Crystalline forms and methods for producing them

Abstract

Provided herein are crystalline forms of the compound of formula (I) defined herein (Forms I, II, IIA, IIB, IIC, and IID). Also provided herein are methods for preparing crystalline Forms I, II, IIA, IIB, IIC, and IID, as well as pharmaceutical compositions and methods of treatment comprising crystalline Form I.

Description

[Technical Field]

[0001] This application claims priority to Australian Provisional Patent Application No. 2022903939, filed on 21 December 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates to crystalline forms of the compound of formula (I) as defined herein (Forms I, II, IIA, IIB, IIC, and IID). The present disclosure also relates to methods for preparing Forms I, II, IIA, IIB, IIC, and IID, as well as pharmaceutical compositions and methods of treatment comprising crystalline Form I. [Background technology]

[0003] Wound healing is a complex process by which skin and other organs and tissues repair themselves after injury. In some cases, wounds may heal slowly or not at all. Many factors affect wound healing. For example, the overall health and age of the injured person, diseases such as diabetes, other diseases that may affect circulation, the presence of infection, the presence of foreign bodies or necrotic tissue, and in some cases, medications can affect the rate of wound healing. In addition, in some wounds, imperfectly regulated wound healing can lead to fibrosis and excessive scar formation, resulting in scar tissue that is functionally and aesthetically inferior to normal tissue.

[0004] Much research has been done into improving wound healing and reducing scar tissue, but there is a need to identify agents that can promote wound healing.

[0005] EBC-1013 is a semi-synthetic small molecule currently being developed as a therapeutic agent. The compound targets various stages of the wound healing process and has been proposed for use in a variety of difficult-to-manage wounds, including chronic non-healing ulcers, traumatic acute wounds, and burns, as well as for reducing scarring and treating conditions such as bacterial infections, psoriasis, and eczema. EBC-1013 has the following potential: [ka] and is described, for example, in WO 2014 / 169356.

[0006] Research and development to identify new therapies for treating medical conditions such as wound healing is an extremely challenging task. Completing the process from new drug discovery to market approval typically takes more than a decade and is associated with a high failure rate. Novel pharmaceuticals have many requirements beyond efficacy and safety. For example, the active ingredient must be reproducibly available in high purity and be capable of large-scale production. The active ingredient must also be physically and chemically stable over time, including exposure to a variety of temperature and humidity conditions.

[0007] Many organic compounds exist in a variety of solid forms, including amorphous and crystalline forms, and some molecules may exist in many different crystalline forms (polymorphs). Polymorphs of a given compound may have different properties, for example, with respect to hygroscopicity, stability, solubility, and other properties. If a particular form of a given compound is unstable or metastable, difficulties may arise in the manufacture, storage, and even use of the compound.

[0008] Identifying solid forms of active pharmaceutical ingredients, and especially finding solid forms with desired properties, is often a challenging and unpredictable task: it is not clear how many polymorphs may exist, what their respective properties will be, or what synthetic processes may provide for obtaining the polymorphs. Summary of the Invention [Problem to be solved by the invention]

[0009] It would therefore be desirable to provide a solid form of compound EBC-1013 that has properties such as high stability and low hygroscopicity, as well as high purity and reproducible and scalable production.

[0010] It would also be desirable to provide a method for reproducibly providing such solid forms of EBC-1013 in high purity.

[0011] It would also be desirable to provide intermediate materials useful in such processes. [Means for solving the problem]

[0012] The present disclosure is based, at least in part, on the discovery of a polymorphic form of EBC-1013 (crystalline Form I) that possesses desirable properties for pharmaceutical use, such as stability and lack of hygroscopicity. Additionally, a method has been discovered that enhances the production of Form I of EBC-1013 by producing additional polymorphic forms (crystalline Forms II, IIA, IIB, IIC, or IID), which method reproducibly produces Form I material in high purity and good yield, and is amenable to scale-up.

[0013] In a first aspect, the compound of formula (I): [ka] There is provided a crystalline form (Form I) of the compound Here, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.3° 2θ as determined by X-ray powder diffraction.

[0014] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 8.9, 10.2, 11.0, 12.1, 13.1, 17.1, 18.3, and 18.5 degrees 2θ±0.3 2θ.

[0015] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 5.1, 6.5, 8.9, 9.7, 10.2, 11.0, 12.1, 13.1, 15.9, 17.1, 18.3, and 18.5 degrees 2θ±0.3 2θ.

[0016] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG.

[0017] In some embodiments, the crystalline form has a differential scanning calorimetry profile that exhibits an endothermic peak with an onset at 77°C ± 5°C and a peak at 87°C ± 5°C.

[0018] In some embodiments, the crystalline form exhibits a mass loss of 0.3% or less upon heating to 100° C. when subjected to thermogravimetric analysis.

[0019] In some embodiments, the crystalline form is substantially unsolvated.

[0020] In some embodiments, the compound of Formula (I) has a purity of at least 98% by weight.

[0021] In another embodiment, a compound of formula (I): [ka] There is provided a crystalline form (Form II) of the compound Here, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.6, 13.3, and 20.0 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction.

[0022] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.4, 9.4, 16.9, 17.9, 18.6, 20.9, and 22.5 degrees 2θ±0.2 2θ.

[0023] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.6, 7.4, 9.4, 13.3, 16.9, 17.9, 18.6, 20.0, 20.9, and 22.5 degrees 2θ±0.2 2θ.

[0024] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG.

[0025] In some embodiments, the crystalline form has a differential scanning calorimetry profile that exhibits an endothermic peak with an onset at 75°C ± 5°C and a peak at 81°C ± 5°C.

[0026] In some embodiments, the crystalline form exhibits a mass loss of at least 1.5% upon heating to 100° C. when subjected to thermogravimetric analysis.

[0027] In some embodiments, the crystalline form is a solvate.

[0028] In some embodiments, the solvate is an acetone solvate.

[0029] In some embodiments, the compound of Formula (I) has a purity of at least 97.5% by weight.

[0030] In another embodiment, a compound of formula (I): [ka] A crystalline form (Form IIA) of the compound of formula (I) is provided: wherein the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.7, 9.5, 13.3, 18.8, and 19.9 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction.

[0031] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.6, 11.3, 16.9, 17.8, 21.1, and 22.5 degrees 2θ±0.2 2θ.

[0032] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.7, 7.6, 9.5, 11.3, 13.3, 16.9, 17.8, 18.8, 19.9, 21.1, and 22.5 degrees 2θ±0.2 2θ.

[0033] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG.

[0034] In some embodiments, the crystalline form has a differential scanning calorimetry profile that exhibits an endothermic peak with an onset at 61°C ± 5°C and a peak at 68°C ± 5°C.

[0035] In some embodiments, the crystalline form exhibits a mass loss of at least 1.5% upon heating to 100° C. when subjected to thermogravimetric analysis.

[0036] In some embodiments, the crystalline form is a solvate.

[0037] In some embodiments, the solvate is an isopropanol solvate.

[0038] In some embodiments, the compound of Formula (I) has a purity of at least 97.5% by weight.

[0039] In another embodiment, a compound of formula (I): [ka] A crystalline form (Form IIB) of the compound of wherein the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.4, 9.3, 13.1, and 17.7 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction.

[0040] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.3, 11.1, 16.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.2 2θ.

[0041] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.4, 7.3, 9.3, 11.1, 13.1, 16.7, 17.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.2 2θ.

[0042] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG.

[0043] In some embodiments, the crystalline form is a solvate.

[0044] In some embodiments, the solvate is a tert-butanol solvate.

[0045] In some embodiments, the compound of Formula (I) has a purity of at least 97.5% by weight.

[0046] In another embodiment, a compound of formula (I): [ka] A crystalline form (Form IIC) of the compound of Here, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.5, 9.4, and 13.1 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction.

