein.

[0125] The crystalline forms provided herein can be formulated into pharmaceutical compositions using methods available in the art and methods disclosed herein. Any crystalline form disclosed herein can be provided as a suitable pharmaceutical composition and administered via a suitable route of administration.

[0126] Administration of the compositions described herein to a subject may be by topical or non-systemic means, such as topical, subcutaneous, intradermal, or intralesional administration. In some embodiments, the composition may be administered by topical administration. In some embodiments, the composition may be administered by intradermal administration. In some embodiments, the composition may be administered intralesionally, such as by intralesional injection.

[0127] The methods provided herein include the step of administering a pharmaceutical composition prepared from at least one crystalline form of one of the compounds described herein, either alone or in combination with one or more suitable and pharmaceutically acceptable carriers, such as diluents or adjuvants, or in combination with another agent for treating a MEK inhibitor-responsive disorder or disease, MEK inhibitor-responsive skin disorder or skin disease, MEK-mediated disorder or disease, or MEK-mediated skin disorder or skin disease in which the subject requires treatment.

[0128] In some embodiments, the second agent can be formulated or packaged together with the crystalline form of the compound provided herein. Naturally, the formulation of the second agent together with the crystalline form of the compound provided herein is only done if a person skilled in the art determines that this co-formulation will not interfere with the activity or method of administration of either agent. In some embodiments, the crystalline form of the compound provided herein and the second agent are formulated separately. They may be packaged together or separately, depending on the convenience of a person skilled in the art.

[0129] In clinical practice, the active agents provided herein may be administered by any preferred route, particularly topically, subcutaneously, intradermally, intralesionally, or orally, parenterally, rectally, or by inhalation (e.g., in the form of an aerosol). In some embodiments, compositions prepared from the crystalline forms of the compounds provided herein are administered topically, subcutaneously, intradermally, or intralesionally. In some embodiments, compositions prepared from the crystalline forms of the compounds provided herein are administered topically. In some embodiments, compositions prepared from the crystalline forms of the compounds provided herein are administered intradermally. In some embodiments, compositions prepared from the crystalline forms of the compounds provided herein are administered intralesionally.

[0130] Tablets, pills, hard gelatin capsules, powders, or granules can be used as solid compositions for oral administration. These compositions contain a mixture of an active ingredient and one or more inert diluents or adjuvants, such as sucrose, lactose, or starch.

[0131] These compositions may include substances other than diluents, such as lubricants like magnesium stearate, or coatings for controlled release.

[0132] Pharmaceutically acceptable solutions, suspensions, emulsions, syrups, and elixirs containing water or an inert diluent such as liquid paraffin can be used as liquid compositions for oral administration. These compositions may also contain substances other than the diluent, in some embodiments, wetting agents, sweeteners, or flavorings.

[0133] Lotions, tinctures, creams, emulsions, gels, or ointments can be used as topical administration compositions. These compositions contain an active agent mixed with one or more inert excipients, including water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof.

[0134] Compositions for parenteral, intralesional, or intradermal administration may be emulsions or sterile solutions. Propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, or organic esters for injection, and in some embodiments ethyl oleate, may be used as solvents or media. These compositions may contain auxiliaries, particularly wetting agents, isotonic agents, emulsifiers, dispersants, and stabilizers. Sterilization can be carried out in several ways, in some embodiments by the use of bacterial filters, radiation, or heating. These compositions may be prepared in the form of sterile solid compositions that are soluble in sterile water or any other sterile medium for injection at the time of use.

[0135] The rectal administration composition is a suppository or rectal capsule containing an active ingredient as well as an excipient such as cocoa butter, semi-synthetic glyceride, or polyethylene glycol.

[0136] The composition may also be an aerosol. When used in the form of a liquid aerosol, the composition may be a stable sterile solution or a solid composition that dissolves at the time of use in non-pyrogenic sterile water, saline solution, or any other pharmaceutically acceptable medium. When used in the form of a dry aerosol intended for direct inhalation, the active ingredient is pulverized and combined with a water-soluble solid diluent or medium, in some embodiments dextran, mannitol, or lactose.

[0137] In some embodiments, the compositions provided herein are pharmaceutical compositions or single-unit dosage forms. These pharmaceutical compositions or single-unit dosage forms typically comprise one or more prophylactic or therapeutic agents (e.g., the compounds provided herein, or other prophylactic or therapeutic agents) in a prophylactic or therapeutic dose, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the term “pharmaceutically acceptable” means that it is approved by a federal or state regulatory authority or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more specifically in humans. The term “carrier” includes diluents, adjuvants (e.g., Freund’s adjuvants (complete and incomplete)), excipients, or media through which the therapeutic agent is administered. These pharmaceutical carriers may be sterile liquids, such as water, and oils, including petroleum, animal, plant, or synthetic oils such as peanut oil, soybean oil, mineral oil, and sesame oil. When the pharmaceutical composition is administered intravenously, water may be used as the carrier. Physiological saline, as well as glucose aqueous solutions and glycerin aqueous solutions, may be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0138] Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical art, and in some embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, and ethanol. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or single dosage form depends on how the unit dosage form is administered to the subject and various factors well known in the art, including but not limited to specific active ingredients in the dosage form. If desired, the composition or single unit dosage form may also contain trace amounts of wetting agents, emulsifiers, or pH buffers.

[0139] The lactose-free compositions provided herein may include excipients that are well known to those skilled in the art and, in some embodiments, are listed in the United States Pharmacopeia (USP 36-NF 31 S2). Generally, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in pharmaceutically compatible and pharmaceutically acceptable amounts. An exemplary lactose-free dosage form contains an active ingredient, crystalline cellulose, pregelatinized starch, and magnesium stearate.

[0140] Since water can accelerate the decomposition of several compounds, aqueous pharmaceutical compositions and dosage forms containing active ingredients are further encompassed herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a means of promoting long-term storage to determine properties such as the shelf life or stability over time of a formulation. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp. 379 80. In fact, water and heat accelerate the decomposition of several compounds. Therefore, the effect of water on a formulation can be very important, given that formulations are normally encountered with moisture and / or humidity during manufacturing, handling, packaging, storage, transport, and use.

[0141] The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low-water-content components and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine may be anhydrous if substantial contact with moisture and / or humidity is expected during manufacture, packaging, and / or storage.

[0142] Anhydrous pharmaceutical compositions should be prepared and stored in such a way that their anhydrous nature is maintained. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water, so that they may be included in a suitable formulation kit. Suitable packaging in some embodiments includes, but is not limited to, airtight foil, plastic, unit dose containers (e.g., vials), blister packs, and strip packs.

[0143] Further provided are pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which the active ingredient degrades. These compounds, referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0144] Pharmaceutical compositions and single-unit dosage forms may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. These compositions and unit dosage forms contain a prophylactic or therapeutically effective dose of the prophylactic or therapeutic agent, in some embodiments in its pure form, along with a suitable amount of carrier to provide a suitable form for appropriate administration to the subject. The formulation should be suitable for the mode of administration. In some embodiments, the pharmaceutical composition or single-unit dosage form is sterile and in a form suitable for administration to the subject, in some embodiments animal subjects, e.g., mammalian subjects, and in some embodiments human subjects.

[0145] Pharmaceutical compositions are formulated to suit their intended route of administration. In some embodiments, the route of administration includes, but is not limited to, parenteral administration, such as intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, bursal, and rectal administration. In some embodiments, the route of administration is intradermal, topical, or intralesional. In some embodiments, the route of administration is non-systemic. In some embodiments, the composition is formulated as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans according to routine procedures. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration to humans according to routine procedures. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the composition may also contain a solubilizer and a local anesthetic such as lignocaine to relieve pain at the injection site.

[0146] In some embodiments, the dosage forms include, but are not limited to, tablets; caplets; capsules such as soft-elastic gelatin capsules; cachets; lozenges; licks; dispersions; suppositories; ointments; poultices; pastes; powders; bandages; creams; plasters; solutions; patches; aerosols (e.g., nasal drops or inhalants); gels; suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs, liquid dosage forms suitable for oral or mucosal administration to a subject; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to obtain liquid dosage forms suitable for parenteral administration to a subject.

[0147] Typically, the composition, form, and type of dosage forms provided herein vary depending on their intended use. In some embodiments, dosage forms used in the initial treatment of MEK inhibitor-responsive disorders or diseases, MEK inhibitor-responsive skin disorders or skin diseases, MEK-mediated disorders or diseases, or MEK-mediated skin disorders or skin diseases may contain a greater amount of one or more active ingredients than dosage forms used in maintenance treatment of the same disorder or disease. Similarly, parenteral dosage forms may contain a smaller amount of one or more active ingredients than oral dosage forms used to treat the same disease or disorder. It will be obvious to those skilled in the art that the specific dosage forms contained herein differ from one another in these and other respects. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0148] Generally, the components of a composition are supplied separately or as a mixture in unit dosage forms, in some embodiments as lyophilized powders or anhydrous concentrates, in sealed containers such as ampoules or sachets that indicate the amount of active ingredient. When the composition is to be administered by injection, it can be dispensed using injection bottles containing pharmaceutical-grade sterile water or sterile saline. When the composition is to be administered by injection, ampoules of sterile water for injection or sterile saline can be prepared so that the components can be mixed before administration.

[0149] Typical dosage forms contain approximately 0.1 mg to approximately 1000 mg of the compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, per day, and are administered as a single dose once daily in the morning, or as divided doses throughout the day taken with meals. Specific dosage forms may contain approximately 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, or 1000 mg of the active compound.

[0150] Oral dosage form Pharmaceutical compositions suitable for oral administration can be presented as separate dosage forms, including but not limited to tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). These dosage forms contain a predetermined amount of the active ingredient and can be prepared by pharmaceutical methods well known to those skilled in the art. See Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012) for general information.

[0151] In some embodiments, the oral dosage form is solid and is prepared under anhydrous disease or disorder using anhydrous components, as described in detail herein. However, the range of compositions provided herein extends beyond anhydrous solid oral dosage forms. Therefore, further embodiments are described herein.

[0152] Typical oral dosage forms are prepared by homogeneously mixing and combining the active ingredient with at least one excipient according to conventional pharmaceutical formulation techniques. Excipients can take a wide variety of forms depending on the desired preparation for administration. In some embodiments, suitable excipients for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavorings, preservatives, and colorants. In some embodiments, suitable excipients for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starch, sugars, crystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants.

[0153] Tablets and capsules are the most advantageous oral dosage forms due to their ease of administration, in which case solid excipients are used. If desired, tablets can be coated with standard aqueous or non-aqueous techniques. These dosage forms can be prepared by any pharmaceutical method. Generally, pharmaceutical compositions and dosage forms are prepared by homogeneously and uniformly mixing the active ingredient with a liquid carrier, a micronized solid carrier, or both, and then shaping the product to the desired appearance as needed.

[0154] In some embodiments, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing an active ingredient in a readily flowable form, such as a powder or granules, mixed with an excipient, in a suitable machine. Molded tablets can be prepared by molding a mixture of compound powders moistened with an inert liquid diluent in a suitable machine.

[0155] In some embodiments, excipients usable in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic rubber, e.g., gum arabic, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., 2208, 2906, 2910), crystalline cellulose, and mixtures thereof.

[0156] In some embodiments, suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), crystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. Typically, binders or fillers in a pharmaceutical composition are present in about 50 to about 99 percent by weight of the pharmaceutical composition or dosage form.

[0157] In some embodiments, preferred forms of crystalline cellulose include, but are not limited to, materials marketed as AVISEL PH 101, AVISEL PH 103, AVISEL RC 581, and AVISEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pennsylvania), and mixtures thereof. A specific binder is a mixture of crystalline cellulose and sodium carboxymethylcellulose, marketed as AVISEL RC 581. Suitable anhydrous or low-moisture excipients or additives include AVISEL PH 103® and Starch 1500 LM.

[0158] Disintegrants are used in a composition to provide a tablet that disintegrates when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant should be used to form a solid oral dosage form, neither too much nor too little, so as not to adversely alter the release of the active ingredient. The amount of disintegrant used varies depending on the type of formulation and is readily apparent to those skilled in the art. A typical pharmaceutical composition contains about 0.5 to about 15 weight percent of disintegrant, particularly about 1 to about 5 weight percent of disintegrant.

[0159] Disintegrants usable in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, crystalline cellulose, croscarmellose sodium, crospovidone, polaritrin potassium, sodium starch glycolate, potato starch or tapioca starch, pregelatinized starch, other starches, clay, other algins, other celluloses, gums, and mixtures thereof.

[0160] Lubricants usable in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. In some embodiments, further lubricants include syloid silica gel (AEROSIL 200, manufactured by WR Grace Co., Baltimore, Maryland), synthetic silica solidification aerosol (sold by Degussa Co., Plano, Texas), CAB O SIL (pyrogenic silicon dioxide product, sold by Cabot Co., Boston, Massachusetts), and mixtures thereof. When used in small amounts, lubricants are typically used in amounts less than about 1 weight percent of the pharmaceutical composition or dosage form in which they are incorporated.

[0161] Delayed-release dosage form Compositions prepared from active ingredients such as the crystalline form of the compounds provided herein can be administered by controlled release means or delivery devices well known to those skilled in the art. In some aspects, U.S. Patents No. 3,845,770; No. 3,916,899; No. 3,536,809; No. 3,598,123; No. 4,008,719; No. 5,674,533; No. 5,059,595; No. 5,591,767; No. 5,120,548; No. 5,073,543; No. 5,639,476; No. 5,354,556; No. 5,639,480; No. 5,733,566; No. 5,739,108; No. 5,891,474; No. 5,922,356; No. 5,972,891; No. 5,980,945; all of which are incorporated herein by reference in their entirety. Examples include, but are not limited to, those described in Patent Nos. 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500. These dosage forms can be used in some embodiments to achieve delayed or controlled release of one or more active ingredients using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof in various ratios to achieve a desired release profile. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Accordingly, single-unit dosage forms suitable for oral administration, such as but not limited to tablets, capsules, gel capsules, and caplets adapted for controlled release, are included herein.

[0162] All controlled-release pharmaceutical products share the common goal of improving drug therapy compared to the drug therapy achieved by their uncontrolled counterparts. Ideally, the use of optimally designed controlled-release formulations in medical treatment is characterized by the use of the smallest amount of active pharmaceutical ingredient in the smallest amount of time to cure or control a disease or disorder. Advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and improved patient compliance. Furthermore, controlled-release formulations can be used to influence the time of action or other properties such as the blood level of the drug, and therefore can influence the occurrence of side effects (e.g., adverse effects).

[0163] Most controlled-release formulations are designed to release an initial amount of the drug (active ingredient) to rapidly produce the desired therapeutic effect, followed by a gradual, continuous release of other amounts of the drug to maintain this level of therapeutic or prophylactic effect over a longer period. To maintain this constant drug level in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by various diseases or disorders, including but not limited to pH, temperature, enzymes, water, or other physiological disorders or compounds.

[0164] In some embodiments, drugs can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In some embodiments, pumps can be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In some embodiments, polymer materials can be used. In some embodiments, controlled-release systems can be placed within the target at a suitable site determined by those skilled in the art, i.e., this reduces the amount required to a fraction of the total body volume (see, for example, Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled-release systems are described in Langer's review article (Science 249:1527-1533 (1990)).The active ingredient is an external polymer membrane insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene, and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyl oxyethanol The active ingredient can be dispersed in a solid internal matrix surrounded by a polymer copolymer, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate. The active ingredient is then diffused through the external polymer membrane during the release rate control step. The proportion of the active ingredient in these parenteral compositions depends largely on their specific properties and the requirements of the target.

[0165] Parenteral dosage form In some embodiments, parenteral dosage forms are provided. In some embodiments, parenteral dosage forms can be administered to subjects via a variety of routes, including but not limited to subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial routes. In some embodiments, parenteral dosage forms can be administered to subjects via a variety of routes, including but not limited to local, intradermal, or intralesional routes. Since the administration of parenteral dosage forms usually bypasses the subject's natural defenses against contaminants, parenteral dosage forms are usually sterile or can be sterilized before administration to the subject. In some embodiments, parenteral dosage forms include, but are not limited to, solutions prepared for injection, dry preparations prepared to dissolve or suspend in a pharmaceutically acceptable injection medium, suspensions prepared for injection, and emulsions.

[0166] Suitable media that can be used to obtain parenteral dosage forms are well known to those skilled in the art. In some embodiments, suitable media include, but are not limited to, water for injection (USP); aqueous media such as sodium chloride injection, Ringer's solution, glucose injection, glucose-sodium chloride injection, and lactated Ringer's solution; water-miscible media such as, but are not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous media such as, but are not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0167] Compounds that increase the solubility of one or more active ingredients disclosed herein may be incorporated into the parenteral dosage form.

[0168] Transdermal dosage form, topical dosage form, and mucosal dosage form Transdermal, topical, and mucosal dosage forms are also provided. Transdermal, topical, and mucosal dosage forms include, but are not limited to, eye drops, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissue in the oral cavity can be formulated as mouthwashes or oral gels. Furthermore, transdermal dosage forms include "reservoir" or "matrix" patches, which can be applied to the skin and worn for a specific period of time to allow for the penetration of a desired amount of the active ingredient.

[0169] The term “pharmaceutically acceptable carrier” means any pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting any subject composition or its components. Each carrier must be “acceptable” in the sense that it is compatible with the subject composition and its components and is not harmful to the patient. Suitable carriers (e.g., excipients and diluents) and other materials that can be used to obtain the topical, transdermal, and mucosal dosage forms contained herein are well known to those skilled in the art of pharmaceuticals and depend on the specific tissue to which a given pharmaceutical composition or dosage form is applied. With that in mind, typical carriers for forming non-toxic and pharmaceutically acceptable lotions, tinctures, creams, emulsions, gels, or ointments include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof.In some embodiments, materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose, and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) Pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic and compatible substances used in pharmaceutical formulations. Moisturizers or water-retaining agents may be added to the pharmaceutical composition and dosage form if desired. Examples of these further components are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0170] Depending on the specific tissue to be treated, additional components may be used before, simultaneously with, or after treatment with the provided active ingredient. In some embodiments, a permeation enhancer may be used to assist in the delivery of the active ingredient to the tissue. Suitable permeation enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; coridone grade (povidone, polyvidone); urea; and various water-soluble or water-insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[0171] Furthermore, the pH of the pharmaceutical composition or dosage form, or the pH of the tissue to which the pharmaceutical composition or dosage form is applied, can be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity, ionic strength, or isotonicity of the solvent carrier can be adjusted to improve delivery. Compounds such as stearate esters can be added to the pharmaceutical composition or dosage form to favorably modify the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearate esters can act as a lipid medium in the formulation, as an emulsifier or surfactant, and as a delivery accelerator or permeation accelerator. Different salts, hydrates, or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.

[0172] Topical preparations In some embodiments, the pharmaceutical compositions described herein are topical formulations. The topical formulations can be any one of the formulations described in PCT / US2019 / 000066, the entire contents of which are incorporated herein by reference for all purposes. In some embodiments, the topical formulation is prepared from any one of the crystalline forms of the compound of formula (I), each of which is any one of crystalline forms A, B, C, E, F, and H as defined and described herein. In some embodiments, the topical formulation is prepared from crystalline form A of the compound of formula (I) as defined and described herein.

[0173] In some embodiments, the topical formulation is a lotion, a lotion, a spray, an ointment, a cream, a gel, or a patch.

[0174] VI. Methods In a third aspect, the disclosure provides a method of treating a skin disorder. The method comprises treating a skin disease by administering a crystalline form of the compound of formula (I), each of which is any one of crystalline forms A, B, C, E, F, and H as defined and described herein, or a pharmaceutical composition thereof as defined and described herein. In some embodiments, the crystalline form is Form A as defined and described herein.

[0175] In some embodiments, provided herein is a method for treating in a subject a skin disorder for which the subject needs treatment, which is a MEK inhibitor-responsive skin disorder or skin disease or a MEK-mediated skin disorder or skin disease. In some embodiments, the method comprises treating the skin disease by administering to the subject a therapeutically effective amount or a prophylactically effective amount of a crystalline form of a compound of formula (I), which is any one of crystalline forms A, B, C, E, F, and H, each of which is as defined and described herein, or a pharmaceutical composition thereof as defined and described herein. In some embodiments, the method comprises treating the skin disease by administering to the subject a therapeutically effective amount or a prophylactically effective amount of crystalline form A of a compound of formula (I) or a pharmaceutical composition thereof, both of which are as defined and described herein. In some embodiments, the method comprises treating the skin disease by administering to the subject a therapeutically effective amount of a crystalline form of a compound of formula (I), which is any one of crystalline forms A, B, C, E, F, and H, each of which is as defined and described herein, or a pharmaceutical composition thereof as defined and described herein. In some embodiments, the method comprises treating the skin disease by administering to the subject a therapeutically effective amount of crystalline form A of a compound of formula (I) or a pharmaceutical composition thereof, both of which are as defined and described herein.

[0176] In some embodiments, the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is selected from the group consisting of cutaneous RASopathies, neurofibromatosis type 1, cutaneous neurofibromas, subcutaneous neurofibromas, and superficial plexiform neurofibromas.

[0177] In some embodiments, the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is neurofibromatosis type 1.

[0178] In some embodiments, administration involves bringing a crystalline form of the compound of formula (I), each of which is one of crystalline forms A, B, C, E, F, and H as defined and described herein, or a pharmaceutically acceptable composition thereof, to the skin, mucous membrane, vagina, penis, larynx, vulva, cervix, or anus of a subject by topical or non-systemic application, such as topical application. In some embodiments, the crystalline form is crystalline form A as defined and described herein.

[0179] In some embodiments, tumors associated with neurofibromatosis type 1 (NF1), such as cutaneous neurofibromas, subcutaneous neurofibromas, or superficial plexiform neurofibromas, are treated when, for example, their size or total tumor volume is reduced by at least about 15% (e.g., about 15% to about 60%) compared to a reference standard. In some embodiments, the reference standard is the size or total tumor volume in an untreated control, for example, from the same or a different subject.

[0180] In some embodiments, the size or total tumor volume of tumors associated with neurofibromatosis type 1 (NF1), such as cutaneous neurofibromas, subcutaneous neurofibromas, or superficial plexiform neurofibromas, is reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, and at least about 60% compared to a reference standard. In some embodiments, the reference standard is the size or total tumor volume in an untreated control, for example, from the same or different subjects.

[0181] In some embodiments, the method includes a step of evaluating the subject using magnetic resonance imaging (MRI) or optical imaging, for example, an evaluation of the amount of tumor obtained from the subject, for example, before, during, and / or after the procedure.

[0182] Neurofibromatosis type 1 (NF1) In some aspects, skin disorders are associated with NF1. NF1, also known as neurofibromatosis recklinghausen's disease or peripheral neurofibromatosis, occurs in approximately 1 in 3,000 births and is one of the most common genetic disorders and neurocutaneous disorders. NF1 is caused by neurofibromin deficiency, which leads to overactivation of various signaling pathways, such as Ras and Rho, and is associated with several skin disorders, including dermal neurofibromas (DF); subcutaneous neurofibromas; superficial plexiform neurofibromas (PF); cutaneous neurofibromas (CF); café-au-lait spots; and axillary and groin blemishes. DF occurs in over 95% of NF1 patients. DF can appear anywhere on the body, and 88% of NF1 patients over 40 years of age have more than 100 DFs. DF can cause severe physical distress, cosmetic impairment, and social anxiety. Facial neurofibromas (DFs) can create severe social anxiety problems and pain in affected individuals. DFs (also known as cutaneous neurofibromas or focal neurofibromas) grow from small nerves in or just beneath the skin and usually appear as small bumps around puberty. Current treatment options for DFs are limited to surgical excision and CO2 laser removal, both of which cause scarring and are neither preventative.

[0183] Other cutaneous RAS diseases In some embodiments, skin disorders are associated with increased Ras activation. In some embodiments, skin disorders are selected from psoriasis, keratoacanthoma (KA), keratosis, papilloma, Noonan syndrome (NS), cardiac-facial-cutaneous syndrome (CFC), Costello syndrome (facial-cutaneous-skeletal syndrome or FCS syndrome), ectodermal syndrome, café-au-lait spots, and lentigo polycarcinoma (formerly known as leopard syndrome).

[0184] In some or all aspects, the disease to be reduced, reduced, treated or prevented is not cancer (e.g., melanoma).

[0185] In some aspects, the diseases to be reduced, reduced in remission, treated or prevented are cancer, cutaneous RAS disease, skin disorders associated with neurofibromatosis type 1, namely cutaneous neurofibroma, subcutaneous neurofibroma, or superficial plexiform neurofibroma, psoriasis, keratoacanthoma (KA), keratosis, papilloma, Noonan syndrome (NS), cardiac-facial-cutaneous syndrome (CFC), Costello syndrome (facial-cutaneous-skeletal syndrome or FCS syndrome), ectodermal syndrome, café-au-lait spots, and lentigo polycarcinoma (formerly known as leopard syndrome).

[0186] In some embodiments, the disease to be reduced, reduced, reduced, treated or prevented is cancer. In some embodiments, the disease to be reduced, reduced, treated or prevented is selected from the group consisting of basal cell carcinoma, squamous cell carcinoma, actinic keratosis, Kaposi's sarcoma, cutaneous lymphoma, cervical cancer, HPV-associated squamous cell carcinoma, and melanoma.

[0187] In some aspects, the diseases to be reduced, reduced in remission, treated or prevented are cutaneous RAS disease, skin disorders associated with neurofibromatosis type 1, namely cutaneous neurofibromas, subcutaneous neurofibromas, or superficial plexiform neurofibromas, psoriasis, keratoacanthoma (KA), keratosis, papilloma, Noonan syndrome (NS), cardiac-facial-cutaneous syndrome (CFC), Costello syndrome (facial-cutaneous-skeletal syndrome or FCS syndrome), ectodermal syndromes, café-au-lait spots, and lentigo polycarcinoma (formerly known as leopard syndrome).

[0188] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used to reduce MEK inhibitor-responsive skin disorders or skin diseases or MEK-mediated skin disorders or skin diseases in which a subject requires it.

[0189] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the remission of a MEK inhibitor-responsive skin disorder or skin disease or a MEK-mediated skin disorder or skin disease in which the subject requires it.

[0190] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the prevention of MEK inhibitor-responsive skin disorders or skin diseases or MEK-mediated skin disorders or skin diseases in which the subject requires it.

[0191] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the treatment of MEK inhibitor-responsive skin disorders or skin diseases or MEK-mediated skin disorders or skin diseases in which the subject requires it.

[0192] In some embodiments, methods for treating a skin disorder in which a subject requires treatment, such as a birthmark, are provided herein. In some embodiments, the method includes administering to a subject a therapeutically effective or prophylactically effective amount of a crystalline form of the compound of formula (I), or a pharmaceutically effective composition thereof, each of which is one of crystalline forms A, B, C, E, F, and H as defined and described herein. In some embodiments, the crystalline form is crystalline form A as defined and described herein.

[0193] In some cases, birthmarks are port-wine stains (capillary malformations). Port-wine stains can be present at birth. Port-wine stains can occur anywhere on the body, and the affected area of ​​skin grows with overall growth. Thickening or development of nodules of the lesion may occur in adulthood and may interfere with normal function (for example, if the port-wine stain is near the eye or mouth). In some cases, port-wine stains may be part of a syndrome such as Sturge-Weber syndrome or Klippel-Trenaunay-Weber syndrome.

[0194] In some embodiments, methods are provided herein for treating birthmarks (capillary malformations) to reduce aesthetic degradation or the progression of blemishes. In some embodiments, methods are provided herein for prophylactically treating birthmarks (capillary malformations) to reduce the progression of blemishes, delay the onset of blemishes, or delay the progression of blemishes.

[0195] In some embodiments, the blemish is an epidermal nevus. An epidermal nevus is a benign skin growth with localized epidermal hyperplasia that often presents at birth or within the first year of life. Typically, it appears as one or more rectangular or linear growths that are skin-colored, brown, or gray. The surface can be verrucous or fibrotic and can have sharp borders. In some cases, malignant transformation can occur in middle-aged or elderly subjects. Epidermal nevi are subclassified into keratinocytic nevi and organoid nevi. Organoid nevi include sebaceous nevi (NS). In some embodiments, the blemish is a sebaceous nevus. Non-organoid keratinocytic epidermal nevi (KEN) are characterized by benign congenital hyperpigmented skin lesions. Other types of epidermal nevi, including nevus comedonicus, are encompassed within the scope of the embodiments presented herein. Nevus comedonicus (NC) is an error tumor of the folliculosebaceous unit that typically presents at birth or in childhood, like other epidermal nevi. Clinically, NC lesions consist of linear rows or clusters of dilated follicular openings filled with keratin and resemble comedones.

[0196] In some embodiments, methods are provided herein for treating epidermal nevi to reduce aesthetic degradation or the progression of blemishes. In some embodiments, methods are provided herein for prophylactically treating epidermal nevi to reduce the progression of blemishes, delay the onset of blemishes, or delay the progression of blemishes.

[0197] In some embodiments, the birthmark is a sebaceous nevus. In some embodiments, methods for treating a sebaceous nevus birthmark to reduce cosmetic impairment or the progression of the birthmark are provided herein. In some embodiments, methods for prophylactically treating a sebaceous nevus birthmark to reduce the progression of the birthmark, delay the onset of the birthmark, or delay the progression of the birthmark are provided herein.

[0198] In some aspects, birthmarks are pigmented nevi, including congenital nevi, blue nevi, and acquired pigmented nevi. Occasionally, malignant melanoma develops from pigmented nevi (nevus cell nevi, also commonly known as moles). Reasons for treating pigmented nevi (i.e., nevus cell nevi) include preventing malignant changes, limiting malignant progression, improving cosmetic appearance, or preventing other functional or anatomical changes.

[0199] In some embodiments, methods for treating pigmented nevi to reduce the risk of cosmetic impairment or the progression of birthmarks are provided herein. In some embodiments, methods for prophylactically treating pigmented nevi to reduce the progression of birthmarks, delay the onset of birthmarks, or delay the progression of birthmarks are provided herein.

[0200] In some cases, birthmarks are dysplastic nevi. Dysplastic nevi (or atypical lentigo) are benign moles that have an unusual appearance and may resemble melanoma. People with atypical lentigo have an increased risk of developing melanoma in moles or other locations on their body.

[0201] In some embodiments, methods for treating dysplastic nevi to reduce cosmetic impairment or the progression of birthmarks are provided herein. In some embodiments, methods for prophylactically treating dysplastic nevi to reduce the progression of birthmarks, delay the onset of birthmarks, or delay the progression of birthmarks are provided herein.

[0202] In some forms, birthmarks are nevus flats. Nevus flats (also known as punctate nevus and herpetiform nevus) are skin lesions that appear as light brown spots due to hyperpigmentation, with several small dark brown dots within these spots.

[0203] In some embodiments, methods for treating nevus flatus birthmarks to reduce cosmetic impairment or the progression of the birthmark are provided herein. In some embodiments, methods for prophylactically treating nevus flatus birthmarks to reduce the progression of the birthmark, delay the onset of the birthmark, or delay the progression of the birthmark are provided herein.

[0204] In some embodiments, birthmarks are arteriovenous malformations in the skin (e.g., blue rubber nipple nevus syndrome) and may manifest as skin lesions consisting of compressible, blue subcutaneous nodules.

[0205] In some embodiments, methods for treating arteriovenous malformations to reduce cosmetic impairment or the progression of birthmarks are provided herein. In some embodiments, methods for prophylactically treating arteriovenous malformations to reduce the progression of birthmarks, delay the onset of birthmarks, or delay the progression of birthmarks are provided herein.

[0206] In some forms, birthmarks are lymphatic malformations. Lymphatic malformations are a type of vascular nevus or birthmark caused by malformations and dilations of lymphatic vessels. Cysts (also called "cystic lymphangioma" and "lymphangioma cysticum") are "macrocytic" lymphatic malformations consisting of large spaces filled with fluid. They appear as skin-colored, red, or bluish lesions, are somewhat transparent, and swell beneath the skin. Cavernous lymphangiomas can affect any part of the body, including the tongue. Focal lymphangiomas are "microcytic" lymphatic malformations. They appear as clusters of small, firm herpes filled with lymph, resembling frog eggs.

[0207] In some embodiments, methods for treating lymphatic malformations to reduce the risk of cosmetic impairment or the progression of birthmarks are provided herein. In some embodiments, methods for prophylactically treating lymphatic malformations to reduce the progression of birthmarks, delay the onset of birthmarks, or delay the progression of birthmarks are provided herein.

[0208] In some cases, birthmarks are congenital pigmented nevi. Congenital pigmented nevi appear as localized, light brown to black spots or plaques, with uneven firmness, covering surface areas and parts of the body of any size. Congenital pigmented nevi carry a risk of malignant degeneration.

[0209] In some embodiments, methods for treating congenital pigmented nevi to reduce the risk of cosmetic impairment or the progression of birthmarks are provided herein. In some embodiments, methods for prophylactically treating congenital pigmented nevi to reduce the progression of birthmarks, delay the onset of birthmarks, or delay the progression of birthmarks are provided herein.

[0210] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for reducing bruises in the subject in question.

[0211] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the remission of bruises in the subject concerned.