[0047] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.3, 11.3, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ±0.2 2θ.

[0048] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.5, 7.3, 9.4, 11.3, 13.1, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ±0.2 2θ.

[0049] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG.

[0050] In some embodiments, the crystalline form has a differential scanning calorimetry profile that exhibits an endothermic peak with an onset at 54°C ± 5°C and a peak at 62°C ± 5°C.

[0051] In some embodiments, the crystalline form exhibits a mass loss of at least 1.25% upon heating to 100° C. when subjected to thermogravimetric analysis.

[0052] In some embodiments, the crystalline form is a solvate.

[0053] In some embodiments, the solvate is a methyl ethyl ketone solvate.

[0054] In some embodiments, the compound of Formula (I) has a purity of at least 97.5% by weight.

[0055] In another embodiment, a compound of formula (I): [ka] A crystalline form (Form IID) of the compound of formula (I) is provided: Here, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.4, 9.3, and 13.1 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction.

[0056] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.3, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.2 2θ.

[0057] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.4, 7.3, 9.3, 13.1, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.2 2θ.

[0058] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG.

[0059] In some embodiments, the crystalline form is a solvate.

[0060] In some embodiments, the solvate is a tetrahydrofuran solvate.

[0061] In some embodiments, the compound of Formula (I) has a purity of at least 97.5% by weight.

[0062] In another aspect, there is a method for preparing crystalline Form II, IIA, IIB, IIC or IID of the compound of formula (I) as defined herein, comprising the steps of: slowly adding water to a solution of a compound of formula (I) in an organic solvent selected from the group consisting of acetone, isopropanol, methyl ethyl ketone, THF, and tert-butanol; forming a solid precipitate; separating the solid precipitate from the water:organic solvent mixture; A method is provided that includes:

[0063] In some embodiments, the crystalline form is Form II and the organic solvent is acetone.

[0064] In some embodiments, water is added to a solution of a compound of Formula (I) in an organic solvent at a temperature ranging from 20 to 30°C.

[0065] In some embodiments, following the addition of water, the mixture is cooled to a temperature in the range of 0-5°C.

[0066] In some embodiments, the mixture is cooled over a period ranging from about 90 minutes to 3 hours, optionally about 2 hours.

[0067] In some embodiments, following cooling, the mixture is held at the cooled temperature for a period ranging from about 90 minutes to 3 hours, optionally about 2 hours.

[0068] In some embodiments, the amount of organic solvent in which the compound of Formula (I) is dissolved ranges from 2 to 15 volumes, optionally about 10 volumes.

[0069] In some embodiments, the amount of water added to the solution of the compound of Formula (I) in the organic solvent ranges from 5 to 40 volumes, optionally about 10 volumes.

[0070] In some embodiments, the solid precipitate is separated from the water:organic solvent mixture by filtration.

[0071] In some embodiments, the separated solid precipitate is washed with water, optionally with an amount of water ranging from 1 to 5 volumes, optionally with about 2 volumes of water.

[0072] In another aspect, there is a method for preparing crystalline Form I of the compound of formula (I) defined herein, comprising the steps of: subjecting crystalline Form II, IIA, IIB, IIC or IID of the compound of formula (I) as defined herein to vacuum conditions at a temperature of up to 70°C to produce crystalline Form I. A method is provided that includes:

[0073] In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is obtained by practicing the methods provided herein.

[0074] In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions at a temperature ranging from 30 to 60°C.

[0075] In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions for a period ranging from 6 to 120 hours.

[0076] In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions for a period ranging from 12 to 18 hours.

[0077] In another aspect, there is provided a pharmaceutical composition comprising crystalline Form I of the compound of formula (I) as defined herein and a pharmaceutically acceptable excipient.

[0078] In another aspect, there is provided crystalline Form I of compound of formula (I) as defined herein, or a pharmaceutical composition comprising said crystalline form, for use in the treatment of wounds; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating bacterial infections; preventing or treating inflammatory skin disorders, such as psoriasis or eczema; treating ulcers; and / or treating burns.

[0079] In another aspect, there is provided a method for treating a wound in a subject; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating a bacterial infection; preventing or treating an inflammatory skin disorder, such as psoriasis or eczema; treating an ulcer; and / or treating a burn, said method comprising administering to a subject an effective amount of crystalline Form I of the compound of formula (I) as defined herein, or an effective amount of a pharmaceutical composition comprising said crystalline form.

[0080] In another aspect, there is provided the use of crystalline Form I of compound of formula (I) as defined herein for the manufacture of a medicament for the treatment of wounds; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating bacterial infections; preventing or treating inflammatory skin disorders, such as psoriasis or eczema; treating ulcers; and / or treating burns. [Brief explanation of the drawings]

[0081] [Figure 1] FIG. 1 shows a photographic image of a batch of amorphous EBC-1013. [Figure 2] FIG. 1 shows the X-ray powder diffraction pattern of a batch of amorphous EBC-1013. [Figure 3] FIG. 1 shows the results of DSC experiments performed on batches of amorphous EBC-1013. [Figure 4] FIG. 1 shows the results of TG experiments performed on batches of amorphous EBC-1013. [Figure 5] FIG. 1 shows the X-ray powder diffractogram of a batch of crystalline Form I of EBC-1013 overlaid with the diffractogram of a reference batch of crystalline Form I of EBC-1013. [Figure 6] FIG. 1 shows a photographic image of a batch of crystalline Form I of EBC-1013. [Figure 7] FIG. 1 shows the X-ray powder diffractogram of a batch of crystalline Form I of EBC-1013. [Figure 8] FIG. 1 shows the results of a DVS experiment performed on a batch of crystalline form I of EBC-1013. [Figure 9] FIG. 1 shows the results of TG / DSC experiments performed on a batch of crystalline form I of EBC-1013. [Figure 10] FIG. 1 shows a microscope image of crystalline Form I of crystalline EBC-1013. [Figure 11] FIG. 1 shows the X-ray powder diffraction pattern of a batch of crystalline Form II of EBC-1013. [Figure 12] FIG. 1 shows the results of a DVS experiment performed on a batch of crystalline Form II of EBC-1013 produced from acetone:water. [Figure 13] FIG. 1 shows the results of TG / DSC experiments performed on batches of crystalline Form II of EBC-1013 produced from acetone:water. [Figure 14-1] FIG. 1 shows an HPLC chromatogram of a batch of crystalline Form I of EBC-1013. [Figure 14-2] FIG. 1 shows an expanded region of the HPLC chromatogram of a batch of crystalline Form I of EBC-1013. [Figure 15]FIG. 1 shows the X-ray powder diffractogram of a batch of crystalline Form IIA of EBC-1013 prepared from isopropanol:water. [Figure 16] FIG. 1 shows the results of TG / DSC experiments performed on a batch of crystalline Form IIA of EBC-1013 produced from isopropanol:water. [Figure 17] FIG. 1 shows the X-ray powder diffractogram of a batch of crystalline Form IIB of EBC-1013 prepared from tert-butanol:water. [Figure 18] FIG. 1 shows the X-ray powder diffractogram of a batch of crystalline Form IIC of EBC-1013 prepared from methyl ethyl ketone:water. [Figure 19] FIG. 1 shows the results of TG / DSC experiments performed on a batch of crystalline form IIC of EBC-1013 produced from methyl ethyl ketone:water. [Figure 20] FIG. 1 shows the X-ray powder diffractogram of a batch of crystalline Form IID of EBC-1013 prepared from tetrahydrofuran:water. [Figure 21] FIG. 1 shows the X-ray powder diffraction pattern of a batch of crystalline form I of EBC-1013 produced from crystalline form IIA of EBC-1013. [Figure 22] FIG. 1 shows the X-ray powder diffraction pattern of a batch of crystalline form I of EBC-1013 produced from crystalline form IIB of EBC-1013. [Figure 23] FIG. 1 shows the X-ray powder diffraction pattern of a batch of crystalline form I of EBC-1013 produced from crystalline form IIC of EBC-1013. [Figure 24] FIG. 1 shows the X-ray powder diffraction pattern of a batch of crystalline form I of EBC-1013 produced from crystalline form IID of EBC-1013.