[0212] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the prevention of bruises (e.g., MEK inhibitor-responsive or MEK-mediated bruises) and / or the prevention of the exacerbation of bruises (e.g., when bruises may progress to proliferative disorders) in subjects requiring such prevention.

[0213] In some cases, the required subject is a human being.

[0214] The bruise is not a café au lait spot.

[0215] In some embodiments, administration involves bringing the crystalline form of the compound of formula (I) or a pharmaceutically acceptable composition thereof into contact with the skin of a target, for example, a diseased area of ​​skin, for example, an area of ​​skin having a birthmark.

[0216] In some embodiments, the appearance of the birthmark, such as size, volume, or total surface area, is reduced by at least about 15% compared to a reference standard (e.g., the size of the birthmark before treatment), thereby treating the subject. In some embodiments, the size, volume, or total surface area on the skin is reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared to a reference standard. In one embodiment, the reference standard is the size of the birthmark before treatment.

[0217] In some embodiments, methods for treating a skin disorder requiring treatment in a subject, which is skin cancer, are provided herein. In some embodiments, the method includes administering to a subject a therapeutically effective or prophylactically effective amount of a crystalline form of the compound of formula (I), or a pharmaceutically effective composition thereof, which is one of crystalline forms A, B, C, E, F, and H, as defined and described herein. In some embodiments, the crystalline form is crystalline form A, as defined and described herein.

[0218] In some embodiments, skin cancer is MEK inhibitor-responsive or MEK-mediated skin cancer.

[0219] In some aspects, skin cancer is cutaneous squamous cell carcinoma (cSCC).

[0220] In some embodiments, cutaneous squamous cell carcinoma is associated with ultraviolet radiation exposure or immunosuppression in parenchymal organ transplant recipients (SOTRs).

[0221] In some embodiments, cutaneous squamous cell carcinoma in parenchymal organ transplant recipients is MEK inhibitor-responsive or MEK-mediated cutaneous squamous cell carcinoma.

[0222] In some embodiments, administration involves bringing a crystalline form of the compound of formula (I), each of which is one of crystalline forms A, B, C, E, F, and H as defined and described herein, or a pharmaceutically acceptable composition thereof, to the skin, mucous membrane, vagina, penis, larynx, vulva, cervix, or anus of a target by topical or non-systemic application of a soft MEK inhibitor, such as topical application, intradermal application, or intralesional application, or by suppository application. In some embodiments, the crystalline form is crystalline form A as defined and described herein.

[0223] In some embodiments, tumors associated with cutaneous squamous cell carcinoma (cSCC), such as dermal carcinoma, are treated when, for example, their size or total tumor volume is reduced by at least about 15% (e.g., about 15% to about 60%) compared to a reference standard. In some embodiments, the reference standard is the size or total tumor volume in an untreated control, for example, from the same or a different subject.

[0224] The SOTR population includes patients who currently have SCC, patients who have previously had cSCC, or patients with precancerous conditions, including normally located squamous cell carcinoma (also known as Bowen's disease), or actinic keratosis, all of which are known to progress to SCC.

[0225] In some embodiments, methods for treating cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who currently have cSCC, have previously had cSCC, have precancerous conditions including normally located squamous cell carcinoma (also known as Bowen's disease), or have actinic keratosis are provided herein to reduce the progression of cSCC. In some embodiments, methods for treating cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients to reduce the progression of cSCC are provided herein. In some embodiments, methods for treating cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who previously had cSCC are provided herein to reduce the progression of cSCC. In some embodiments, methods for treating cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who have precancerous conditions including normally located squamous cell carcinoma (also known as Bowen's disease) are provided herein to reduce the progression of cSCC. In some embodiments, methods for treating cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients currently having actinic keratosis are provided herein to reduce the progression of cSCC.

[0226] In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who currently have cutaneous squamous cell carcinoma (cSCC), have previously had cutaneous squamous cell carcinoma (cSCC), have precancerous conditions including normally located squamous cell carcinoma (also known as Bowen's disease), or have actinic keratosis, in order to reduce the risk of tumor progression of cutaneous squamous cell carcinoma (cSCC). In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients, in order to reduce the risk of tumor progression of cutaneous squamous cell carcinoma (cSCC). In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who have previously had cutaneous squamous cell carcinoma (cSCC), in order to reduce the risk of tumor progression of cutaneous squamous cell carcinoma (cSCC), are provided herein. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients having precancerous conditions, including normally located squamous cell carcinoma (also known as Bowen's disease), in order to reduce the risk of tumor progression of cSCC. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma in parenchymal organ transplant recipients having actinic keratosis, in order to reduce the risk of tumor progression of cSCC, are provided herein.

[0227] In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who currently have cutaneous squamous cell carcinoma (cSCC), have previously had cutaneous squamous cell carcinoma (cSCC), have precancerous conditions including normally located squamous cell carcinoma (also known as Bowen's disease), or have actinic keratosis, in order to delay the progression of cutaneous squamous cell carcinoma (cSCC). In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients, in order to delay the progression of cutaneous squamous cell carcinoma (cSCC). In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who have previously had cutaneous squamous cell carcinoma (cSCC), in order to delay the progression of cutaneous squamous cell carcinoma (cSCC). In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients having precancerous conditions, including normally located squamous cell carcinoma (also known as Bowen's disease), in order to delay the progression of cSCC are provided herein. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients having actinic keratosis, in order to delay the progression of cSCC are provided herein.

[0228] In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who currently have cutaneous squamous cell carcinoma (cSCC), have previously had cutaneous squamous cell carcinoma (cSCC), have precancerous conditions including normally located squamous cell carcinoma (also known as Bowen's disease), or have actinic keratosis, in order to prevent the progression of cutaneous squamous cell carcinoma (cSCC). In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients, in order to prevent the progression of cutaneous squamous cell carcinoma (cSCC). In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients who previously had cutaneous squamous cell carcinoma (cSCC), in order to prevent the progression of cutaneous squamous cell carcinoma (cSCC), are provided herein. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients having precancerous conditions, including normally located squamous cell carcinoma (also known as Bowen's disease), in order to prevent the progression of cSCC are provided herein. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in parenchymal organ transplant recipients having actinic keratosis, in order to prevent the progression of cSCC are provided herein.

[0229] In some embodiments, methods for treating cutaneous squamous cell carcinoma (cSCC) in patients having chronic lymphocytic leukemia (CLL) and being immunocompromised, which makes them susceptible to a significantly increased rate of cSCC progression, are provided herein. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in patients having chronic lymphocytic leukemia (CLL) and being immunocompromised, which makes them susceptible to a significantly increased rate of cSCC progression, are provided herein. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma (cSCC) in patients having chronic lymphocytic leukemia (CLL) and being immunocompromised, which makes them susceptible to a significantly increased rate of cSCC progression, are provided herein.

[0230] In some embodiments, methods for treating cutaneous squamous cell carcinoma in patients with inoperable cSCC to reduce the progression of cSCC are provided herein. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma in patients with inoperable cSCC to reduce the risk of tumor progression of cSCC are provided herein. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma in patients with inoperable cSCC to delay or prevent the progression of cSCC are provided herein.

[0231] In some embodiments, methods for treating cutaneous squamous cell carcinoma in patients whose cSCC has been previously surgically removed are provided herein to reduce the progression of cSCC. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma in patients whose cSCC has been previously surgically removed are provided herein to reduce the risk of tumor progression of cSCC. In some embodiments, methods for prophylactically treating or preventing cutaneous squamous cell carcinoma in patients whose cSCC has been previously surgically removed are provided herein to delay or prevent the progression of cSCC.

[0232] In some or any aspect, tumors or skin cancers associated with cutaneous squamous cell carcinoma that should be reduced, treated preventively, or prevented using the methods described herein are carcinomas.

[0233] In some embodiments, the disease to be reduced, reduced in remission, treated or prevented is skin cancer. In some embodiments, the disease to be reduced, reduced in remission, treated or prevented is selected from the group consisting of basal cell carcinoma, squamous cell carcinoma, normally located squamous cell carcinoma (also known as Bowen's disease), actinic keratosis, and HPV-associated squamous cell carcinoma. In some embodiments, the disease to be reduced, reduced in remission, treated or prevented is skin disorders associated with squamous cell carcinoma. In some embodiments, the disease to be reduced, reduced in remission, treated or prevented is skin disorders associated with squamous cell carcinoma in parenchymal organ transplant recipients. In some embodiments, the disease to be reduced, reduced in remission, treated or prevented is skin disorders associated with squamous cell carcinoma in patients with chronic lymphocytic leukemia (CLL).

[0234] In some embodiments, the crystalline form of the compound of formula (I) described herein or a pharmaceutically acceptable composition thereof is used for the reduction of MEK inhibitor-responsive skin cancer or MEK-mediated skin cancer in a subject who requires it.

[0235] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the remission of MEK inhibitor-responsive skin cancer or MEK-mediated skin cancer in which the subject requires it.

[0236] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the prevention of MEK inhibitor-responsive skin cancer or MEK-mediated skin cancer in a subject who requires it.

[0237] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the treatment of MEK inhibitor-responsive squamous cell carcinoma or MEK-mediated squamous cell carcinoma in which the subject requires it.

[0238] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the reduction of MEK inhibitor-responsive squamous cell carcinoma or MEK-mediated squamous cell carcinoma in a subject who requires it.

[0239] In some embodiments, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable composition thereof described herein is used for the remission of MEK inhibitor-responsive squamous cell carcinoma or MEK-mediated squamous cell carcinoma in which the subject requires it.

[0240] In some embodiments, the crystalline form of the compound of formula (I) or a pharmaceutically acceptable composition thereof described herein is used for the prevention of MEK inhibitor-responsive squamous cell carcinoma or MEK-mediated squamous cell carcinoma in a subject who requires it.

[0241] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the treatment of cutaneous squamous cell carcinoma in subjects requiring treatment.

[0242] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the reduction of cutaneous squamous cell carcinoma in subjects requiring it.

[0243] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the remission of cutaneous squamous cell carcinoma in subjects requiring it.

[0244] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition described herein is used for the prevention of cutaneous squamous cell carcinoma in subjects requiring it.

[0245] In some cases, the required subject is a human being.

[0246] In some embodiments, if the pharmaceutical composition is a topical formulation, the topical formulation is administered topically.

[0247] In some embodiments, topical formulations are administered as ointments, lotions, sprays, ointments, creams, gels, or patches.

[0248] VII. Combination Therapy In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition provided herein is useful in a method of treating a skin disorder in which a subject requires treatment, comprising a further administration of a second agent effective in treating the skin disorder. The second agent may be any agent known to those skilled in the art that is useful in treating skin disorders or skin diseases, including agents currently approved by the U.S. Food and Drug Administration or other similar agencies in countries other than the United States.

[0249] In some embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition provided herein is administered in combination with one second agent. In further embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition provided herein is administered in combination with two second agents. In even further embodiments, the crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition provided herein is administered in combination with two or more second agents.

[0250] In some embodiments, the method comprises administering (e.g., topically) a combination of a crystalline form of the compound of formula (I) provided herein or a pharmaceutically acceptable composition thereof, and a second agent, to a target subject in an amount effective for treating or preventing a skin disorder (e.g., MEK inhibitor-responsive or MEK-mediated skin disorder). The crystalline form of the compound of formula (I) may be any one of the crystalline forms A, E, F, B, C, and H described herein; the pharmaceutically acceptable composition may be any one of the compositions described herein; and the second agent may be any second agent described in the art or herein.

[0251] As used herein, the term “in combination” includes the use of two or more therapeutic agents (e.g., one or more prophylactic and / or therapeutic agents). The use of the term “in combination” does not restrict the order in which therapeutic agents (e.g., prophylactic and / or therapeutic agents) are administered to a person with a disorder. The first therapeutic agent (a prophylactic or therapeutic agent such as a compound provided herein) may be administered to a subject with a disorder before (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks before) or simultaneously with or after (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapeutic agent (for example, a prophylactic or therapeutic agent).

[0252] As used herein, the term “synergistic” includes combinations of compounds provided herein with other therapeutic agents (e.g., prophylactic or therapeutic agents) that have been used or are currently used to prevent, manage, or treat a disorder, and which are more effective than the additive effect of the therapeutic agents themselves. The synergistic effect of a combination of therapeutic agents (e.g., a combination of prophylactic or therapeutic agents) enables the use of one or more therapeutic agents at lower doses and the administration of such therapeutic agents to subjects with the disorder at a lower frequency. The ability to use lower doses of therapeutic agents (e.g., prophylactic or therapeutic agents) and / or administer such therapeutic agents at a lower frequency reduces the toxicity associated with the administration of such therapeutic agents to subjects without reducing the effectiveness of the therapeutic agents in preventing or treating the disorder. Furthermore, the synergistic effect may improve the effectiveness of the agents in preventing or treating the disorder. Finally, the synergistic effect of a combination of therapeutic agents (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce one or more adverse effects or undesirable side effects associated with the use of any therapeutic agent alone.

[0253] The crystalline form of the compound of formula (I) or its pharmaceutically acceptable composition provided herein may be administered in combination with, or alternately with, another therapeutic agent, particularly an agent effective in treating a skin disorder requiring treatment (e.g., MEK inhibitor-responsive or MEK-mediated skin disorder). In combination therapy, two or more effective doses of the agents are administered together, while in alternating or sequential therapy, effective doses of each agent are administered sequentially or sequentially. The dose administered depends on the absorption rate, inactivation rate, and excretion rate of the drugs, as well as other factors known to those skilled in the art. It should also be noted that the dose value will vary depending on the severity of the bruise to be alleviated. Furthermore, it should be understood that for any particular subject, specific administration regimens and schedules should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0254] In some embodiments, the dosage of the second agent used in combination therapy is shown herein. In some embodiments, a lower dosage than that used or currently used to treat MEK inhibitor-responsive or MEK-mediated skin conditions is used in the combination therapy provided herein. Recommended dosages of the second agent can be derived from the knowledge of those skilled in the art. For second agents approved for clinical use, recommended dosages are described, for example, in Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Therapeutics 9th Ed, McGraw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein in their entirety by reference.

[0255] This disclosure provides a combination therapy involving the administration of a crystalline form of a compound of formula (I) described herein or a pharmaceutically acceptable composition thereof, together with one or more further agents or compositions thereof. In some embodiments, one or more further agents are selected from the following: Acne treatment agents (e.g., Accutane, azelaic acid, benzoyl peroxide, salicylic acid); Analgesics (e.g., acetaminophen, capsaicin), Cox-2 inhibitors (e.g., celecoxib); Anesthetics (e.g., benzocaine, benzocaine / menthol, dibucaine, diperodone, lidocaine, lidocaine / prilocaine, pramoxin); Anti-infective drugs (e.g., crotamiton); Antipruritic drugs (e.g., ammonium lactate, benzocaine, ascomycin macrolactam, e.g., pimecrolimus); Antipruritic drugs / 5HT3 receptor antagonists (e.g., ondansetron); Antibiotics (e.g., clindamycin, doxycycline, erythromycin, tetracycline); Anticholinergic antiemetics (e.g., diphenhydramine); Antifibrotic drugs (e.g., collagenase, pirfenidone); Antihistamines (e.g., triprolidine (Actifed®), fexofenadine (Allergra®, Allegra® D-12, Allegra®-24), Astepro / Astelin nasal spray (azelastine (Azalastine)) (Dymista®), hydroxyzine hydrochloride (Atarax®), diphenhydramine hydrochloride (Benadryl®), brompheniramine (Dimetapp®). Cold and Allergy Elixir, Zyrtec (registered trademark) (cetirizine), Chlor-Trimeton (registered trademark) (chlorpheniramine), Descoratadine (Clarinex (registered trademark), Clarinex (registered trademark) D-12, and Clarinex (registered trademark) D-24), Loratadine (Claritin (registered trademark), Claritin (registered trademark) D-12, Claritin (registered trademark) D-24, and Alavert (registered trademark)), Dimenhydrinate (Dramamine (registered trademark)), Diphenhydramine (Benadryl (registered trademark) Allergy, Nytol (registered trademark), Sominex (registered trademark)), Doxylamine (Vicks (registered trademark), NyQuil (registered trademark), Alka-Seltzer (registered trademark) Plus Night-Time Cold) Medicine), cyproheptadine (Periactin®), promethazine (Phenergan®), acribastine (Semprex®, Semprex®-D), clemastine (Tavist®), doxylamine (Unisom®), levocetirizine (Xyzal®); Mast cell stabilizers (e.g., β2-adrenergic agonists, cromoglycic acid, cromolin sodium, Gastrocrom®, ketotifen, methylxanthine, omalizumab, pemirolast, quercetin, ketotifen (Zaditen®))); Anti-inflammatory agents (e.g., NSAIDs (e.g., aspirin, choline salicylate and magnesium salicylate, diclofenac potassium (Cataflam®), diclofenac sodium (Voltaren®, Voltaren® XR), diclofenac sodium / misoprostol (Arthrotec®), diflunisal (Dolobid®), etodolac (Lodine®, Lodine® XL), fenoprofen calcium (Nalfon®) (Trademarks)), Flurbiprofen (Ansaid®), Ibuprofen (Advil®, Motrin®, Motrin®IB, Nuprin®), Indomethacin (Indocin®, Indocin®SR), Ketoprofen (Actron®, Orudis®, Orudis®KT, Oruvail®), Magnesium salicylate (Arthritab, Bayer®Select, Doan's) Pills, Magan, Mobidin, Mobogesic), sodium meclofenamate (Meclomen®), mefenamic acid (Ponstel®), meloxicam (Mobic®), nabumetone (Relafen®), naproxen (Naprosyn®, Naprelan®), sodium naproxen (Aleve®, Anaprox®), oxaprozine (Daypro®), piroxicam (Feldene®), rofecoxib (Vioxx®), salsalate (Amigesic, Anaflex 750, Disalcid, Marthritic, Mono-Gesic, Salflex, Salsitab), sodium salicylate, sulindac (Clinoril®), sodium tolmethin (Tolectin®), valdecoxib (Bextra®)); Receptor tyrosine kinase inhibitors (e.g., sunitinib); Alkylating agents (e.g., dacarbazine, carboplatin); CDK 4 / 6 inhibitors (e.g., LEE011); PKC inhibitors (e.g., AEB071); MAPK inhibitors (e.g., RAS inhibitors / farnesyltransferase inhibitors (e.g., tipifanib), Raf kinase inhibitors (e.g., sorafenib (BAY 43-9006, Nexavar), vemurafenib, dabrafenib, LGX818, TAK-632, MLN2480, PLX-4720)), ERK inhibitors (e.g., SCH772984, VTX11e); BRAF inhibitors (e.g., vemurafenib, dabrafenib) PI3K inhibitors (e.g., LY294002); AKT inhibitors (e.g., MK 2206); PI3K / AKT inhibitors (e.g., buparisib, cizutumumab); mTOR inhibitors (e.g., topical rapamycin, RAD001 (everolimus / rapamycin), temsirolimus, sirolimus); Tyrosine kinase inhibitors (e.g., imatinib (Gleevec®), cabozantinib (an inhibitor of tyrosine kinase c-Met and VEGFR2), nilotinib (Tasigna®)); VEGF inhibitors (e.g., ranibizumab (Lucentis®), cediranib); Immunomodulators (e.g., topical imiquimod, interferon, PEG interferon); Calcium channel blockers (e.g., Avocil (Mederma) / 15% verapamil, vitamin D, doxycycline injection separately); Statins (e.g., lovastatin, methotrexate, vinblastine, pregabalin, temozolomide, PLX3397); HDAC inhibitors (e.g., AR-42); HSP-90 inhibitors (e.g., ganetespib); Retinoids (e.g., adapalene, isotretinoin, tazarotene, tretinoin); Steroids (e.g., alclomethasone, amcinonide, betamethasone, betamethasone dipropionate, enhanced betamethasone dipropionate, budesonide, clobetasol propionate, cortisone, desonide, dexamethasone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flulandrenolide, fluticasone propionate, halobetazole propionate, halocinonide, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, methylprednisolone, mometasone, mometasone furoate, prednicarbate, prednisolone, prednisone, triamcinolone, triamcinolone acetonide); Topical calcineurin inhibitors (e.g., pimecrolimus (Elidel® cream 1%, Novartis), tacrolimus (Protopic® ointment, Astellas)); and Non-pharmacological therapeutic interventions (e.g., photodynamic therapy (topical Levulan Kerastick + light), electro-drying (ED), YAG laser).

[0256] In various embodiments, the therapeutic agent (e.g., the compound provided herein and the second agent) is administered at intervals of less than 5 minutes, less than 30 minutes, 1 hour, about 1 hour, about 1 to about 2 hours, about 2 to about 3 hours, about 3 to about 4 hours, about 4 to about 5 hours, about 5 to about 6 hours, about 6 to about 7 hours, about 7 to about 8 hours, about 8 to about 9 hours, and about 9 hours. The drugs are administered at intervals of approximately 10 hours, 10 to 11 hours, 11 to 12 hours, 12 to 18 hours, 18 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 ​​to 52 hours, 52 to 60 hours, 60 to 72 hours, 72 to 84 hours, 84 to 96 hours, or 96 to 120 hours. In various embodiments, the therapeutic agents are administered at intervals of 24 hours or less or 48 hours or less. In some embodiments, two or more therapeutic agents are administered within the same patient visit. In some embodiments, the crystalline form of the compound provided herein and the second agent are administered simultaneously.

[0257] In some embodiments, the crystalline form of the compound provided herein or its pharmaceutically acceptable composition, and the second agent, are administered at intervals of about 2 to 4 days, about 4 to 6 days, about 1 week, about 1 to 2 weeks, or more than 2 weeks.

[0258] In some embodiments, the same drug can be administered repeatedly, with intervals of at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0259] In some embodiments, the compound and the second agent provided herein are administered to a patient, in some embodiments, a mammal, such as a human, in an order and time interval such that they act together to show increased benefit compared to when the compound and the other agent are administered separately. In some embodiments, the second active agent may be administered simultaneously or sequentially in any order at different time points; however, if not administered simultaneously, they should be administered with a sufficiently short time interval to obtain the desired therapeutic or prophylactic effect. In some embodiments, the crystalline form of the compound and the second active agent provided herein exert their effects over an overlapping period. Each second active agent may be administered separately in any suitable form and by any preferred route. In some embodiments, the crystalline form or pharmaceutically active composition of the compound provided herein is administered before, simultaneously with, or after the administration of the second active agent.

[0260] In some embodiments, the crystalline form of the compound provided herein or its pharmaceutically acceptable composition, and a second agent, are administered to a patient periodically. Periodic therapy involves administering a first agent (e.g., a first prophylactic or therapeutic agent) for a period, followed by a second and / or third agent (e.g., a second and / or third prophylactic or therapeutic agent) for a period, and repeating this sequential administration. Periodic therapy can reduce the development of resistance to one or more therapeutic agents, avoid or reduce one or more side effects of a therapeutic agent, and / or improve the effectiveness of the treatment.

[0261] In some embodiments, the crystalline form or pharmaceutically active ingredient of the compound provided herein, and a second active agent, are administered in cycles of about once every three weeks, about once every two weeks, about once every 10 days, or about once per week. One cycle may include administration of the compound provided herein and the second agent by infusions lasting about 90 minutes per cycle, about 1 hour per cycle, or about 45 minutes per cycle. Each cycle may include at least one week of rest, at least two weeks of rest, or at least three weeks of rest. The number of cycles performed is about 1 to about 12 cycles, more typically about 2 to about 10 cycles, and more typically about 2 to about 8 cycles.

[0262] In some embodiments, the treatment process is carried out simultaneously for the patient, i.e., individual doses of the second agent are administered separately, but within a time interval in which the compounds provided herein can act together with the second active agent. In some embodiments, the administration of one component once a week can be combined with other components that can be administered once every two weeks or once every three weeks. In other words, even if the therapeutic agents are not administered simultaneously or on the same day, the administration regimen is carried out simultaneously.

[0263] The second agent may act additively or synergistically with the compound provided herein. In some embodiments, the crystalline form of the compound provided herein is administered simultaneously with one or more second agents in the same pharmaceutical composition. In some embodiments, the compound provided herein is administered simultaneously with one or more second agents in separate pharmaceutical compositions. In some embodiments, the compound provided herein is administered before or after the administration of the second agent. Administration of the compound provided herein and the second agent by the same or different routes of administration, e.g., oral and parenteral routes, is also conceivable. In some embodiments, when the compound provided herein is administered simultaneously with a second agent that potentially causes one or more adverse side effects, including but not limited to toxicity, it may be advantageous to administer the second active agent at a dose below the threshold that induces the adverse side effect.

[0264] VIII. Kit Kits are also provided for use in methods of treating MEK inhibitor-responsive disorders or diseases, MEK inhibitor-responsive skin disorders or skin diseases, MEK-mediated disorders or diseases, or MEK-mediated skin disorders or skin diseases, or MEK inhibitor-responsive disorders or diseases, MEK inhibitor-responsive skin disorders or skin diseases, MEK-mediated disorders or diseases, or MEK-mediated skin disorders or skin diseases. In some embodiments, the kit includes a crystalline form of the compound of formula (I) provided herein or a pharmaceutically active composition thereof, a second agent or composition, and instructions for providing healthcare providers with information on how to use the kit to treat MEK inhibitor-responsive disorders or diseases, MEK inhibitor-responsive skin disorders or skin diseases, MEK-mediated disorders or diseases, or MEK-mediated skin disorders or skin diseases. The instructions may be provided in printed form, or in the form of an electronic medium such as a floppy disk, CD, or DVD, or in the form of a website address from which the instructions can be obtained. The unit doses of the compounds or pharmaceutically active compositions thereof provided herein, or of the second agent or composition, may include doses such that, when administered to a subject, therapeutically or prophylactically effective plasma levels of the compound or pharmaceutically active composition are maintained in the subject for at least one day.

[0265] Kits are also provided for use in methods of treating bruises in subjects requiring treatment (e.g., MEK inhibitor-responsive or MEK-mediated bruises). In some embodiments, the kit includes a crystalline form of the compound of formula (I) provided herein or a pharmaceutically acceptable composition thereof, a second agent or composition, and instructions for providing healthcare providers with information on how to use the compound or composition for treating bruises (e.g., MEK inhibitor-responsive or MEK-mediated bruises). The instructions may be provided in printed form, or in the form of an electronic medium such as a floppy disk, CD, or DVD, or in the form of a website address from which the instructions can be obtained. The unit dose of the compound or pharmaceutically acceptable composition provided herein, or the second agent or composition, may include a dose such that, when administered to a subject, therapeutically effective plasma levels of the compound or pharmaceutically acceptable composition are maintained in the subject for at least one day.

[0266] Kits are also provided for use in methods of treating skin cancers (e.g., MEK inhibitor-responsive or MEK-mediated skin cancers) in subjects requiring treatment. In some embodiments, the kit includes a crystalline form of the compound of formula (I) provided herein or a pharmaceutically acceptable composition thereof, a second agent or composition, and instructions for providing healthcare providers with information on how to use the compound or composition for treating skin cancers (e.g., MEK inhibitor-responsive or MEK-mediated skin cancers). The instructions may be provided in printed form, or in the form of an electronic medium such as a floppy disk, CD, or DVD, or in the form of a website address from which the instructions can be obtained. The unit dose of the compound or pharmaceutically acceptable composition provided herein, or the second agent or composition, may include a dose that, when administered to a subject, maintains a therapeutically effective plasma level of the compound or pharmaceutically acceptable composition in the subject for at least one day.

[0267] In some embodiments, suitable packaging is provided. “Packaging” as used herein comprises a solid matrix or solid material that is conventionally used in a system and is suitable for administration to a subject, and is capable of holding the compound and / or second agent provided herein within certain limits. These materials include glass bottles and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic foil laminate packaging bags. When electron beam sterilization is used, the packaging should have a density low enough to allow sterilization of the contents.

[0268] IX. Manners IX-1. Crystal form E Mode E1 Equation (I): A crystalline form E of a compound having TIFF0007879134000008.tif43128, Crystal form E is characterized by an X-ray powder diffraction (XRPD) pattern that includes peaks at 18.0, 18.3, 20.1, 20.4, and 23.5°²θ (±0.2°²θ).

[0269] Mode E2 Crystal form E according to embodiment E1, wherein the X-ray powder diffraction pattern further includes peaks at 7.3, 15.1, 21.2, 22.8, and 24.4°²θ (±0.2°²θ).

[0270] Mode E3 Crystal form E according to embodiment E1 or E2, wherein the X-ray powder diffraction pattern further includes peaks at 18.5, 21.9, 24.6, and 25.8°²θ (±0.2°²θ).

[0271] Mode E4 Crystal form E according to embodiment E1, wherein the X-ray powder diffraction pattern substantially matches that of Figure 5.

[0272] Pattern E5 Crystalline form E according to any one of embodiments E1 to E4, substantially free from other crystalline or amorphous forms of the compound having formula (I).

[0273] Mode E6 Crystal form E according to any one of embodiments E1 to E5, further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at approximately 190.2°C.

[0274] Mode E7 Crystal form E according to embodiment E6, wherein the endothermic peak has an onset temperature of approximately 188.0°C.

[0275] Pattern E8 Crystal form E according to embodiment E6, wherein the DSC thermogram substantially matches that of Figure 6.

[0276] Pattern E9 Crystal form E according to any one of embodiments E1 to E8, further characterized by a weight loss of approximately 0.3% when heated from approximately 39°C to approximately 180°C, as measured by thermogravimetric analysis (TGA).

[0277] Appearance E10 Crystal form E according to one of embodiments E1 to E8, further characterized by a thermogravimetric analysis (TGA) thermogram that is substantially consistent with Figure 7.

[0278] Appearance E11 Crystal form E according to any one of embodiments E1 to E10, which is anhydrous.

[0279] IX-2. Crystal form F Phenomenon F1 Equation (I): A crystalline form F of a compound having TIFF0007879134000009.tif43128, Crystalline form F is characterized by an X-ray powder diffraction (XRPD) pattern that includes peaks at 12.1, 17.8, 19.3, 22.1, and 23.3°²θ (±0.2°²θ).

[0280] Phenomenon F2 Crystal form F according to embodiment F1, wherein the X-ray powder diffraction pattern further includes peaks at 18.9, 19.2, 19.5, 21.1, and 22.4°²θ (±0.2°²θ).

[0281] Mode F3 Crystal form F according to embodiment F1, wherein the X-ray powder diffraction pattern substantially matches that of Figure 8.

[0282] Pattern F4 Crystalline form F according to any one of embodiments F1 to F3, substantially free from other crystalline or amorphous forms of the compound having formula (I).

[0283] Pattern F5 Crystal form F according to any one of embodiments F1 to F4, further characterized by a differential scanning calorimetry (DSC) thermogram including one or more endothermic peaks at approximately 162.7°C and 187.5°C.

[0284] Pattern F6 Crystal form F according to embodiment F5, wherein the endothermic peak at approximately 162.7°C has an onset temperature of approximately 158.9°C.

[0285] Phenomenon F7 Crystal form F according to embodiment F5, wherein the endothermic peak at approximately 187.5°C has an onset temperature of approximately 185.3°C.

[0286] Phenomenon F8 Crystal form F according to embodiment F5, the DSC thermogram substantially matches that of Figure 9.

[0287] Pattern F9 Crystal form F according to any one of embodiments F1 to F8, further characterized by a weight loss of approximately 0.4% when heated from approximately 50°C to approximately 180°C, as measured by thermogravimetric analysis (TGA).

[0288] Phenomenon F10 Crystal form F as described in any one of embodiments F1 to F8, further characterized by a thermogravimetric analysis (TGA) thermogram that is substantially consistent with Figure 10.

[0289] Pattern F11 Crystal form F according to any one of embodiments F1 to F10, which is an anhydrous form.

[0290] IX-3. Crystal form B Appearance B1 Equation (I): A crystalline form B of a compound having TIFF0007879134000010.tif43128, Crystalline form B is characterized by an X-ray powder diffraction (XRPD) pattern that includes peaks at 5.1, 15.1, 17.3, 17.8, and 23.8°²θ (±0.2°²θ).

[0291] Appearance B2 Crystal form B according to embodiment B1, wherein the X-ray powder diffraction pattern further includes peaks at 14.8, 16.5, 20.8, 25.0, and 28.5°2θ (±0.2°2θ).

[0292] Appearance B3 Crystal form B according to embodiment B1, wherein the X-ray powder diffraction pattern substantially matches that of Figure 11.

[0293] Appearance B4 Crystalline form B according to any one of embodiments B1 to B3, substantially free from other crystalline or amorphous forms of the compound having formula (I).

[0294] Appearance B5 Crystal form B according to any one of embodiments B1 to B4, further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at approximately 95.4°C.

[0295] Appearance B6 Crystal form B according to embodiment B5, wherein the endothermic peak at approximately 95.4°C has an onset temperature of approximately 80.0°C.

[0296] Appearance B7 Crystalline form B according to embodiment B5 or B6, wherein the DSC thermogram further includes one or more endothermic peaks at approximately 151.1°C, approximately 170.3°C, and 185.3°C.

[0297] Feature B8 Crystalline form B according to embodiment B5, wherein the DSC thermogram substantially matches that of Figure 12.