[0082] Detailed Description definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0083] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. For purposes of the present invention, the following terms are defined below.

[0084] This disclosure may refer to the contents of certain documents, the contents of which are incorporated herein by reference. In the event of conflicting teachings between the teachings of this disclosure and the contents of the documents, the teachings of this disclosure shall control.

[0085] Where a prior art document is referred to herein, it is to be understood that no admission is made that the document forms part of the common general knowledge in the art.

[0086] As used herein, the term "and / or," e.g., "X and / or Y," is understood to mean either "X and Y" or "X or Y," and is understood to explicitly endorse both meanings or either meaning.

[0087] As used herein, the term about refers to + / - 10% of the specified value unless specifically stated to the contrary.

[0088] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, a reference to a single step, composition of matter, group of steps, or group of compositions of matter is understood to include one and a plurality (i.e., one or more) of that step, composition of matter, group of steps, or group of compositions of matter. Thus, as used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, reference to "a" includes the singular and more than one, reference to "an" includes the singular and more than one, reference to "the" includes the singular and more than one, and so forth.

[0089] Unless specifically indicated otherwise, terms such as "first," "second," etc. are used herein merely as labels and are not intended to impose any order, position, or hierarchical requirements on the items to which they refer. Furthermore, a reference to a "second" item does not require or exclude the presence of lower-numbered items (e.g., the "first" item) and / or higher-numbered items (e.g., the "third" item).

[0090] As used herein, the phrase "at least one of," when used in conjunction with a list of items, means that different combinations of one or more of the listed items can be used and that only one of the items in the list may be required. An item may be a specific object, thing, or category. In other words, "at least one of" means that any combination of items or any number of items from the list may be used, but not necessarily all items in the list. For example, "at least one of item A, item B, and item C" may mean item A; item A and item B; item B; item A, item B, and item C; or item B and item C. In some cases, "at least one of item A, item B, and item C" may mean, but is not limited to, two items A, one item B, and ten items C; four items B and seven items C; or some other suitable combination.

[0091] As used herein, the word "comprise" and other forms of that word, such as "comprising" and "comprises," means including but not limited to, and is not intended to exclude, for example, other additives, ingredients, integers, or steps.

[0092] As used herein, the term "subject" refers to an organism susceptible to a disease or condition. For example, a subject can be an animal, a mammal, a primate, a livestock animal (e.g., sheep, cows, horses, pigs), a companion animal (e.g., dog, cat), or a laboratory animal (e.g., mouse, rabbit, rat, guinea pig, hamster). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0093] As used herein, the term "treatment" includes curing a disease or disorder and alleviating or reducing the symptoms or pathology associated with a disease or disorder. Treatment also includes slowing the progression of a disease or disorder.

[0094] As used herein, the term "prevention" includes prophylactic treatment and includes reducing the likelihood of contracting a disease or disorder or a symptom thereof.

[0095] Each embodiment of the present disclosure described herein shall apply mutatis mutandis to every other embodiment unless specifically stated otherwise or the context requires otherwise.

[0096] Compounds of formula (I) The present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form of the compound of formula (I).

[0097] The compound of formula (I) has the chemical name (1aR,1bR,1cS,2aR,3S,3aS,6aS,6bR,7R,8R,8aS)-3,3a,6b-trihydroxy-2a-(hydroxymethyl)-1,1,5,7-tetramethyl-4-oxo-1,1a,1b,1c,2a,3,3a,4,6a,6b,7,8-dodecahydro-8aH cyclopropa[5',6']benzo[1',2':7,8]azuleno[5,6-b]oxirene-8,8a-diyldihexanoate. This compound is also known as 12,13-dihexanoyl-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tiglian-3-one and EBC-1013. This compound has the molecular formula C 32 H 48 O 10 and has a molecular weight of 592.73 g / mol.

[0098] The compound of formula (I), its preparation, and / or therapeutic use are disclosed in WO 2014 / 169356, WO 2018 / 018097, WO 2018 / 170559, WO 2020 / 206504, and WO 2020 / 252535, the entire contents of each of which are incorporated herein by reference. The process described in WO 2014 / 169356 for preparing the compound of formula (I) produces an amorphous material.

[0099] Crystal form I In one embodiment, a compound of formula (I): [ka] There is provided a crystalline form (Form I) of the compound Here, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.3° 2θ as determined by X-ray powder diffraction.

[0100] Crystalline Form I of the compound of formula (I) can be prepared as a highly crystalline material. This crystalline form is generally not a solvate, has good stability, and is low in hygroscopicity. This crystalline form also has solubility properties suitable for use as an active pharmaceutical ingredient. This crystalline form can also be prepared in good yield and high purity.

[0101] Characterization of this crystalline form by X-ray powder diffraction revealed the presence of characteristic peaks at 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.3 2θ obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å.

[0102] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.2 2θ as determined by X-ray powder diffraction.

[0103] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.1 degrees 2θ as determined by X-ray powder diffraction.

[0104] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.3 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0105] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.2 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0106] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.1 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0107] Characterization of the crystalline form of Form I by X-ray powder diffraction also revealed the presence of additional characteristic peaks at 8.9, 10.2, 11.0, 12.1, 13.1, 17.1, 18.3, and 18.5 degrees 2θ±0.3 2θ obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0108] Thus, in some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 8.9, 10.2, 11.0, 12.1, 13.1, 17.1, 18.3, and 18.5 degrees 2θ±0.3 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0109] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 8.9, 10.2, 11.0, 12.1, 13.1, 17.1, 18.3, and 18.5 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0110] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 8.9, 10.2, 11.0, 12.1, 13.1, 17.1, 18.3, and 18.5 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0111] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 5.1, 6.5, 8.9, 9.7, 10.2, 11.0, 12.1, 13.1, 15.9, 17.1, 18.3, and 18.5 degrees 2θ±0.3 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0112] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 5.1, 6.5, 8.9, 9.7, 10.2, 11.0, 12.1, 13.1, 15.9, 17.1, 18.3, and 18.5 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0113] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 5.1, 6.5, 8.9, 9.7, 10.2, 11.0, 12.1, 13.1, 15.9, 17.1, 18.3, and 18.5 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0114] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 5.1, 6.5, 9.7, and 15.9 degrees 2θ ± 0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å), and further having six or more, or seven or more, or eight or more, or nine or more, or ten peaks selected from the group consisting of 8.9, 10.2, 12.1, 13.1, 13.6, 14.2, 17.1, 18.3, 18.5, and 19.2 degrees 2θ ± 0.1 2θ.

[0115] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 5.1, 6.5, 9.7, 13.1, 15.9, 18.3, and 18.5 degrees 2θ ± 0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å), and further having three or more, or four or more, or five or more, or six or more, or seven peaks selected from the group consisting of 8.9, 10.2, 12.1, 13.6, 14.2, 17.1, and 19.2 degrees 2θ ± 0.1 2θ.

[0116] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 5.1, 6.5, 8.9, 9.7, 10.2, 12.1, 13.1, 13.6, 14.2, 15.9, 17.1, 18.3, 18.5, and 19.2 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0117] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 7 (eg, obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å).

[0118] Exemplary conditions for characterization of the crystalline form of Form I by X-ray powder diffraction include those set forth in 2.9.33 of the European Pharmacopoeia 11.0 or in the United States Pharmacopoeia <941> Exemplary conditions for characterization of the Form I crystalline form include the use of a Bruker D8-Advance diffractometer using, for example, the following conditions: Cu tube anode, generator voltage 40 kV; generator current 40 mA; α1 wavelength 1.54056 Å; α2 wavelength 1.54439 Å; intensity ratio (α2 / α1) 0.5; spinner off; 2θ° angle range 3.00-50.00; 2θ° step size 0.02 2θ°; and / or time per step 0.5 seconds.