[0298] Phenomenon B9 Crystalline form B according to any one of embodiments B1 to B8, further characterized by a weight loss of approximately 3.4% when heated from approximately 80°C to approximately 145°C, as measured by thermogravimetric analysis (TGA).

[0299] Appearance B10 Crystal form B as described in any one of embodiments B1 to B8, further characterized by a thermogravimetric analysis (TGA) thermogram that is substantially consistent with Figure 13.

[0300] Appearance B11 Crystal form B, which is monohydrated, as described in any one of embodiments B1 to B10.

[0301] IX-4. Crystal form C Appearance C1 Equation (I): The crystalline form C of a compound having TIFF0007879134000011.tif43128, Crystalline form C is characterized by an X-ray powder diffraction (XRPD) pattern that includes peaks at 14.4, 17.4, 19.1, 19.4, and 22.3°²θ (±0.2°²θ).

[0302] Appearance C2 Crystal form C according to embodiment C1, wherein the X-ray powder diffraction pattern further includes peaks at 6.9, 11.7, 23.7, 24.9, and 25.1°²θ (±0.2°²θ).

[0303] Appearance C3 Crystal form C according to embodiment C1, wherein the X-ray powder diffraction pattern substantially matches that of Figure 14.

[0304] Mode C4 Crystalline form C according to any one of embodiments C1 to C3, substantially free from other crystalline or amorphous forms of the compound having formula (I).

[0305] Appearance C5 Crystalline form C according to any one of embodiments C1 to C4, which is the chloroform solvated form.

[0306] Appearance C6 Crystal form C according to embodiment C5, wherein the molar ratio of the chloroform-paired compound (I), determined by the crystal volume of X-ray powder diffraction (XRPD), is 1:1 or less.

[0307] Phenomenon C7 As shown in Figures 15A and 15B 1 Crystal form C according to embodiment C5, wherein the molar ratio of the chloroform-paired compound (I), as determined by the 1H NMR spectrum, is approximately 0.4:1.

[0308] IX-5. Crystal form H Mode H1 Equation (I): The crystalline form H of the compound having TIFF0007879134000012.tif43128, Crystalline form H is characterized by an X-ray powder diffraction (XRPD) pattern that includes peaks at 5.1, 17.3, 18.7, 23.4, and 25.6°²θ (±0.2°²θ).

[0309] Mode H2 Crystal form H according to embodiment H1, wherein the X-ray powder diffraction pattern further includes peaks at 14.3, 16.5, 18.1, 21.02, and 22.5°²θ (±0.2°²θ).

[0310] Mode H3 Crystalline form H according to embodiment H1 or H2, wherein the X-ray powder diffraction pattern further includes peaks at 15.8, 16.3, 18.9, and 19.6°²θ (±0.2°²θ).

[0311] Mode H4 Crystal form H according to embodiment H1, wherein the X-ray powder diffraction pattern substantially matches that of Figure 16.

[0312] Mode H5 Crystalline form H according to any one of embodiments H1 to H4, substantially free from other crystalline or amorphous forms of the compound having formula (I).

[0313] Mode H6 A methanol solvated form of crystal form H according to any one of embodiments H1 to H5.

[0314] Phenomenon H7 Crystal form H according to embodiment H6, wherein the molar ratio of the methanol-paired compound (I), as determined by the crystal volume of X-ray powder diffraction (XRPD), is 1:1 or less.

[0315] IX-6. Compositions and Methods Appearance 1 A step of combining a crystalline form according to any one of embodiments E1-E11, F1-F11, B1-B11, C1-C7, and H1-H7 with one or more pharmaceutically acceptable excipients. A pharmaceutical composition prepared by a method comprising [a certain substance].

[0316] Appearance 2 A pharmaceutical composition according to embodiment 1, which is a topical preparation.

[0317] Appearance 3 The pharmaceutical composition according to embodiment 2, wherein the topical preparation is a topical preparation, lotion, spray, ointment, cream, gel, or patch.

[0318] Pattern 4 A method for treating a skin disorder, comprising the step of administering a crystalline form according to any one of embodiments E1-E11, F1-F11, B1-B11, C1-C7, and H1-H7 or a pharmaceutical composition according to any one of embodiments 1-3.

[0319] Appearance 5 The method according to embodiment 4, wherein the skin disorder is a MEK inhibitor-responsive skin disorder or a MEK-mediated skin disorder.

[0320] Appearance 6 The method according to embodiment 5, wherein the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is neurofibromatosis type 1.

[0321] Appearance 7 The method according to embodiment 5, wherein the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is a cutaneous neurofibroma.

[0322] Appearance 8 The method according to embodiment 5, wherein the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is a subcutaneous neurofibroma.

[0323] Appearance 9 The method according to embodiment 5, wherein the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is a superficial plexiform neurofibroma.

[0324] Appearance 10 The method according to embodiment 5, wherein the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is cutaneous RAS disease.

[0325] Appearance 11 The method according to embodiment 10, wherein the cutaneous RAS disease is selected from the group consisting of psoriasis, keratoacanthoma (KA), keratosis, papilloma, Noonan syndrome (NS), cardiac-facial-cutaneous syndrome (CFC), Costello syndrome (facial-cutaneous-skeletal syndrome or FCS syndrome), ectophthalmic syndrome, café-au-lait spots, and lentigo multifocal syndrome (formerly known as leopard syndrome).

[0326] Appearance 12 The method described in Embodiment 4, wherein the skin disorder is a bruise.

[0327] Appearance 13 The method according to embodiment 12, wherein the birthmark is selected from the group consisting of port-wine stain / capillary malformation, nevus cell nevus, dysplastic nevus, capillary hemangioma, epidermal nevus, sebaceous nevus, flat nevus, arteriovenous malformation, lymphatic malformation, and congenital pigmented nevus.

[0328] Appearance 14 The method according to embodiment 12 or 13, wherein the bruise is related to the activation of p-ERK.

[0329] Appearance 15 The method according to embodiment 13 or 14, wherein the birthmark associated with p-ERK activation is selected from the group consisting of epidermal nevi, sebaceous nevi, flat nevi, arteriovenous malformations, capillary malformations / port-wine stains, congenital pigmented nevi, and lymphatic malformations.

[0330] Appearance 16 The method described in aspect 4, wherein the skin disorder is skin cancer.

[0331] Appearance 17 The method according to embodiment 16, wherein the skin cancer is cutaneous squamous cell carcinoma.

[0332] Appearance 18 The method according to embodiment 16, wherein the skin cancer is MEK inhibitor-responsive or MEK-mediated cutaneous squamous cell carcinoma.

[0333] Appearance 19 The method according to embodiment 17 or 18, wherein cutaneous squamous cell carcinoma is associated with p-ERK activation.

[0334] Appearance 20 The method according to any one of embodiments 4 to 19, wherein the pharmaceutical composition is a topical preparation, and the topical preparation is administered topically.

[0335] Appearance 21 The method according to embodiment 20, wherein the topical preparation is administered as a topical preparation, lotion, spray, ointment, cream, gel, or patch. [Examples]

[0336] The following examples are provided for illustrative purposes only, and not to limit this description.

[0337] A. Abbreviations and acronyms TIFF0007879134000013.tif132141TIFF0007879134000014.tif234160

[0338] Other standard abbreviations are used, including the following: NMR = Nuclear Magnetic Resonance; d = Doublet; dd = Doublet of Doublets; t = Triplet; m = Multiplet; g = Gram; mg = Milligram; μg = Microgram; ng = Nanogram; μM = Micromoles; mM = Millimoles; nM = Nanomoles; h or hr = Hours; min = Minutes; kDa = Kilodaltons; kg = Kilograms; l or L = Liters; ml or mL = Milliliters; μl or μL = Microliters; LC = Liquid Chromatography; HPLC = High-Performance Liquid Chromatography; UPLC = Ultra-High-Performance Liquid Chromatography; AUC (in chromatogram) = Area under the curve; LCMS = Liquid Chromatography-Mass Spectrometry; m / z = Mass-to-charge ratio; MS = Mass Spectrometry; M = Molar concentration; N = Normality; rac = Racemic; Rt = Retention time; sat. = Saturation; TLC = Thin-Layer Chromatography.

[0339] B. Glossary TIFF0007879134000015.tif811601: Some of the hygroscopic terms and definitions developed by SSCI are based on the following concepts: Newman, AW; Reutzel-Edens, SM; Zografi, G. Characterization of the "Hygroscopic" Properties of Active Pharmaceutical Ingredients. J. Pharm. Sci. 2008, 97, 1047-1059. TIFF0007879134000016.tif151160

[0340] C. Equipment technology The following methods were used to characterize the compound of formula (I).

[0341] X-ray powder diffraction (XRPD) transparentXRPD patterns were collected using a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer with an incident Cu beam generated using a long fine-focus radiation source. An ellipsoidal multilayer mirror was used to focus the CuKα X-rays onto the detector through the specimen. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to confirm that the observed position of the Si 111 peak matched the NIST certified position. The specimen was sandwiched between 3 μm thick films and analyzed in transmission configuration. Background caused by air was minimized using a beam stop, a short extension for scattering prevention, and a scattering prevention knife edge. Solar slits were used for the incident and diffracted beams to minimize axial divergence spread and asymmetry. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen, and Data Collector software v. 5.5.

[0342] reflection XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu Kα lines generated using a long fine-focus radiation source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to confirm that the observed position of the Si 111 peak matched the NIST certified position. The sample specimen was prepared as a thin circular layer on a zero-background silicon substrate. A scattering prevention slit (SS) was used to minimize background caused by air. Solar slits were used for the incident and diffracted beams to minimize axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample, and Data Collector software v. 5.5.

[0343] XRPD IndexIn the referenced diagram for a given indexed XRPD pattern, the agreement between the allowed peak positions, indicated by red bars, and the observed peaks indicates a consistent determination of the unit cell. Unless otherwise noted, successful indexing of the pattern indicates that the sample is composed primarily of a single crystalline phase. The space group, unit cell parameters, and derived quantities corresponding to the assigned extinction symbols are shown in the table below the diagram. To confirm the provisional indexing solution, the molecular packing motifs within the crystalline unit cell must be determined. No attempt at molecular packing was made.

[0344] Differential Scanning Calorimetry (DSC) DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in a sealed aluminum DSC dish, its weight was accurately recorded, a hole was made in the lid, and the sample was inserted into the DSC cell. The weighed aluminum dish, configured as the sample dish, was placed on the reference side of the cell. The sample was analyzed from -30°C to 250°C at a rate of 10°C / min.

[0345] Thermogravimetric analysis (TGA) TG analysis was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using calcium oxalate, indium, tin, and zinc. The sample was placed in an aluminum dish. The dish was sealed, a hole was made in the lid, and then it was placed in the TG furnace. The weighed aluminum dish, configured as the sample dish, was placed on the control stage. The furnace was heated under nitrogen. The sample was analyzed from 25°C to 350°C at a rate of 10°C / min.

[0346] Dynamic water vapor adsorption (DVS) Automated water vapor adsorption (VS) data were collected using a Surface Measurement System DVS Intrinsic instrument. Samples were not dried before analysis. Adsorption and desorption data were collected under nitrogen scavenging with 10% RH increments over a range of RH from 5% to 95%. The equilibrium criterion used for analysis was a weight change of less than 0.0100% in 5 minutes, and the maximum equilibrium time was 3 hours. Data were not corrected for the initial water content of the samples. Post-analysis samples were subjected to XRPD analysis.

[0347] Liquid-state nuclear magnetic resonance (NMR) Solution NMR spectra were acquired using an Avance 600 MHz NMR spectrometer. Samples were prepared by dissolving approximately 5 mg of the sample in DMSO-d6 containing TMS.

[0348] High-speed or ultra-high-speed liquid chromatography (HPLC or ULC) HPLC analysis was performed using a Waters Alliance 2695 HPLC with a Waters 2487 dual-wavelength detector, with the detector set to a predetermined wavelength, using the following method. LC-MS analysis was performed using a Perkin Elmer Sciex API 150EX mass spectrometer connected to a Shimadzu LC-10AD HPLC.

[0349] General analysis method UPLC method for determining the purity of the compound of formula (I) Column: Acquity UPLC CSH C18, 1.7 μm, 2.1 x 150 mm Column temperature: 55℃ Autosampler temperature: 25℃ Detection: 248nm Mobile phase A: 0.05% formic acid in water Mobile phase B: Acetonitrile Gradient: See the table below. Flow rate: 0.3mL / min Injection volume: 1μL Injection mode: Gradient start during injection for H-Class. Data collection time: 22 minutes Re-equilibration time: 7 minutes Total analysis time: 29 minutes Needle cleaning solution: Methanol Seal cleaning solution: Acetonitrile / water, 50:50 TIFF0007879134000017.tif41128

[0350] Chemical development HPLC method Column: Waters Atlantis T3, C18, 3.5 μm, 150 x 4.6 mm Detection: 254nm Mobile phase A: 0.05% formic acid in water Mobile phase B: 0.05% formic acid in acetonitrile Gradient: See the table below. Flow rate: 0.8mL / min TIFF0007879134000018.tif43128

[0351] Example 1 Process for preparing 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (i.e., formula (I))

[0352] Steps 1a) and 1b) Preparation of the compound of formula (VII) To the reactor were added compound (IX) (17.0 kg), DABCO (1.31 kg), and dimethyl carbonate (164 kg, 9 volumes). Stirring was started, dimethylformamide (16.0 kg, 1 volume) was added, and the reactor was heated to 87.4 °C for 24 hours. HPLC analysis showed 99.58% conversion, whereupon the batch was cooled to 20 - 30 °C and distilled under reduced pressure (27.5 inHg, 35.1 °C) to a final volume of 87 L (5 volumes). Ethyl acetate (153 kg, 10 volumes) was added to the reactor, and the batch was distilled under reduced pressure (27.5 inHg, below 40 °C) to a final volume of 84 L (5 volumes). Ethyl acetate (EtOAc) (153 kg, 10 volumes) was added to the reactor, and the batch was distilled under reduced pressure (27.5 inHg, below 40 °C) to a final volume of 85 L (5 volumes), and then the temperature was adjusted to 15 - 25 °C.

[0353] In a separate container, DI H2O (50 L, 3 volumes) and citric acid (6.70 kg) were added to prepare a citric acid solution, which was stirred for 45 minutes to completely dissolve the solid. The citric acid solution was added to the reactor over 1 hour while stirring (Note: The addition of the citric acid solution is slightly exothermic). Ethyl acetate (EtOAc) (46 kg, 3 volumes) was added to the reactor, and the batch was stirred at 15 - 25 °C for 30 minutes. The layers were separated (which took 20 minutes), and after the aqueous layer was added back to the reactor, EtOAc (123 kg, 8 volumes) was added. The layers were stirred for 20 minutes, separated, and after the aqueous layer was added back, EtOAc (123 kg, 8 volumes) was added. The layers were stirred for 20 minutes, separated, and the combined EtOAc layers were added back to a 400 L reactor. The batch was distilled under reduced pressure (27.5 inHg, below 40 °C) to a final volume of 80 L (5 volumes). 1 1H NMR revealed that the residual DABCO was 0%, whereupon DI H2O (171 L, 10 volumes) was added over 30 minutes while maintaining the internal temperature below 55 °C (Note: The addition of water is exothermic). The batch was distilled under reduced pressure (29.1 inHg, below 55 °C) to a final volume of 84 L (5 volumes), and the batch was adjusted to 13.6 °C.

[0354] In a separate container, 170 L of DI H2O (10 volumes) and 28.2 kg of sulfamic acid were added to prepare a sulfamic acid solution, which was stirred for 20 minutes (Note: Not all solids may dissolve). While maintaining the internal temperature at 8-18°C, the sulfamic acid solution was added to the reactor over 15 minutes with stirring. A sodium bisulfite scrubber (48.0 kg; 250 L of DI H2O) was attached to the reactor. In a separate container, 85.0 L of DI H2O (5 volumes) and 25.0 kg of sodium chlorite were added to prepare a sodium chlorite solution, which was stirred for 30 minutes. While maintaining the internal batch temperature at 8-18°C, the sodium chlorite solution was added to the reactor at an N2 flow rate of 60 L / min over 6 hours. Next, the batch temperature was adjusted to 6.7°C, the batch was transferred to a Rosenmund Hastelloy stirring filter, and conditioned until the liquid stopped eluting. DI H2O (37.0 L, 2 volumes) was added to the reactor, and the rinse solution was passed over the solid until the liquid stopped eluting. DI H2O (36.0 L, 2 volumes) was added again to the reactor, and the rinse solution was passed over the solid until the liquid stopped eluting. The solid was transferred to a vacuum oven and dried at 45-55°C for 100 hours to obtain product (VII) (12.7 kg, 62%).