[0119] Characterization of a typical batch of Form I crystalline form by differential scanning calorimetry (DSC) revealed a DSC profile exhibiting an endothermic peak with an onset at approximately 77°C and a peak at 87°C.

[0120] Thus, in some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 77°C ± 15°C and a peak at 87°C ± 15°C.

[0121] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 77°C ± 10°C and a peak at 87°C ± 10°C.

[0122] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 77°C ± 5°C and a peak at 87°C ± 5°C.

[0123] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 77°C ± 2°C and a peak at 87°C ± 2°C.

[0124] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 77°C ± 1°C and a peak at 87°C ± 1°C.

[0125] Exemplary conditions for characterization of Form I crystalline form by DSC include those set forth in 2.2.34 of the European Pharmacopoeia 11.0 or in the United States Pharmacopoeia <891> Includes those listed in.

[0126] Exemplary conditions for characterization of the crystalline form of Form I by DSC include the use of a Mettler Toledo DSC1, e.g., Mettler software STAR eA thermal analysis system is used. For example, DSC analysis can be performed using a linear heating rate of 10°C / min, a sealed aluminum crucible with a pinhole and a volume of 40 μl, under a nitrogen flow (e.g., 50 ml / min), and recording the heat flow from 30 to 250°C using a 5 mg sample for the measurement.

[0127] Characterization of a typical batch of Form I crystalline form by thermogravimetric analysis (TG) revealed minimal mass loss during heating up to 100°C.

[0128] In some embodiments, the crystalline form exhibits a mass loss of 1.0% or less upon heating to 100° C. when subjected to thermogravimetric analysis.

[0129] In some embodiments, the crystalline form exhibits a mass loss of 0.5% or less upon heating to 100° C. when subjected to thermogravimetric analysis.

[0130] In some embodiments, the crystalline form exhibits a mass loss of 0.3% or less upon heating to 100° C. when subjected to thermogravimetric analysis.

[0131] Exemplary conditions for characterization of Form I crystalline form by TG include those described in 2.2.34 of the European Pharmacopoeia 11.0 or in the United States Pharmacopoeia <891> Includes those listed in.

[0132] Exemplary conditions for characterization of the crystalline form of Form I by TG (and also DSC) include the use of a Mettler-Toledo TGA / DSC3+ simultaneous system equipped with an autosampler. For example, TG (and DSC) analysis can be performed using a linear heating rate of 10°C / min, using a sealed aluminum crucible of 100 μl volume with a pinhole, under nitrogen flow (e.g., 150 ml / min), and recording heat flow from 30 to 250°C using a 10 mg sample per measurement.

[0133] Many organic compounds can form complexes in solvents in which they react or in which they precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." Solvates, such as hydrates, exist when a compound incorporates a solvent.

[0134] In some embodiments, the crystalline form contains 1.0% or less by weight of solvent (e.g., organic solvent and / or water). In some embodiments, the crystalline form contains 0.5% or less by weight of solvent (e.g., organic solvent and / or water). In some embodiments, the crystalline form contains 0.3% or less by weight of solvent (e.g., organic solvent and / or water). In some embodiments, the crystalline form contains 0.2% or less by weight of solvent (e.g., organic solvent and / or water). In some embodiments, the crystalline form contains 0.1% or less by weight of solvent (e.g., organic solvent and / or water).

[0135] In some embodiments, the crystalline form is unsolvated or substantially unsolvated (e.g., the crystalline form is substantially free of solvated water or organic solvents).

[0136] Characterization of a typical batch of Form I crystalline form by dynamic vapor sorption (DVS) analysis revealed that the batch exhibited relatively little water uptake when exposed to high relative humidity.

[0137] In some embodiments, the crystalline form exhibits a mass increase of less than 0.2% when exposed to 60% relative humidity conditions at 25°C.

[0138] In some embodiments, the crystalline form exhibits a mass increase of less than 0.1% when exposed to 60% relative humidity conditions at 25°C.

[0139] In some embodiments, the crystalline form exhibits a mass increase of less than 0.2% when exposed to 90% relative humidity conditions at 25°C.

[0140] In some embodiments, the crystalline form exhibits a mass increase of less than 0.1% when exposed to 90% relative humidity conditions at 25°C.

[0141] Exemplary conditions for characterization of Form I crystalline forms include those set forth in 2.9.39 of the European Pharmacopoeia 11.0 or in the United States Pharmacopoeia <1241> Includes those listed in.

[0142] Exemplary conditions for conducting DVS analysis and measuring mass gain upon exposure to high relative humidity conditions include performing the analysis at a fixed temperature of 25±0.1°C. As a preconditioning step, the sample can be dried under a continuous flow of dry air (relative humidity, RH<0.1%) for 6 hours to determine the dry mass. The relative humidity can then be increased from 0% to 90% RH (in 10% RH steps) and then similarly decreased to 0% RH until two complete adsorption / desorption cycles are completed. The instrument can be operated in dm / dt mode (mass change over time), and a fixed dm / dt value of 0.002% / min can be selected to reach equilibrium at each step. Experiments can be performed, for example, with a maximum dm / dt stage time of 3 hours and a minimum dm / dt stability duration of 1 hour. In the final step, the sample can be held under a dry air flow for 3 hours to allow the weight to equilibrate.

[0143] In some embodiments, measurements may be made using a DVS Intrinsic1 system (Surface Measurement Systems Ltd UK) and refined using, for example, Intrinsic Control Software and DVS Analysis Suite software.

[0144] The identification of Form I crystalline morphology and its method of manufacture allows for the preparation of highly pure material.

[0145] In some embodiments, crystalline Form I of the compound of Formula (I) has a purity of at least 97%, at least 97.5%, at least 98%, at least 98.5%, at least 99%, or at least 99.5% (e.g., as measured by HPLC).

[0146] Also provided herein are compounds of Formula (I) having a purity of at least 97%, at least 97.5%, at least 98%, at least 98.5%, at least 99%, or at least 99.5% (e.g., as measured by HPLC).

[0147] In some embodiments, crystalline Form I of the compound of Formula (I) is a crystalline form that is obtained or obtainable by slurrying amorphous compound of Formula (I) in a mixture of water:acetonitrile (e.g., 90:10 or 95:5 v / v) at room temperature, or that is obtained or obtainable by subjecting crystalline Form II of the compound of Formula (I) to vacuum conditions at a temperature of up to 70°C.

[0148] Crystalline Forms II, IIA, IIB, IIC and IID The present disclosure also provides crystalline forms II, IIA, IIB, IIC, and IID of the compound of formula (I). These crystalline forms are considered different pseudopolymorphs and have similar XRPD patterns, but are different solvates depending on the organic solvent used in their preparation.

[0149] Thus, in another embodiment, a compound of formula (I): [ka] There is provided a crystalline form (Form II) of the compound Here, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.6, 13.3, and 20.0 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

[0150] Crystalline Form II of the compound of formula (I) can be prepared as a highly crystalline material. This crystalline form can be prepared in good yield and high purity, and can also be used as an intermediate form of the compound of formula (I) that can be easily converted to crystalline Form I.

[0151] Characterization of this crystalline form by X-ray powder diffraction revealed the presence of characteristic peaks at 6.6, 13.3, and 20.0 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å.

[0152] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.6, 13.3, and 20.0 degrees 2θ±0.1 degrees 2θ as determined by X-ray powder diffraction.

[0153] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.6, 13.3, and 20.0 degrees 2θ±0.2 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0154] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.6, 13.3, and 20.0 degrees 2θ±0.1° 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0155] Characterization of the crystalline form of Form II by X-ray powder diffraction also revealed the presence of additional characteristic peaks at 7.4, 9.4, 16.9, 17.9, 18.6, 20.9, and 22.5 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0156] Thus, in some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.4, 9.4, 16.9, 17.9, 18.6, 20.9, and 22.5 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0157] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.4, 9.4, 16.9, 17.9, 18.6, 20.9, and 22.5 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0158] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.6, 7.4, 9.4, 13.3, 16.9, 17.9, 18.6, 20.0, 20.9, and 22.5 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0159] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.6, 7.4, 9.4, 13.3, 16.9, 17.9, 18.6, 20.0, 20.9, and 22.5 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0160] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.6, 13.3, and 20.0 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å), and further having three or more, or four or more, or five or more, or six or more, or seven peaks selected from the group consisting of 7.4, 9.4, 16.9, 17.9, 18.6, 20.9, and 22.5 degrees 2θ±0.1 2θ.

[0161] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 11 (eg, obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å).

[0162] Characterization of a typical batch of crystalline Form II prepared from acetone:water by differential scanning calorimetry (DSC) revealed a DSC profile exhibiting an endothermic peak with an onset at approximately 75°C and a peak at 81°C.

[0163] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 75°C ± 15°C and a peak at 81°C ± 15°C.

[0164] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 75°C ± 10°C and a peak at 81°C ± 10°C.

[0165] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 75°C ± 5°C and a peak at 81°C ± 5°C.

[0166] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 75°C ± 2°C and a peak at 81°C ± 2°C.

[0167] In some embodiments, the crystalline form has a DSC profile that exhibits an endothermic peak with an onset at 75°C ± 1°C and a peak at 81°C ± 1°C.

[0168] Characterization of a typical batch of crystalline Form II prepared from acetone:water by thermogravimetric analysis (TG) revealed that a weight loss of 2.22% occurred during heating to 100°C.

[0169] In some embodiments, the crystalline form exhibits a mass loss of at least 1.5% upon heating to 100° C. when subjected to thermogravimetric analysis.

[0170] In some embodiments, crystalline Form II is a solvate.

[0171] In some embodiments, crystalline Form II is an acetone solvate.

[0172] In some embodiments, crystalline Form II is a solvate having a molar ratio of compound of Formula (I) to solvent ranging from 4:1 to 2:1, or a molar ratio of compound of Formula (I) to solvent of about 3:1.

[0173] In another embodiment, a compound of formula (I): [ka] A crystalline form (Form IIA) of the compound of formula (I) is provided: wherein the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.7, 9.5, 13.3, 18.8, and 19.9 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

[0174] Crystalline Form IIA of the compound of formula (I) can be prepared as a highly crystalline material. This crystalline form can be prepared in good yield and high purity, and can also be used as an intermediate form of the compound of formula (I) that can be easily converted to crystalline Form I.

[0175] Characterization of this crystalline form by X-ray powder diffraction revealed the presence of characteristic peaks at 6.7, 9.5, 13.3, 18.8, and 19.9 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å.

[0176] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.7, 9.5, 13.3, 18.8, and 19.9 degrees 2θ±0.1 degrees 2θ as determined by X-ray powder diffraction.

[0177] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.7, 9.5, 13.3, 18.8, and 19.9 degrees 2θ±0.2 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0178] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.7, 9.5, 13.3, 18.8, and 19.9 degrees 2θ±0.1 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0179] Characterization of the crystalline form of Form IIA by X-ray powder diffraction also revealed the presence of additional characteristic peaks at 7.6, 11.3, 16.9, 17.8, 21.1, and 22.5 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0180] Thus, in some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.6, 11.3, 16.9, 17.8, 21.1, and 22.5 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0181] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.6, 11.3, 16.9, 17.8, 21.1, and 22.5 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0182] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.7, 7.6, 9.5, 11.3, 13.3, 16.9, 17.8, 18.8, 19.9, 21.1, and 22.5 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0183] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.7, 7.6, 9.5, 11.3, 13.3, 16.9, 17.8, 18.8, 19.9, 21.1, and 22.5 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0184] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.7, 9.5, 13.3, 18.8, and 19.9 degrees 2θ ± 0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å), and further having two or more, or three or more, or four or more, or five or more, or six peaks selected from the group consisting of 7.6, 11.3, 16.9, 17.8, 21.1, and 22.5 degrees 2θ ± 0.1 2θ.

[0185] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 15 (eg, obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å).

[0186] Characterization of a typical batch of crystalline Form IIA produced from isopropanol:water by differential scanning calorimetry (DSC) revealed a DSC profile exhibiting an endothermic peak with an onset at approximately 61°C and a peak at 68°C.

[0187] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 61°C ± 15°C and a peak at 68°C ± 15°C.

[0188] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 61°C ± 10°C and a peak at 68°C ± 10°C.

[0189] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 61°C ± 5°C and a peak at 68°C ± 5°C.

[0190] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 61°C ± 2°C and a peak at 68°C ± 2°C.

[0191] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 61°C ± 1°C and a peak at 68°C ± 1°C.

[0192] In some embodiments, the crystalline form exhibits a mass loss of at least 1.5% upon heating to 100° C. when subjected to thermogravimetric analysis.

[0193] In some embodiments, crystalline Form IIA is a solvate.

[0194] In some embodiments, crystalline Form IIA is an isopropanol solvate.

[0195] In some embodiments, crystalline Form IIA is a solvate having a molar ratio of compound of formula (I) to solvent ranging from 4:1 to 2:1, or a molar ratio of compound of formula (I) to solvent of about 3:1.

[0196] In another embodiment, a compound of formula (I): [ka] A crystalline form (Form IIB) of the compound of wherein the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.4, 9.3, 13.1, and 17.7 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

[0197] Crystalline Form IIB of the compound of formula (I) can be prepared as a highly crystalline material. This crystalline form can be prepared in good yield and high purity, and can also be used as an intermediate form of the compound of formula (I) that can be easily converted to crystalline Form I.

[0198] Characterization of this crystalline form by X-ray powder diffraction revealed the presence of characteristic peaks at 6.4, 9.3, 13.1, and 17.7 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å.

[0199] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.4, 9.3, 13.1, and 17.7 degrees 2θ±0.1 degrees 2θ as determined by X-ray powder diffraction.

[0200] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.4, 9.3, 13.1, and 17.7 degrees 2θ±0.2 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0201] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.4, 9.3, 13.1, and 17.7 degrees 2θ±0.1 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0202] Characterization of the crystalline form of Form IIB by X-ray powder diffraction also revealed the presence of additional characteristic peaks at 7.3, 11.1, 16.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å.

[0203] Thus, in some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.3, 11.1, 16.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0204] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.3, 11.1, 16.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0205] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.4, 7.3, 9.3, 11.1, 13.1, 16.7, 17.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0206] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.4, 7.3, 9.3, 11.1, 13.1, 16.7, 17.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0207] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.4, 9.3, 13.1, and 17.7 degrees 2θ ± 0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å), and further having 7 or more, or 8 or more, or 9 or more, or 10 or more, or 11 or more, or 12 peaks selected from the group consisting of 7.3, 11.1, 16.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ ± 0.1 2θ.

[0208] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 17 (eg, obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å).

[0209] In some embodiments, crystalline form IIB is a solvate.

[0210] In some embodiments, crystalline Form IIB is a tert-butanol solvate.

[0211] In some embodiments, crystalline Form IIB is a solvate having a molar ratio of compound of Formula (I) to solvent ranging from 4:1 to 2:1, or a molar ratio of compound of Formula (I) to solvent of about 3:1.