[0355] Specifications of the obtained solid: 1 1H NMR (matches compound (VII)); Appearance: Bright yellow solid; KF (water content %): 0.60%, relative to 1,4-dimethoxybenzene 1 ¹H NMR (d6-DMSO) gravimetric assay (92.29%); HPLC purity (area %) at 247 nm: 77.8%.

[0356] Process 2) Preparation of the compound of formula (VI) Compound (VII) (12.7 kg) and methanol (202 kg, 20 vols) were added to a 400 L reactor that had been inactivated for 19 hours with a flow of N2 at 10 L / min. Stirring was started at 60 RPM and the batch temperature was adjusted to 10°C. Concentrated sulfuric acid (23.4 kg, 1 vol) was added over 45 minutes while maintaining the batch temperature at 10–20°C (Note: This addition is exothermic). The batch temperature was adjusted to 58–68°C and maintained in this range for 21 hours. The batch was cooled to 15–25°C. HPLC analysis revealed that compound (VI) was formed in a proportion of compound (VII) of over 97%, so the batch was subjected to vacuum distillation (28 inHg, less than 40°C) to a final volume of 64 L (5 vols).

[0357] In a separate container, DI H2O (154 L, 12 volumes) and 50 wt% sodium hydroxide (18.3 kg) were mixed with stirring to prepare a sodium hydroxide solution (Note: This addition is exothermic). The batch was cooled to 9.8°C, and the sodium hydroxide solution was added to the reactor over 45 minutes while maintaining the batch temperature at 10-20°C (Note: This addition is exothermic). Upon completion of the addition, the pH was 1.73. In a separate container, DI H2O (38 L, 3 volumes) and sodium bicarbonate (3.67 kg) were added to prepare a sodium bicarbonate solution, and the mixture was stirred for 30 minutes until all solids were completely dissolved. The sodium bicarbonate solution was added to the reactor over 20 minutes, and upon completion of the addition, the pH was 6.66. The batch temperature was adjusted to 15-25°C, and the batch was transferred to a Rosenmund Hastelloy stirring filter and conditioned until the liquid stopped eluting. DI H2O (10¹ L, 8 volumes) was added to the reactor, and the rinse solution was transferred from the kettle onto the cake as a displacement washing solution. DI H2O (38.1 L, 3 volumes) was added to the reactor, and the rinse solution was transferred from the kettle to the solid, and the mixture was conditioned until the liquid stopped eluting. The product was dried under a nitrogen stream at 50°C for 10 days to obtain compound (VI) (12.1 kg, yield 88%).

[0358] Specifications of the obtained solid: 11H NMR (matches compound (VI)); Appearance: Yellowish-white solid; KF (water content %): 0.52%; relative to 1,4-dimethoxybenzene 1 ¹H NMR (d6-DMSO) gravimetric assay (90.84%); HPLC purity (area %) at 247 nm: 97.2%.

[0359] Process 3) Preparation of the compound of formula (V) Compound (VI) (12.1 kg), sodium tert-butoxide (21.4 kg), and anhydrous toluene (109 L, 9 volumes) treated with StatSafe (50 ppm) were added to a 400 L reactor inactivated with a 20 L / min N2 flow for 20 hours. The batch was stirred at 80 RPM and heated to 103°C over 90 minutes, held at this temperature for 45 minutes, and then cooled to -5°C to 5°C. HPLC analysis showed a product yield of 94.3%.

[0360] In a separate container, 54.5 L (4.5 vol) of DI H2O and 20.1 kg of ammonium chloride were added to prepare a sodium bicarbonate solution, and the solution was stirred until all solids were completely dissolved. A 2M HCl scrubber was attached to the reactor, and the ammonium chloride solution was added to the reactor over 5 hours while maintaining a batch temperature of 5–10°C (Note: This addition is highly exothermic, and decomposition will occur if heated above 15°C). 73.0 L (6 vol) of DI H2O was added to the reactor, and the batch temperature was adjusted to 15–25°C (Note: The addition of DI H2O is slightly exothermic). 44 kg (4 vol) of pharmaceutically acceptable phosphate (44 kg) was added, and the batch was stirred for 15 minutes, after which the layers were separated. The aqueous layer was added back to the reactor, then 87.5 L (8 vol) of phosphate (87.5 L) was added, and the layers were stirred for 15 minutes. The layers were separated, and the combination of organic layers from the first two extractions was added back to the kettle.

[0361] The batch was subjected to vacuum distillation (29 inHg, less than 65°C) to a final volume of 124 L (10 volumes). Methanol (182 L, 15 volumes) was added to the reactor, and the batch was subjected to vacuum distillation (27.5 inHg, 16.7°C) until the final volume was 128 L (10 volumes). Methanol (182 L, 15 volumes) was added to the reactor, and the batch was subjected to vacuum distillation (27.3 inHg, 17.0°C) until the final volume was 128 L (10 volumes). The batch was adjusted to 50.5°C, and DI H2O (182 L, 15 volumes) was added over 2 hours while maintaining the batch temperature at 45-55°C. The batch was subjected to vacuum distillation (28.4 inHg, less than 65°C) to a final volume of 122 L (10 volumes). DI H2O (60.5 L, 5 volumes) was added to the batch, and the temperature was adjusted to 15-25°C. The batch was stirred at this temperature for 60 hours, then transferred to a Rosenmund Hastelloy stirring filter and conditioned until the liquid stopped eluting. DI H2O (121 L, 10 volumes) was added to the reactor, the rinse solution was transferred to the solid, and conditioned until the liquid stopped eluting. The product was dried under a nitrogen stream at 40–70°C for 6 days to obtain compound (V) (13.0 kg, yield 88%).

[0362] Specifications of the obtained solid: 1 1H NMR (matches compound (V)); Appearance: Bright yellow solid; KF (water content %): 0.02%; relative to 1,4-dimethoxybenzene 1 ¹H NMR (d6-DMSO) gravimetric assay (96.3%); HPLC purity (area %) at 247 nm: 99.1%.

[0363] Steps 4a) and 4b) Preparation of the compound of formula (III) TIFF0007879134000022.tif3616015 L / min of N2 was used to inactivate a 400 L reactor for several days, and 1 M LiHMDS (83.5 kg, 15.1 vol) was added, stirring was started, and the batch temperature was adjusted to -5°C to 5°C. Compound (V) (6.20 kg), anhydrous THF (23.1 kg (4.45 kg reserved for washing the kettle and lines after transfer), 5 vol (total)), and hexachloroethane (7.27 kg) were added to another container which was also used to inactivate a 15 L / min of N2 for several days, and the contents were stirred for 20 minutes to ensure that all solids were completely dissolved. The reaction solution was transferred to the reactor over 50 minutes to ensure that the batch temperature remained between 0 and 10°C (during this time, the above solution container was rinsed using the reserved 4.45 kg of THF, which was also added to the reactor). After stirring at 0-10°C for 1 hour, HPLC analysis revealed 100% conversion to compound (IVa).

[0364] 2-fluoro-4-iodoaniline (6.64 kg) and anhydrous THF (11.1 kg, 2 volumes) were added to a separate container inactivated with a 15 L / min N2 stream for 1 hour, and the mixture was stirred for 75 minutes to ensure that all solids were completely dissolved. The 2-fluoro-4-iodoaniline solution was added to the reactor over 1 hour to ensure that the batch temperature remained between 0 and 10°C. The batch temperature was adjusted to 15 to 25°C and stirred for 9.5 hours. HPLC analysis revealed a 1.2% residue of compound (IVa), at which point the batch temperature was adjusted to -5°C to 5°C.

[0365] In a separate container, 18.6 kg of DI H2O and 6.88 kg of ammonium chloride were added to prepare an ammonium chloride solution, and the solution was stirred for 12 minutes (Note: Not all solids may dissolve completely). To ensure that the batch temperature remained at 5-15°C, the ammonium chloride solution was transferred to the reactor over 75 minutes, and the batch was distilled under reduced pressure (27.16 inHg, maximum temperature 35.2°C) to a final volume of 48.5 L (8 volumes). 75 L of DI H2O was added, and the batch was distilled under reduced pressure to a final volume of 94 L (16 volumes). The batch temperature was adjusted to 10-20°C, and while maintaining the batch temperature at 10-20°C, 22.0 kg of EtOH (4.5 volumes) was added, the resulting suspension was stirred for 15 minutes, and the batch was filtered. The reactor was rinsed with DI H2O (62.8 L, 10 volumes), the rinse solution was transferred to a filter, and the solid was conditioned until the liquid stopped dripping.

[0366] The filtered solid and EtOH (48.9 kg, 10 volumes) were added to the reactor, and the batch was heated to 40-50°C while stirring. The batch was kept at 40-50°C for 30 minutes, then cooled to 0-10°C. The batch was filtered through the same filter used earlier, EtOH (25 kg, 5 volumes) was added to the reactor, and the rinse solution was passed over the filtered solid. The solid was conditioned until the liquid stopped dripping, then transferred to a vacuum oven at 50°C and dried for 64 hours to obtain product (III) (11.7 kg, 93.6%).

[0367] Specifications of the obtained solid: 1 1H NMR (matches compound (III)); Appearance: Brown solid; KF (water content %): 0.041%; relative to 1,4-dimethoxybenzene 1 ¹H NMR (d6-DMSO) gravimetric assay (99.4%); HPLC purity (area %) at 247 nm: 100%.

[0368] Step 5) Preparation of the compound of formula (II) Compound (III) (11.7 kg) and 1,4-dioxane (52.5 L, 4.5 vol) were added to a 400 L reactor fitted with a 2 M NaOH scrubber, which had been inactivated for 1 day with a flow of N2 at 10 L / min. The batch was kept at 15-25°C and stirring was started. Thionyl chloride (29.7 kg) was added over 45 minutes while maintaining the batch temperature below 30°C (Note: This addition is slightly exothermic). A 4 M HCl 1,4-dioxane solution (39.3 kg, 6.0 equivalents) was added over 45 minutes while maintaining the batch temperature below 30°C (Note: This addition is slightly exothermic). The batch was heated to 50-55°C and maintained at this temperature for 17 hours. HPLC analysis revealed a 98% conversion from compound (III) to compound (II), so the batch temperature was adjusted to 15-25°C.

[0369] n-heptane (120 L, 10 volumes, treated with 200 ppm Statsafe 6000) was added to the reactor, and the batch was subjected to vacuum distillation (28 inHg, maximum temperature 35.6°C) to a final volume of 86 L (7.5 volumes). n-heptane (123 L, 10 volumes) was added to the reactor, and the batch was subjected to vacuum distillation (28 inHg, maximum temperature 24.0°C) to a final volume of 86 L (7.5 volumes). n-heptane (123 L, 10 volumes) was added to the reactor, and the batch was subjected to vacuum distillation (29 inHg, maximum temperature 20.6°C) to a final volume of 86 L (7.5 volumes). n-heptane (116 L, 10 volumes) was added to the reactor, and the batch was subjected to vacuum distillation (29 inHg, maximum temperature 21.0°C) to a final volume of 80 L (7.5 volumes). n-heptane (120 L, 10 volumes) was added to the reactor, and the batch was subjected to vacuum distillation (28 inHg, maximum temperature 22.0°C) to a final volume of 83 L (7.5 volumes). The batch was filtered under N2, the reactor was rinsed with n-heptane (55.0 L, 5 volumes), and the rinse solution was passed over the filtered solid. The material was dried under vacuum in a filter with a N2 flow of 50 L / min for 3 days to obtain product (II) (11.8 kg, over 100%).

[0370] Specifications of the obtained solid: 11H NMR (NA); Appearance: Gray powder; KF (moisture content %): 0.015%; Relative to 1,4-dimethoxybenzene 1 1H NMR (d6-DMSO) gravimetric assay (NA); HPLC purity (area %) at 247 nm: 95.9%.

[0371] Steps 6a) and 6b) Preparation of the compound of formula (I) TIFF0007879134000024.tif47128 In a 400L reactor inactivated with a flow of N2 at 15 L / min for 26.5 hours, 2-(aminooxy)ethanol (2.43 kg), THF (63 L, 6 volumes), and 4-methylmorpholine (7.68 L) were added, and the batch temperature was adjusted to -5°C to 5°C while stirring. Chlorotrimethylsilane (4.29 L) was added over 30 minutes to maintain the batch temperature at 0-10°C, and the mixture was stirred at this temperature for 45 minutes.

[0372] Compound (II) (10.5 kg) and THF (105 L, 10 volumes) were added to a separate container inactivated with a 10 L / min N2 flow for 5 hours, and the mixture was stirred at room temperature for 20 minutes to form a homogeneous suspension. The suspension of compound (II) was added to the reactor over 1.5 hours, ensuring the batch temperature remained below 10°C, and the batch was stirred at -5°C to 5°C for 30 minutes. HPLC analysis revealed that the residual compound (II) was 0.87% relative to compound (I), at which point the batch temperature was adjusted to 15–25°C.

[0373] Darco G-60 (5.25 kg) was added to a 200 L Schott reactor that had been inactivated for 2 hours with a 20 L / min N2 flow. The batch was transferred to the Schott reactor and stirred with charcoal for 45 minutes. This was filtered through a 0.4 μm inline filter and returned to the reactor. DI H2O (105 L, 10 volumes) was added to the reactor over 45 minutes (during which time the batch temperature rose from 13.6°C to 24.0°C). The batch was distilled under reduced pressure (27 in Hg, maximum temperature 20.7°C) to a total volume of 155 L (15 volumes). The batch temperature was maintained at 15-25°C and MTBE (94.5 L, 9 volumes) was added to the reactor. The batch was distilled under reduced pressure (26 in Hg, maximum temperature 26.6°C) to a final volume of 133 L (13 volumes). The batch temperature was maintained at 15-25°C, and MTBE (94.5 L, 9 volumes) was added to the reactor. The batch was subjected to vacuum distillation (26 inHg, maximum temperature 19.3°C) to a final volume of 133 L (13 volumes). The batch temperature was maintained at 15-25°C, and EtOH (94.5 L) was added to the reactor.

[0374] The solid was filtered, DI H2O (52.5 L, 5 vols) was added to the reactor, and the rinse solution was passed over the collected solid. MTBE (52.5 L, 5 vols) was added to the reactor, and the rinse solution was passed over the collected solid. MTBE (52.5 L, 5 vols) was added again to the reactor, and the rinse solution was passed over the collected solid. After adding the solid to the reactor, DI H2O (105 L, 10 vols) was added, and the suspension was stirred at 15-25°C for 40 minutes. The batch was filtered using the same filter configuration, and the solid was conditioned until the liquid stopped dripping. After adding the solid to the reactor, EtOH (141 L, 13.5 vols) was added, and the batch was heated to 70-80°C, and stirred at this temperature for 32 minutes until the solid was almost completely dissolved. DI H2O (105 L, 10 vols) was added to the reactor over a minimum of 2 hours to maintain the batch temperature at 70-80°C. The batch was cooled to 10-20°C over 13 hours, and then filtered into a newly constructed filter. DI H2O (52.5 L, 5 volumes) was added to the reactor in four separate additions, with the rinse solution passed over the collected solid as a replacement washing solution each time. The solid was conditioned until the liquid stopped dripping, and then dried in a vacuum oven at 70°C for 7 days to obtain product (I) (5.7 kg, 53.7%).

[0375] Example 2 Crystal form A Crystal form A was prepared according to step 6 of Example 1.

[0376] We successfully indexed the XRPD pattern of crystal form A. This indicates that this pattern represents a single crystalline phase. The indexing results showed that the estimated crystal volume was consistent with that of the anhydrous form. Form A was characterized using the method shown in Table 1.

[0377] (Table 1) Characterization of crystal form A TIFF0007879134000025.tif68165

[0378] Form A exhibited limited hygroscopicity and simultaneous melting / decomposition around 187°C. Form A was identified as the most thermodynamically stable form compared to anhydrous forms E and F at room temperature to 50°C (see Examples 9 and 10). Furthermore, Form A was found to be the dominant form compared to known hydrates in solvent systems with a water activity of 0.3 or less (see Example 11).

[0379] XRPD patterns were analyzed for morphology A, and favorable orientation and particle statistical effects were not evaluated. Observed peaks are shown in Figure 1 and Table 2A, and prominent peaks are listed in Table 2B.

[0380] (Table 2A) Observed peaks of the XRPD pattern shown in Figure 1 for morphology A TIFF0007879134000026.tif152165

[0381] (Table 3B) Prominent peaks in the XRPD pattern shown in Figure 1 for morphology A TIFF0007879134000027.tif117128

[0382] Example 3 Crystal form E We successfully indexed the XRPD pattern of morphology E. The indexing results showed that this pattern represents a single crystalline phase, and that the estimated crystal volume was consistent with that of the anhydrous form. Morphology E was characterized using the method shown in Table 3.

[0383] (Table 3) Characterization of crystal form E TIFF0007879134000028.tif32165

[0384] The DSC thermogram in Figure 6 shows endothermic melting / decomposition that begins around 188°C. This event is identical to that observed for morphology A. The TGA thermogram in Figure 7 shows a very slight weight loss below 180°C, which is consistent with the anhydrous form. The significant weight loss above 180°C is due to decomposition.

[0385] Anhydrous form E was identified as having higher thermodynamic stability than anhydrous form F but lower stability than form A at room temperature to 50°C (see Examples 9 and 10). A small number of experiments, including high-temperature slurry experiments in IPA, vapor diffusion in acetone and MTBE, and slow cooling experiments in dry CAN, showed that form E was most frequently observed as a mixture with the other forms (see Example 12).

[0386] XRPD patterns were analyzed for morphology E, and favorable orientation and particle statistical effects were not evaluated. Observed peaks are shown in Figure 5 and Table 4A, and prominent peaks are listed in Table 4B.

[0387] (Table 4A) Observed peaks of the XRPD pattern shown in Figure 5 for morphology E TIFF0007879134000029.tif172165

[0388] (Table 5B) Prominent peaks in the XRPD pattern shown in Figure 5 for morphology E TIFF0007879134000030.tif117128

[0389] Example 4 Crystal form F We successfully indexed the XRPD pattern of crystal form F. This indicates that this pattern represents a single crystalline phase. The indexing results showed that the estimated crystal volume was consistent with that of the anhydrous form. Form F was characterized using the method shown in Table 5.

[0390] (Table 5) Characterization of crystal form F TIFF0007879134000031.tif52165

[0391] The DSC thermogram in Figure 9 shows a simultaneous endothermic / exothermic event that begins around 159°C. This event is likely the melting of morphology F, followed by recrystallization. Endothermic melting / decomposition that begins around 186°C is also observed in the DSC. The TGA thermogram in Figure 10 shows a very slight weight loss below 180°C, which is consistent with the anhydrous form. The significant weight loss above 180°C is due to decomposition.

[0392] Form F was found to be the least thermodynamically stable form compared to forms A and E at room temperature to 50°C (see Example 10). Form F was observed in several cooling experiments in ACN or toluene (see Example 12).

[0393] XRPD patterns were analyzed for morphology F, and favorable orientation and particle statistical effects were not evaluated. Observed peaks are shown in Figure 8 and Table 6A, and prominent peaks are listed in Table 6B.

[0394] (Table 6A) Observed peaks of the XRPD pattern shown in Figure 8 for morphology F TIFF0007879134000032.tif139165

[0395] (Table 7B) Prominent peaks in the XRPD pattern shown in Figure 8 for morphology F TIFF0007879134000033.tif81128

[0396] Example 5 Crystal form B We successfully indexed the XRPD pattern of morphology B. The indexing results showed that this pattern represents a single crystalline phase, and that the estimated crystal volume corresponds to 1 mol / mol of water. Morphology B was characterized using the method shown in Table 7.

[0397] (Table 7) Characterization of crystal form B TIFF0007879134000034.tif44165

[0398] As shown in the DSC curve in Figure 12, dehydration and endothermic reactions begin around 80°C, followed by a series of events leading to decomposition around 200°C. The TGA thermogram in Figure 13 shows that a 3.4% weight loss occurs simultaneously with the dehydration and endothermic reactions between 80°C and 145°C. This loss corresponds to the evaporation of approximately 1 mol / mol of water.

[0399] Numerous experiments have shown that monohydrate form B is dominant as a mixture with other forms (see Example 12). Form B can be readily obtained from aqueous solvent mixtures with a water activity of 0.5 or higher (see Example 11). High-temperature exposure under reduced pressure causes the material to become disordered (see Example 9).

[0400] XRPD patterns were analyzed for morphology B, and favorable orientation and particle statistical effects were not evaluated. Observed peaks are shown in Figure 11 and Table 8A, and prominent peaks are listed in Table 8B.

[0401] (Table 8A) Observed peaks of the XRPD pattern shown in Figure 11 for morphology B TIFF0007879134000035.tif125165

[0402] (Table 9B) Prominent peaks in the XRPD pattern shown in Figure 11 for morphology B TIFF0007879134000036.tif66128

[0403] Example 6 Crystal form C We successfully indexed the XRPD pattern of crystalline form C. This indicates that this pattern represents a single crystalline phase. The indexing results showed that the estimated crystal volume can correspond to up to 1 mol / mol of chloroform. Morphology C was characterized by the method shown in Table 9.

[0404] (Table 9) Characterization of crystal form C TIFF0007879134000037.tif32165

[0405] Solutions in Figures 15A and 15B1 The 1H NMR spectrum includes a peak attributed to chloroform, which integrates to approximately 0.4 moles of chloroform per mole of compound (I).

[0406] XRPD patterns were analyzed for morphology C, and favorable orientation and particle statistical effects were not evaluated. Observed peaks are shown in Figure 14 and Table 10A, and prominent peaks are listed in Table 10B.

[0407] (Table 10A) Observed peaks of the XRPD pattern shown in Figure 14 for morphology C TIFF0007879134000038.tif112165

[0408] (Table 9B) Prominent peaks in the XRPD pattern shown in Figure 14 for morphology C TIFF0007879134000039.tif88128

[0409] Example 7 Crystal form H We successfully indexed the XRPD pattern of crystalline form H as a wet solid. This indicates that the pattern represents a single crystalline phase. The indexing results showed that the estimated crystal volume can correspond to up to 1 mol / mol of methanol. Form H was characterized by the method shown in Table 11.

[0410] (Table 11) Characterization of crystal form H TIFF0007879134000040.tif18165

[0411] XRPD patterns were analyzed for morphology H, and favorable orientation and particle statistical effects were not evaluated. Observed peaks are shown in Figure 16 and Table 12A, and prominent peaks are listed in Table 12B.

[0412] (Table 12A) Observed peaks of the XRPD pattern shown in Figure 16 for morphology H TIFF0007879134000041.tif145165

[0413] (Table 13B) Prominent peaks in the XRPD pattern shown in Figure 16 for morphology H TIFF0007879134000042.tif110128

[0414] Example 8 Material D Material D was identified as a hemihydrate, and it was not possible to index the XRPD pattern of material D to confirm the purity of the phase. Dehydration endothermic reaction, starting around 30°C, was observed in the DSC curve. This occurred simultaneously with a 1.3% weight loss due to TGA (occurring between 40°C and 75°C). This loss corresponds to the volatilization of approximately 0.4 mol / mol of water. The remaining events thereafter were similar to those observed for morphology F. From a small number of experiments conducted in Example 12, material D was predominantly observed as a mixture with other morphologies. Results from the water activity experiments in Example 11 suggest that material D preferentially arises from an aqueous solvent system with a water activity of approximately 0.4. Material D was characterized by the method shown in Table 13.

[0415] (Table 13) Characterization of material D TIFF0007879134000043.tif44165

[0416] Example 9 Crystalline Stability The physical stability of morphology A was investigated. It was confirmed that morphology A is stable under reduced pressure at ambient temperature for 1 day. Furthermore, morphology A was stable when exposed to 90% RH at ambient temperature for 7 days.

[0417] The physical stability of morphology F was investigated. Morphology F was stable under reduced pressure at room temperature for 5 days. Furthermore, morphology F was stable when exposed to 90% RH at ambient temperature for 7 days.

[0418] The physical stability of morphology B was investigated. Morphology B was stable under reduced pressure at ambient temperature for two days. However, exposure to 45°C under reduced pressure resulted in a slightly disordered XRPD pattern with additional unidentified peaks. In-situ variable-temperature X-ray powder diffraction (vtXRPD) experiments suggested that morphology B eventually converts / crystallizes to anhydrous form E at relatively high temperatures (e.g., 178°C).

[0419] The physical stability of morphology C was investigated. Morphology C became slightly disordered when exposed to high temperatures (approximately 42°C to 45°C) under reduced pressure, for example, at approximately 42°C for one day or at approximately 45°C for three days.

[0420] Since the solid of form H was initially isolated in a wet state due to excess MeOH (see Example 7), an attempt was made to remove the excess solvent under reduced pressure (i.e., at room temperature for 2 days). The resulting solid was confirmed by XRPD patterning to be a disordered mixture of form H and form A. This suggests that solvated form H is not physically stable under these conditions.

[0421] Example 10 Two-way competition and interconversion experiment - Thermodynamic relationship between forms A, E, and F Phase transitions in solids can be thermodynamically reversible or irreversible. Crystal forms that are reversibly transformed at a specific transition temperature are called tautomorphs. If crystal forms are not interconvertible under these conditions, the system is unautomorphic (a single thermodynamically stable form). Several rules using calorimetric data can help predict the relative thermodynamic stability of polymorphs and whether the relationships between polymorphs are tautomorphic or unautomorphic. Unfortunately, the calorimetric data obtained in this study were not suitable for this purpose because decomposition occurs simultaneously during melting.

[0422] Instead, interconversion experiments were conducted to determine the thermodynamic relationships between polymorphs. Interconversion experiments, or competing slurry experiments, are solution-mediated processes that realize a pathway for growing the less soluble (more stable) crystal instead of the more soluble crystal form [Bernstein, J. Polymorphism in Molecular Crystals. Clarendon Press, Oxford, 2006; and Polymorphism in Pharmaceutical Solids. Brittain, Harry G. ed. Marcek Dekker, Inc. New York. 1999]. Apart from the formation or decomposition of solvates, the more stable polymorph obtained from interconversion experiments is independent of the solvent used, because the more thermodynamically stable polymorph exhibits lower energy and therefore lower solubility. The choice of solvent affects the dynamics of polymorphic transformation but not the thermodynamic relationships between polymorphs [Gu, CH., Young, V. Jr., Grant, DJ. J. Pharm. Sci. 2001, 90(11):1878-1890].

[0423] Slurries were prepared at ambient temperature and 50°C using binary mixtures of morphs A / F, A / E, and E / F. Saturated solutions of the compound of formula (I) in ƒ or ACN were prepared at room temperature or 50°C. The solutions were filtered, and approximately equal volumes of the two polymorphs were added to the solution. The samples were slurryed at a given temperature over several days, and the solids were collected by positive pressure filtration or centrifugation / decantation. The solids were recovered and analyzed by XRPD.

[0424] The results of the interconversion tests are shown in Table 14.

[0425] (Table 14) Experiments in two-way competition and interconversion of slurry TIFF0007879134000044.tif69165

[0426] Solution-mediated interconversion processes provide a pathway for growing the less soluble (more stable than the other) crystal form instead of the more soluble crystal form. However, if neither of the forms involved in a two-competition slurry experiment is the most thermodynamically stable form, then it is possible that the most stable crystal will grow instead of the other two more soluble crystal forms. See form A obtained in a two-competition mixture of forms E and F. This solvent-mediated polymorphic conversion is controlled by the nucleation rate, which is generally faster in solvents that yield higher solubility. In addition to solubility, the strength of the solvent-solute interaction is also important. Agitation and temperature also alter the polymorphic conversion by influencing the crystallization dynamics of the more stable polymorph. In solvents that yield low solubility, the metastable region may be wider than the solubility difference between the two polymorphs due to high interfacial energy, and therefore the critical free energy barrier for nucleation cannot be overcome (see Gu et. al., J. Pharm. Sci. 2001).

[0427] Form A was obtained when used in a binary mixture. This confirms that form A is more stable than form E or F. When form A did not spontaneously nucleate, form E arose from the binary mixture of form E / F, or became the dominant form. This indicates that form E is more stable than form F. Monotropy is inferred within the tested temperature range. In short, the thermodynamic stability from room temperature to 50°C is ranked as follows: Form A>Form E>Form F (room temperature ~ 50℃)

[0428] Example 11 Two-way competition experiment - Water activity in relation to hydration state The water activity (a) of the compound of formula (I) with respect to its hydration state w The effects of ) were investigated through competitive water activity trituration experiments (slurry experiments) in aqueous ACN, MeOH, or EtOH. Using slurry experiments of binary mixtures of form A / form B or form A / material D, various a wThe dominant morphology of the compound was determined. The obtained solid phase was characterized by XRPD.

[0429] Water activity and relative humidity are expressed as RH% = a wThis is linked by x 100. This makes it possible to directly correlate the anhydrous / hydrated stability in slurry experiments with solid-phase stability. The literature suggests that slurry techniques with controlled water activity enable a precise method for rapidly predicting physically stable forms in anhydrous / hydrated systems [Ticehurst MD, Storey RA, Claire W. Application of slurry bridging experiments at controlled water activities to predict the solid-state conversion between anhydrous and hydrated forms using theophylline as a model drug. Int J Pharm. 2002;247:1-10; Sacchetti M. Determining the relative physical stability of anhydrous and hydrous crystal forms of GW2016. Int J Pharm. 2004;273:195-202; Zhu H, Yuen C, Grant DJW. Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 1. Theophylline. Int J Pharm. 1996;135:151-160; and Zhu H, Grant DJW. Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 2. Ampicillin. Int J Pharm. 1996;139:33-43]. Because solvent-mediated polymorphic conversion accelerates the conversion process, this method is particularly useful when true equilibrium cannot be reached within a reasonable timeframe due to the relatively slow conversion kinetics in the solid phase.

[0430] The results are shown in Table 15.

[0431] (Table 15) Two-way competition slurry experiment TIFF0007879134000045.tif66165a: Water activity calculated using a UNIFAC computer; *: XRPD pattern obtained in a wet / wet solid.

[0432] 0.30 a w In the following, the anhydrous form A is the dominant form, 0.50 a w Based on the above, monohydrate form B is dominant. Even if material D, which is hemihydrate, was not present in the initial mixture used, it would be 0.40 a, which is the intermediate value between the stable regions of the monohydrate and anhydrous forms. w This became clear. Given sufficient time, material D would probably have become the dominant form under those conditions. In short, the dominant anhydrous / hydrated forms at a given water activity value at room temperature are ranked as follows: Form A≦0.30a w <Approximately 0.40 a w Material D < 0.50 a w ≤ Form B (at room temperature)

[0433] Example 12 Polymorphic screening experiment A lot of the compound of formula (I), including mixtures of forms A and B, was used in this test. Measured aliquots of various solvents were added to weighed amounts of the material while sonicating, until the solution became clear or reached the maximum volume of the vial. Solubility was calculated based on the total amount of solvent used to obtain the solution. Actual solubility may be higher due to the amount of solvent used or a slower dissolution rate. As shown in Table 16, approximate solubility values ​​for this material were visually estimated using various solvents and solvent mixtures at ambient temperature. Values ​​were rounded to the nearest integer. If dissolution did not occur as determined by visual evaluation, the value was reported as "<". If dissolution occurred as determined by visual evaluation after adding the first aliquot, the value was reported as ">".

[0434] (Table 16) Approximate solubility values ​​of compounds of formula (I) TIFF0007879134000046.tif95165a: Water activity calculated using the UNIFAC computer.

[0435] Limited solubility was observed in acetone, ACN, DCM, SiO, EtOH, MeOH, 3:1 v / v acetone / H2O, and 1:1 v / v THF / H2O. THF showed a slightly improved solubility of 29 mg / mL, while heptane, H2O, and toluene showed low solubility of less than 1 mg / mL. Solubility values ​​were considered in the design of morphological screening experiments.

[0436] Next, the materials described above were used in solvent-based screening designed to crystallize and potentially identify different crystalline forms. More than 40 experiments were conducted in various solvents at different temperatures (below room temperature, room temperature, and high temperature) using numerous crystallization techniques. Crystallization techniques included rapid cooling, slow cooling, rapid evaporation, slow evaporation, slurry experiments, vapor diffusion, and vapor pressurization, as described below.

[0437] Rapid cooling (CC) Clear solutions of the compound of formula (I) in ELISA and IPA were prepared at 50-60°C. The vials were transferred to a freezer at approximately -20°C. The solid was collected using the prescribed technique.

[0438] Slow cooling (SC) A clear solution of the compound of formula (I) in ACN and toluene was prepared at 60°C. Heating to the reactor block was stopped, and the sample was slowly cooled to room temperature in a hot block. The solid was collected using a predetermined technique.

[0439] Rapid evaporation (FE) Clear solutions of the compound of formula (I) were prepared in various solvents. The vials were left uncapped, and the solvent was evaporated under ambient conditions.

[0440] Slow evaporation (SE)Clear solutions of the compound of formula (I) were prepared in various solvents. The vials were capped with perforated aluminum foil, and the solvent was evaporated under ambient conditions.

[0441] Slurry experiment Saturated solutions of the compound of formula (I) were prepared in various solvents and solvent mixtures. The mixtures were stirred at different temperatures (e.g., below room temperature, room temperature, and high temperature) for the specified periods. The solids were collected by centrifugation and subsequent decantation. The wet solids were analyzed by XRPD.