[0212] In another embodiment, a compound of formula (I): [ka] A crystalline form (Form IIC) of the compound of wherein the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.5, 9.4, and 13.1 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

[0213] Crystalline Form IIC of the compound of formula (I) can be prepared as a highly crystalline material. This crystalline form can be prepared in good yield and high purity, and can also be used as an intermediate form of the compound of formula (I) that can be easily converted to crystalline Form I.

[0214] Characterization of this crystalline form by X-ray powder diffraction revealed the presence of characteristic peaks at 6.5, 9.4, and 13.1 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å.

[0215] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.5, 9.4, and 13.1 degrees 2θ±0.1 degrees 2θ as determined by X-ray powder diffraction.

[0216] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.5, 9.4, and 13.1 degrees 2θ±0.2 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0217] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.5, 9.4, and 13.1 degrees 2θ±0.1 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0218] Characterization of the crystalline form of Form IIC by X-ray powder diffraction also revealed the presence of additional characteristic peaks at 7.3, 11.3, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0219] Thus, in some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.3, 11.3, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0220] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.3, 11.3, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0221] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.7, 7.6, 9.5, 11.3, 13.3, 16.9, 17.8, 18.8, 19.9, 21.1, and 22.5 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0222] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.5, 7.3, 9.4, 11.3, 13.1, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0223] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.5, 9.4, and 13.1 degrees 2θ ± 0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å), and further having two or more, or three or more, or four or more, or five or more, or six peaks selected from the group consisting of 7.3, 11.3, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ ± 0.1 2θ.

[0224] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 18 (eg, obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å).

[0225] Characterization of a typical batch of crystalline Form IIC produced from methyl ethyl ketone:water by differential scanning calorimetry (DSC) revealed a DSC profile exhibiting an endothermic peak with an onset at approximately 54°C and a peak at 62°C.

[0226] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 54°C ± 15°C and a peak at 62°C ± 15°C.

[0227] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 54°C ± 10°C and a peak at 62°C ± 10°C.

[0228] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 54°C ± 5°C and a peak at 62°C ± 5°C.

[0229] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 54°C ± 2°C and a peak at 62°C ± 2°C.

[0230] In some embodiments, the crystalline form exhibits a DSC profile that exhibits an endothermic peak with an onset at 54°C ± 1°C and a peak at 62°C ± 1°C.

[0231] In some embodiments, the crystalline form exhibits a mass loss of at least 1.25% upon heating to 100° C. when subjected to thermogravimetric analysis.

[0232] In some embodiments, crystalline form IIC is a solvate.

[0233] In some embodiments, crystalline form IIC is a methyl ethyl ketone solvate.

[0234] In some embodiments, crystalline Form IIC is a solvate having a molar ratio of compound of Formula (I) to solvent ranging from 4:1 to 2:1, or a molar ratio of compound of Formula (I) to solvent of about 3:1.

[0235] In another embodiment, a compound of formula (I): [ka] A crystalline form (Form IID) of the compound of formula (I) is provided: Here, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at 6.4, 9.3, and 13.1 degrees 2θ±0.2° 2θ as determined by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

[0236] Crystalline Form IID of the compound of formula (I) can be prepared as a highly crystalline material. This crystalline form can be prepared in good yield and high purity, and can also be used as an intermediate form of the compound of formula (I) that can be easily converted to crystalline Form I.

[0237] Characterization of this crystalline form by X-ray powder diffraction revealed the presence of characteristic peaks at 6.4, 9.3, and 13.1 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å.

[0238] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.4, 9.3, and 13.1 degrees 2θ±0.1 degrees 2θ as determined by X-ray powder diffraction.

[0239] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.4, 9.3, and 13.1 degrees 2θ±0.2 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0240] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.4, 9.3, and 13.1 degrees 2θ±0.1 2θ, respectively, as measured by X-ray powder diffraction obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å.

[0241] Characterization of the crystalline form of Form IID by X-ray powder diffraction also revealed the presence of additional characteristic peaks at 7.3, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.2 2θ obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å.

[0242] Thus, in some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.3, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0243] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at any of 7.3, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0244] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.4, 7.3, 9.3, 13.1, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0245] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.4, 7.3, 9.3, 13.1, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.1 2θ (e.g., obtained using copper wavelengths λ1 and λ2=1.54056 Å and 1.54439 Å).

[0246] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.4, 9.3, and 13.1 degrees 2θ ± 0.2 2θ (e.g., obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å), and further having four or more, or five or more, or six or more, or seven or more, or eight or more, or nine peaks selected from the group consisting of 7.3, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ ± 0.1 2θ.

[0247] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern (eg, obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å) substantially as shown in FIG. 20.

[0248] In some embodiments, crystalline form IID is a solvate.

[0249] In some embodiments, crystalline form IID is a tetrahydrofuran solvate.

[0250] In some embodiments, crystalline Form IID is a solvate having a molar ratio of compound of Formula (I) to solvent ranging from 4:1 to 2:1, or a molar ratio of compound of Formula (I) to solvent of about 3:1.

[0251] The identification of crystalline forms II, IIA, IIB, IIC and IID and their methods of preparation have enabled the preparation of highly pure materials.

[0252] In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID of the compound of Formula (I) has a purity of at least 97%, at least 97.5%, at least 98%, at least 98.5%, at least 99%, or at least 99.5% (e.g., as measured by HPLC).

[0253] Also provided herein are compounds of Formula (I) having a purity of at least 97%, at least 97.5%, at least 98%, at least 98.5%, at least 99%, or at least 99.5% (e.g., as measured by HPLC).

[0254] In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID of the compound of Formula (I) is a crystalline form obtained or obtainable by slowly adding water to a solution of the compound of Formula (I) (e.g., an amorphous compound of Formula (I)) in an organic solvent selected from the group consisting of acetone, isopropanol, methyl ethyl ketone, THF, and tert-butanol, forming a solid precipitate, and separating the solid precipitate from the water:organic solvent mixture. In some embodiments, the organic solvent is acetone, and the crystalline form is Form II.

[0255] Exemplary conditions for characterization of the crystalline forms II, IIA, IIB, IIC, and IID by X-ray powder diffraction include those set forth in 2.9.33 of the European Pharmacopoeia 11.0, or 2.9.33 of the United States Pharmacopoeia <941> Exemplary conditions for characterization of crystalline forms II, IIA, IIB, IIC, and IID include the use of a Bruker D8-Advance diffractometer using, for example, the following conditions: Cu tube anode, generator voltage 40 kV; generator current 40 mA; α1 wavelength 1.54056 Å; α2 wavelength 1.54439 Å; intensity ratio (α2 / α1) 0.5; spinner off; 2θ° angle range 3.00-50.00; 2θ° step size 0.02 2θ°; and / or time per step 0.5 seconds.

[0256] Exemplary conditions for characterization of the crystalline forms II, IIA, IIB, IIC, and IID by DSC include those set forth in 2.2.34 of the European Pharmacopoeia 11.0 or in the United States Pharmacopoeia <891> Includes those listed in.

[0257] Exemplary conditions for characterization of crystalline forms II, IIA, IIB, IIC, and IID by DSC include the use of a Mettler Toledo DSC1, e.g., Mettler software STAR e A thermal analysis system is used. For example, DSC analysis can be performed using a linear heating rate of 10°C / min, a sealed aluminum crucible with a pinhole and a volume of 40 μl, under a nitrogen flow (e.g., 50 ml / min), and recording the heat flow from 30 to 250°C using a 5 mg sample for the measurement.

[0258] Exemplary conditions for characterization of the crystalline forms II, IIA, IIB, IIC, and IID by TG include those set forth in 2.2.34 of the European Pharmacopoeia 11.0 or 2.2.34 of the United States Pharmacopoeia <891> Includes those listed in.