[0442] Vapor diffusion (VD) Saturated solutions of the compound of formula (I) in various solvents were prepared in one drum vial. The drum vial was placed in a 20 mL vial containing a given reverse solvent, without capping it. The larger vial was capped and left at ambient temperature for a given amount of time. All solids were collected and analyzed by XRPD.

[0443] Steam pressurization (VS) A solid of the compound of formula (I) was placed in one drum vial. Without capping the drum vial, it was placed in 20 mL vials containing different solvents. The resulting solids were analyzed by XRPD.

[0444] The isolation of the solid may be carried out by any one of the techniques described below.

[0445] Positive pressure filtration The slurry was passed through a syringe-Swinnex filter holder assembly at a predetermined temperature, and the solid was collected on a 0.2 μm nylon or PTFE filter. Generally, the solid was dried quickly by blowing air from a 20 mL syringe onto the filter.

[0446] Decantation Remove the clear solution using a disposable pipette and discard it, leaving the moist solid behind.

[0447] The resulting solids were observed using polarized light microscopy (PLM) and / or analyzed by X-ray powder diffraction (XRPD). Many samples were analyzed by XRPD while still wet with the crystallization solvent. Subsequently, most of these samples were dried under reduced pressure at various temperatures to desolvate them.

[0448] The results of the polymorphic screening experiment are listed in Table 17.

[0449] (Table 17) Polymorphic screening experiment TIFF0007879134000047.tif87165TIFF0007879134000048.tif224165*: XRPD patterns obtained on wet / wet solids

[0450] Example 13 Morphological transformation experiment In order to establish reliable morphogenesis conditions, a small number of morphogenesis experiments were conducted by adding 0.5 wt% of form A of compound (I) in various solvents at room temperature. The experiments were carried out by adding a seed crystal of form A of the compound and 20 volumes of each solvent shown in Table 18.

[0451] (Table 18) Morphological transformation experiment TIFF0007879134000049.tif98165

[0452] Entries 1-3 The resulting slurry was stirred at room temperature for 24 hours and then filtered. The compound of formula (I) isolated from each experiment was subjected to XRPD analysis of the wet cake and oven-dried materials. The XRPD patterns of the wet cake and dried materials were similar and consistent with the starting materials of the compound.

[0453] Entry 4The experiment was conducted in EtOH / H2O, with H2O slowly added over 1 hour and 20 minutes at 75°C. After the H2O addition was complete, the batch remained as a solution, and after stirring for 15 minutes under the same conditions, the formation of a dilute slurry began. The batch was then cooled to 10°C over 14 hours, held at 10°C for 5 hours, and then filtered. Analysis of the wet cake isolated from this experiment by XRPD showed that the pattern did not match morphology A.

[0454] Entries 5-6 Two reslurry experiments were conducted using 0.5 wt% seed crystal (morphology A) in CH3CN at 60°C and in acetone at 55°C, respectively. In both experiments, anhydrous crystalline forms, which were similar to each other, were produced. The material was isolated from the room-temperature experiment. However, the crystalline form of the isolated material did not match the desired morphology A.

[0455] Example 14 Crystallization of the compound of formula (I) from THF / MTBE using a seed crystal of form A To develop a robust crystallization process for the compound of formula (I), several experiments were performed from THF / MTBE using morphology A seed crystals, as shown in Table 19. Morphology A from Example 2 (batch 2) was used as the morphology A seed crystal.

[0456] (Table 19) Crystallization of compounds in THF / MTBE using seed crystals of form A TIFF0007879134000050.tif72162

[0457] Entry 1Approximately 4 g of the compound (96.95% AUC) was dissolved in 10 volumes of THF at 55°C, and the solution was cooled to 40°C. While maintaining the batch temperature at 40°C, 20 volumes of MTBE were added over 1 hour, followed by the addition of 8 volumes of MTBE, and then 1% by weight of Form A. In this case, the reaction mixture became a dilute slurry before the addition of the seed crystal. Nevertheless, the HPLC purity of the isolated compound was 99.79% AUC as Form A. The recovery yield was 91.5%, and impurities were removed from 2.6% AUC to 0.11% AUC at 20.7 minutes.

[0458] Entry 2 Another experiment was performed on a 10g scale compound (99.6% AUC) in a nearly identical manner. The only difference was that 4 volumes of MTBE were added to the reaction mixture, followed by 1 wt% of a seed crystal of form A. The seed crystal remained, and the mixture became a slurry. MTBE was continued to be added to the reaction mixture, and after aging at 20°C for 2 hours, the final product was isolated as form A. The recovery rate from this experiment was 88.8%.

[0459] Entry 3 To determine a stable nucleation site, 1 g of the compound (99.6% AUC) was dissolved in THF (10 volumes), and a seed crystal of form A was added at 40°C. After standing for 30 minutes, the seed crystal remained, and a relatively concentrated slurry was formed. Subsequently, MTBE was added while maintaining the batch temperature at 40°C. From this experiment, the final product was isolated as form A with a recovery yield of 86%. This novel recrystallization process was demonstrated in Example 16.

[0460] Example 15 Slurry-to-slurry morphology conversion using seed crystals of morphology A. As shown in Table 20, slurry-to-slurry transformation of the compound of formula (I) was performed in a preliminary mixture of THF / MTBE and EtOH / H2O with various amounts of seed crystals of form A. Form A from Example 2 (batch 2) was used as the seed crystal of form A.

[0461] (Table 20) Slurry transformation of compounds in THF / MTBE and EtOH / H2O using seed crystals of form A TIFF0007879134000051.tif44165

[0462] The above experiments showed that 5–20 wt% seed crystals could convert any other form of the compound of formula (I) to the desired form A in a THF / MTBE system, whereas experiments conducted in EtOH / H2O could not convert it to the desired form. The slurry morphogenesis process in THF / MTBE remains a viable option for producing form A of the compound of formula (I).

[0463] Example 16 Method for preparing form A of the compound of formula (I) TIFF0007879134000052.tif4112810L reactor was mixed with HOCH2CH2NH2·TsOH (227 g, 0.91 mol, 1.25 equivalents) and MTBE (1.36 L, 4.0 vol.), and stirring was started at 20 ± 5°C. NMM (441 mL, 3.54 mol, 5.5 equivalents) was added, and the batch was stirred under the same conditions for 30 minutes. After this, the batch was filtered, and the cake was washed with MTBE (2 x 0.51 L, 2 x 1.5 vol.). The filtrate and washing mixture was returned to the reactor and cooled to 0°C. TMSCl (0.157 L, 1.24 mol, 1.7 equivalents) was slowly added while maintaining the batch temperature below 5°C. After the batch was aged for 45 minutes, the slurry of the compound of formula (II) was added. Compound (II) (340 g, 0.73 mol, 1.0 equivalent) was added to a 5 L three-port RBF equipped with a mechanical stirrer, followed by MTBE (3.4 L, 10 volumes). The mixture was stirred for 35 minutes to obtain a homogeneous slurry, which was then subjected to amide coupling. The slurry of compound (II) was transferred over 1 hour and 20 minutes using a transfer pump while maintaining the reaction temperature below 8°C. The RBF was rinsed with MTBE (0.34 L, 1 volume) and added to the batch. The batch was stirred continuously at 5°C, then the temperature was raised to 20 ± 5°C and stirred at that temperature for 30 minutes. After this, an in-process control sample was taken out, and HPLC analysis showed a 99.85% conversion from compound (II) to compound (I). The batch was filtered to remove all solids, the reactor was rinsed with THF (2 x 0.68 L, 2 x 2 volumes), and THF was applied for cake washing. The filtrate was returned to a clean reactor, and the batch was distilled under reduced pressure to a final volume of approximately 1.7 L (5 volumes). Ethanol (3.4 L, 10 volumes) was added to the reactor, and the batch was distilled again to approximately 1.7 L. 1In 1H NMR, THF was found to be 0.81 mol% relative to EtOH. The mixture was cooled to 20°C and ethanol (2.89 L, 8.5 vol) and water (0.68 L, 2 vol) were added. The mixture was heated to 80°C (all solids did not completely dissolve) and water (2.72 L, 8 vol) was added over 2 hours. After adding approximately 1.8 L of DI H2O, the batch became a solution and remained a clear solution even after the completion of H2O addition. The mixture was cooled to 10°C over 13 hours. The batch was aged at 10°C for 4 hours and then filtered. The reactor was rinsed with water (4 x 1.7 L) and transferred from the reactor to a cake. The wet cake (783 g) was dried at 60°C for 3 days (Note: no weight loss occurred after 26 hours of drying) to obtain 240 g (70%) of crude compound (I). The HPLC purity of crude compound (I) was 98.81% AUC, and the water content determined by KF was 0.28% by weight.

[0464] Crude compound (I) (238 g) and THF (3.4 L) were added to a 10 L reactor. The batch was heated to 51.2°C (target was 60°C) to dissolve the product. After dissolution, the batch was cooled to 40°C, then Darco G60 (170 g, 50 wt%) was added, and the slurry was aged for 30 minutes. After filtration (on 340 g of Celite) to remove carbon, the reactor and filtration cake were rinsed with THF (2 x 1.9 L, 2 x 3.5 vol). The filtrate and washing mixture was passed through a 0.2 μm inline filter and returned to the clean reactor. The batch was distilled under reduced pressure to approximately 1.7 L (5 vol), and then heated to 60-65°C to dissolve. After adding an additional THF (0.68 L, 1+1=2 volumes), the batch was observed to be fully dissolved. The batch temperature was then adjusted to 40°C, and seed crystals of form A (3.4 g, form A, batch 2 of Example 2) were added. Stirring continued under the same conditions for 30 minutes, and then MTBE (4.76 L, 14 volumes) was added to the mixture over 1 hour and 30 minutes while maintaining the batch temperature at 40°C. The batch was cooled to 20°C over 2 hours, aged at 20°C for 1 hour, and then filtered. The reactor and filtered cake were rinsed with MTBE (2 x 0.68 L, 2 x 2 volumes). The wet cake weighed 455 g, which was dried at 45°C for 36 hours to obtain 189 g of compound (I) (yield 55%).1 ¹H NMR analysis was consistent with the assigned structure, HPLC purity was 99.88% AUC, and the XRPD pattern was consistent with morphology A of compound (I) (e.g., Figure 1).

[0465] While the above disclosures have been explained in some detail with illustrations and examples for the purpose of clarifying understanding, those skilled in the art will recognize that certain changes and modifications can be made within the scope of the attached claims. Furthermore, each reference cited herein is incorporated by reference to the same extent as each reference is incorporated by reference individually. In the event of any conflict between this application and the references cited herein, this application shall prevail.

Claims

1. Equation (I): A crystalline form A of an anhydrous compound having, Crystal form A is characterized by an X-ray powder diffraction (XRPD) pattern that includes peaks at 5.3, 8.0, 18.3, 18.5, and 24.3°²θ (±0.2°²θ).

2. Crystal form A according to claim 1, wherein the X-ray powder diffraction pattern further includes peaks at 13.1, 20.5, 20.7, 21.7, and 24.0°²θ (±0.2°²θ).

3. Crystal form A according to claim 1, wherein the X-ray powder diffraction pattern further includes peaks at 9.6, 16.0, 16.6, 19.3, and 21.4°²θ (±0.2°²θ).

4. The X-ray powder diffraction pattern is shown in Figure 1 below: Figure 1 Crystal form A according to claim 1, which is consistent with the above.

5. Crystalline form A according to claim 1, which does not include other crystalline or amorphous forms of the compound having formula (I).

6. The crystal form A according to claim 1, further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at 189.9°C.

7. Crystal form A according to claim 6, wherein the endothermic peak has an onset temperature of 187.1°C.

8. The DSC thermogram is shown in Figure 2 below: Figure 2 Crystal form A according to claim 6, which is consistent with the above.

9. Crystalline form A according to claim 1, further characterized by a weight loss of 0.1% to 1% upon heating to 100°C, as measured by thermogravimetric analysis (TGA).

10. Crystal form A according to claim 9, wherein the weight loss when heated from 40°C to 100°C, as measured by thermogravimetric analysis, is 0.3%.

11. Figure 3 below: Figure 3 The crystal form A according to claim 1, further characterized by a thermogravimetric analysis (TGA) thermogram that matches the one shown.

12. Crystalline form A according to claim 1, further characterized by a 1.1% weight increase after undergoing a dynamic water vapor adsorption cycle at 25°C and relative humidity (RH) from 5% to 95% RH.

13. Crystalline form A according to claim 1, further characterized by a 1.2% weight loss after undergoing a dynamic water vapor desorption cycle at 25°C and relative humidity (RH) 95% to 5% RH.

14. Figure 4 below: Figure 4 Crystalline form A according to claim 1, having a dynamic water vapor adsorption profile as shown.

15. A pharmaceutical composition comprising crystalline form A according to any one of claims 1 to 14 and one or more pharmaceutically acceptable excipients.

16. The pharmaceutical composition according to claim 15, which is a topical preparation.

17. The pharmaceutical composition according to claim 16, wherein the topical preparation is a ointment, lotion, spray, ointment, cream, gel, or patch.

18. The pharmaceutical composition according to claim 15 for use in a method for treating a skin disorder in a subject.

19. The pharmaceutical composition according to claim 18, wherein the skin disorder is a MEK inhibitor-responsive skin disorder or a MEK-mediated skin disorder.

20. The pharmaceutical composition according to claim 19, wherein the MEK inhibitor-responsive skin disorder or MEK-mediated skin disorder is selected from the group consisting of neurofibromatosis type 1, cutaneous neurofibroma, subcutaneous neurofibroma, superficial plexiform neurofibroma, and cutaneous RAS disease.

21. The pharmaceutical composition according to claim 20, wherein the cutaneous RAS disease is selected from the group consisting of psoriasis, keratoacanthoma (KA), keratosis, papilloma, Noonan syndrome (NS), cardiac-facial-cutaneous syndrome (CFC), Costello syndrome (facial-cutaneous-skeletal syndrome or FCS syndrome), ectophthalmic syndrome, café-au-lait spots, and lentigo polycarcinoma (formerly known as leopard syndrome).

22. The pharmaceutical composition according to claim 18, wherein the skin disorder is skin cancer.

23. The pharmaceutical composition according to claim 22, wherein the skin cancer is cutaneous squamous cell carcinoma.

24. The pharmaceutical composition according to claim 22, wherein the skin cancer is MEK inhibitor-responsive or MEK-mediated cutaneous squamous cell carcinoma.

25. The pharmaceutical composition according to claim 23, wherein cutaneous squamous cell carcinoma is associated with the activation of p-ERK.

26. The pharmaceutical composition according to claim 18, wherein, if the pharmaceutical composition is a topical formulation, the topical formulation is administered topically.

27. The pharmaceutical composition according to claim 26, wherein the topical preparation is administered as a ointment, lotion, spray, ointment, cream, gel, or patch.

28. A method for preparing crystal form A according to any one of claims 1 to 14, a) Equation (I): A step of forming a first mixture containing a compound having and tetrahydrofuran (THF) at a first temperature of 50°C to 65°C; b) A step of cooling the first mixture to a second temperature of 35°C to 45°C; c) Adding one or more seed crystals of crystal form A before step d) or during step d) to form a second mixture; d) Adding methyl tert-butyl ether (MTBE) to form a third mixture; e) A step of cooling the third mixture to a third temperature of 25°C or below in order to form a fourth mixture containing precipitates; and f) To obtain crystalline form A, the process includes the step of isolating the precipitate from the fourth mixture, A method wherein steps c) and d) are each maintained at a second temperature.

29. The method according to claim 28, wherein the compound of formula (I) has a purity of 90% to 99%, or 95% to 99%.

30. The method according to claim 28, wherein the compound of formula (I) is present in the first mixture in an amount of 50 g / L to 150 g / L, 75 g / L to 125 g / L, 90 g / L to 110 g / L, or 100 g / L.

31. The method according to claim 28, wherein the volume ratio of THF to MTBE is 1:

2.

32. The method according to claim 28, wherein one or more seed crystals of crystal form A are added before step d).

33. The method according to claim 28, wherein the second mixture is further stirred for 20 to 120 minutes before step d); and step d) is carried out over 1 to 3 hours while maintaining the second temperature.

34. The method according to claim 28, wherein the first mixture is a solution; and the second mixture and / or third mixture are each a slurry.

35. The method according to claim 28, wherein step e) is carried out over 1 to 3 hours; and the fourth mixture is further stirred for 1 to 24 hours while maintaining the third temperature.

36. The method according to claim 28, wherein the first temperature is 55°C to 65°C; the second temperature is 40°C; and the third temperature is 20°C.

37. The method according to claim 28, wherein the precipitate is isolated by filtration and dried to obtain crystalline form A.

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