[0259] Exemplary conditions for characterization of crystalline Forms II, IIA, IIB, IIC, and IID by TG (and also DSC) include the use of a Mettler-Toledo TGA / DSC3+ simultaneous system equipped with an autosampler. For example, TG (and DSC) analysis can be performed using a linear heating rate of 10°C / min, using a sealed aluminum crucible with a pinhole and a volume of 100 μl, under a nitrogen flow (e.g., 150 ml / min), and recording the heat flow from 30 to 250°C using a 10 mg sample for the measurement.

[0260] Preparation of Forms I, II, IIA, IIB, IIC, and IID In another aspect, there is a method for preparing crystalline Form II, IIA, IIB, IIC or IID of the compound of formula (I) as defined herein, comprising the steps of: slowly adding water to a solution of a compound of formula (I) in an organic solvent selected from the group consisting of acetone, isopropanol, methyl ethyl ketone, THF, and tert-butanol; forming a solid precipitate; separating the solid precipitate from the water:organic solvent mixture; A method is provided that includes:

[0261] The method has been found to be scalable and reproducible to provide Form II, IIA, IIB, IIC or IID crystalline forms in good yield and high purity.

[0262] The production of crystalline Form II, IIA, IIB, IIC or IID can be carried out, for example, in ambient atmosphere or in an inert atmosphere such as nitrogen or argon.

[0263] The organic solvent is selected from the group consisting of acetone, isopropanol, methyl ethyl ketone, THF, and tert-butanol. The resulting crystalline form (II, IIA, IIB, IIC, or IID) depends on the organic solvent used.

[0264] In some embodiments, the organic solvent is acetone and the resulting crystalline form is Form II.

[0265] In some embodiments, the organic solvent is isopropanol and the resulting crystalline form is Form IIA.

[0266] In some embodiments, the organic solvent is tert-butanol and the resulting crystalline form is Form IIB.

[0267] In some embodiments, the organic solvent is methyl ethyl ketone and the crystalline form is Form IIC.

[0268] In some embodiments, the organic solvent is tetrahydrofuran and the crystalline form is Form IID.

[0269] In some embodiments, the volume:volume ratio of organic solvent:water ranges from 2:1 to 1:2, or is about 1:1.

[0270] In some embodiments, the amount of organic solvent in which the compound of Formula (I) is dissolved ranges from 2 to 15 volumes, or from 5 to 15 volumes, and optionally is about 10 volumes.

[0271] In some embodiments, the amount of water added to the solution of the compound of Formula (I) in the organic solvent ranges from 5 to 40 volumes, or from 5 to 15 volumes, and optionally is about 10 volumes.

[0272] As referred to herein, the term "volume" refers to the volume in mL of organic solvent or water relative to the amount in g of the compound of formula (I). For example, for a 1 g batch of the compound of formula (I), the use of 10 volumes of acetone refers to the use of 10 mL of acetone.

[0273] The compound of Formula (I) can be dissolved in the organic solvent at any suitable temperature, for example, ambient temperature or elevated temperature. In some embodiments, the compound of Formula (I) is dissolved in the organic solvent at a temperature ranging from 20 to 30°C.

[0274] In some embodiments, the mixture comprising the organic solvent and the compound of Formula (I) is agitated or stirred, for example, during and following the addition of water.

[0275] Water is added gradually to a mixture of a compound of Formula (I) and an organic solvent. In some embodiments, water is added dropwise. In some embodiments, water is added in equal portions periodically. In some embodiments, water is added over a period ranging from 10 minutes to 2 hours, or from 10 minutes to 1 hour, or from 10 minutes to 30 minutes, or from 30 minutes to 2 hours, or from 1 hour to several hours.

[0276] Water can be added to a mixture of the compound of Formula (I) and the organic solvent at any suitable temperature, for example, ambient temperature. In some embodiments, water is added to a solution of the compound of Formula (I) in the organic solvent at a temperature ranging from 20 to 30°C.

[0277] If desired, production of crystalline Form II, IIA, IIB, IIC or IID may be achieved by seeding, for example by adding a small amount of crystalline Form II, IIA, IIB, IIC or IID.

[0278] A solid precipitate is formed, typically following the addition of water and aging the mixture for a suitable period of time, optionally with stirring / agitation, and optionally with cooling.

[0279] In some embodiments, following the addition of water, the mixture is stirred for a period ranging from 1 to 96 hours, 1 to 72 hours, 1 to 24 hours, 1 to 12 hours, 1 to 6 hours, or 1 to 4 hours, or for about 1 hour, about 2 hours, about 3 hours, or about 4 hours.

[0280] In some embodiments, following the addition of water, the mixture is cooled to a temperature in the range of, for example, 0-10°C or 0-5°C, or about 5°C.

[0281] In some embodiments, the mixture is cooled over a period ranging from 1 to 6 hours, or from about 90 minutes to 3 hours, or about 2 hours.

[0282] In some embodiments, following cooling, the mixture is held (e.g., with stirring) at the cooled temperature for a period ranging from 1 to 96 hours, 1 to 72 hours, 1 to 24 hours, 1 to 12 hours, 1 to 6 hours, 1 to 4 hours, or about 90 minutes to 3 hours, or about 1 hour, about 2 hours, about 3 hours, or about 4 hours.

[0283] The solid precipitate is separated from the liquid component, for example, by decantation or filtration. In some embodiments, the solid precipitate is separated from the water:organic solvent mixture by filtration.

[0284] If desired, the separated solid precipitate can be washed, for example, with water. A single washing step or multiple washing steps (e.g., two or three times) can be performed. In some embodiments, the separated solid precipitate is washed with water, optionally in an amount ranging from 1 to 5 volumes, optionally about 2 volumes.

[0285] It has also been found that crystalline Form I of the compound of formula (I) can be produced from each of crystalline Forms II, IIA, IIB, IIC and IID. Accordingly, in another aspect, there is provided a process for preparing crystalline Form I of the compound of formula (I) as defined herein, comprising: subjecting crystalline Form II, IIA, IIB, IIC or IID of the compound of formula (I) as defined herein to vacuum conditions at a temperature of up to 70°C to produce crystalline Form I. A method is provided that includes:

[0286] In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID used in the methods is obtained by carrying out the methods for making crystalline Form II, IIA, IIB, IIC, or IID defined herein.

[0287] Crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions at a temperature of up to 70°C. In some embodiments, the temperature is up to 60°C, or up to 50°C, or up to 40°C. In some embodiments, elevated temperature conditions are used. In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions at a temperature in the range of 30-60°C. In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions at a temperature in the range of 30-35°C.

[0288] The vacuum conditions can be applied for any suitable period of time to effect conversion to crystalline Form I. In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions for a period ranging from 6 to 240 hours. In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions for a period ranging from 6 to 120 hours. In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions for a period ranging from 6 to 72 hours. In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions for a period ranging from 6 to 24 hours. In some embodiments, crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions for a period ranging from 12 to 18 hours.

[0289] Any suitable vacuum pressure can be applied to crystalline Form II, IIA, IIB, IIC, or IID, for example, a vacuum pressure in the range of 0 to 100 mbar, or 0 to 50 mbar, or 0.1 to 50 mbar, or 0.1 to 25 mbar.

[0290] Although less preferred, it is also possible to produce crystalline Form I of the compound of formula (I) directly from an amorphous compound of formula (I). Accordingly, a method for preparing crystalline Form I of the compound of formula (I) as defined herein is provided, which comprises the steps of: slurrying a compound of formula (I) in a mixture of acetone and water; separating the solid material from the acetone:water mixture; Also provided is a method comprising:

[0291] In some embodiments, the volume:volume ratio of acetone to water ranges from 95:5 to 90:10.

[0292] In some embodiments, the slurrying step is carried out for a period ranging from 2 to 10 days.

[0293] In some embodiments, the slurrying step is carried out at ambient temperature.

[0294] Pharmaceutical Composition In some embodiments, crystalline Form I of the compound of formula (I) is provided in the form of a pharmaceutical composition, e.g., for use in treating a disease or disorder as defined herein.

[0295] Accordingly, there is also provided a pharmaceutical composition comprising crystalline Form I of the compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0296] Suitably, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or acceptable excipients. By "pharmaceutically acceptable excipient" is meant a solid or liquid filler, diluent or encapsulating substance, or other pharmaceutically acceptable excipient, such as a binder, disintegrant, lubricant, anti-caking agent, colorant, preservative, antioxidant, buffer or pH adjuster, that can be used safely.

[0297] The pharmaceutical compositions described herein can be provided in unit dosage form. As used herein, "unit dosage form" refers to a composition in a form containing a sufficient amount of a compound or salt to provide a single dose or sub-dose of the compound or salt. Examples of unit dosage forms include pills, capsules, caplets, tablets, sachets, etc.

[0298] The pharmaceutical compositions can be formulated for delivery by any suitable route of administration, such as, for example, topical, rectal, parenteral, sublingual, buccal, intravenous, intraarticular, intramuscular, intradermal, subcutaneous, inhalation, intraocular, intraperitoneal, intracerebroventricular, transdermal, etc.

[0299] The compositions may be prepared according to conventional methods, for example, dissolving, suspending, mixing, granulating or coating methods.

[0300] Examples of dosage forms include tablets, capsules, caplets, dispersions, suspensions, injectables, solutions, syrups, troches, capsules, suppositories, aerosols, transdermal patches, impregnated (occlusive) dressings, creams, gels, etc. These dosage forms may also include injection or implantation devices specially designed or modified to achieve controlled release of the pharmaceutical composition.

[0301] Controlled release of therapeutic agents can be achieved by coating the therapeutic agent with hydrophobic polymers such as acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids, and certain cellulose derivatives such as hydroxypropylmethylcellulose. Controlled release can also be affected by the use of other polymer matrices, liposomes, and / or microspheres.

[0302] Depending on the particular route of administration, various carriers known in the art can be used. For example, these carriers or excipients can be selected from the group including sugars, starches, cellulose and its derivatives, malt, gelatin or other gelling agents, talc, calcium sulfate, vegetable oils, synthetic oils, alcohols and / or polyols, alginic acid, phosphate buffers, emulsifiers, isotonic saline, and pyrogen-free water.

[0303] The compositions of the present invention can incorporate pharmaceutically acceptable carriers and acceptable carriers suitable for, for example, systemic administration.

[0304] Pharmaceutical compositions of the present disclosure suitable for administration can be present, for example, in discrete units such as syringes, vials, tubes, capsules, sachets or tablets, each containing a predetermined amount of crystalline Form I of the compound of formula (I); as a powder or granules; or as a solution or suspension in an aqueous liquid, a cyclodextrin solution, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion; or as a solution or suspension in a cream or gel; or as a suspension of microparticles or nanoparticles, including, but not limited to, silica or polylactic acid microparticles or nanoparticles.

[0305] Such compositions can be prepared by any of the methods of pharmacy, including, for example, the step of bringing into association Form I of the compound of formula (I) with the carrier, which constitutes one or more necessary ingredients. In most cases, the compositions are prepared by uniformly and intimately admixing the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired dosage form.

[0306] In powders, the carrier may be, for example, a finely divided solid, which is in a mixture with the finely divided active ingredient.

[0307] In tablets, the active ingredient can be mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

[0308] Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, etc. The term "preparation" is intended to include formulating the active compound with an encapsulating material as a carrier to provide an encapsulated form, in which the active ingredient is surrounded by the carrier, whether or not the active ingredient is accompanied by a carrier, thereby uniting the active ingredient with the carrier. Similarly, cachets and lozenges are included.

[0309] Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0310] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is then dispersed homogeneously therein, for example, by stirring. The molten homogeneous mixture is then poured into appropriate sized molds and allowed to cool and solidify.

[0311] Formulations suitable for vaginal administration may be presented as, for example, pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0312] Liquid preparations include solutions, suspensions, and emulsions, such as water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be formulated as solutions in aqueous 1,2-propanediol, dimethyl sulfoxide (DMSO), aqueous solutions of gamma cyclodextrin or 2-hydroxypropyl-beta-cyclodextrin, saline, or polyethylene glycol, with or without buffer. The preferred pH range is 3.5 to 4.5. Suitable buffers buffer the preparation at a pH of 3.5 to 4.5 and include, but are not limited to, acetate and citrate buffers.

[0313] Crystalline Form I of the compound of formula (I) can be formulated, for example, for parenteral administration (e.g., injection, e.g., bolus injection or continuous infusion), and can be provided in unit dosage form in ampoules, pre-filled syringes, small-volume injections, or multi-dose containers with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions, for example, in oily or aqueous vehicles, and can contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents. Alternatively, the active ingredient can be in powder form, obtained by aseptic isolation of a sterile solid or by lyophilization from solution, and can be reconstituted with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0314] Aqueous solutions suitable for oral use can be prepared, for example, by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and / or thickening agents as desired.

[0315] Aqueous suspensions suitable for oral use can be prepared, for example, by dispersing the finely divided active ingredient in water with a viscous material, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agent.

[0316] Also included are solid form preparations intended to be converted immediately before use into liquid form preparations for oral administration (liquid preparations). Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0317] For topical administration to the epidermis or other organs, crystalline Form I of the compound of formula (I) can be formulated, for example, as a gel, ointment, emulsion, paste, cream, or lotion, or as a transdermal patch. Gels can be prepared, for example, by adding a suitable thickening agent to an aqueous / alcoholic composition of the active compound. Suitable thickening or gelling agents are known in the art, such as polyvinyl carboxy polymer, Carbomer 940. Ointments and creams can be formulated, for example, with an aqueous or oily base to which a suitable thickening and / or gelling agent has been added. Lotions can be formulated, for example, with an aqueous or oily base and may also contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents, thickening agents, or coloring agents.

[0318] Formulations suitable for topical administration may also include solutions or suspensions that can be administered topically in the form of baths or soaks or sprays, which, when properly applied, can treat skin irritations, insect bites, and foot wounds.

[0319] Compositions suitable for topical administration in the mouth include lozenges, in which the active ingredient is contained in a flavored base, usually sucrose and acacia or tragacanth; pastilles, in which the active ingredient is contained in an inert base, for example, gelatin and glycerin or sucrose and acacia; and mouthwashes, in which the active ingredient is contained in a suitable liquid carrier.

[0320] The solution or suspension can be applied directly to the nasal cavity in a conventional manner, for example, using a dropper, pipette, or spray. These formulations can be provided in single-dose or multi-dose form. In the case of a dropper or pipette, this application can be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this application can be achieved, for example, by using a metered atomizing spray pump. To improve delivery and retention in the nasal cavity, the active ingredient can be encapsulated with cyclodextrin or formulated with agents expected to enhance delivery and retention to the nasal mucosa.

[0321] Administration to the respiratory tract can also be achieved, for example, by aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant, for example, chlorofluorocarbons (CFCs), dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol can also suitably contain a surfactant, such as lecithin. The amount of drug administered can be controlled by providing a metered valve.

[0322] Alternatively, the active ingredient can be provided, for example, in the form of a dry powder, such as a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives, e.g., hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP).

[0323] Suitably, in some embodiments, the powder carrier is capable of forming a gel in the nasal cavity. The powder composition may, for example, be presented in unit dose form in, for example, capsules or cartridges of gelatin or blister packs from which the powder may be administered by means of an inhaler.

[0324] In formulations intended for administration to the respiratory tract, including intranasal formulations, the active ingredient may, for example, be provided in a small average particle size, for example of the order of 1 to 10 microns or less, which may be obtained by methods known in the art, for example by micronization.

[0325] Techniques and compositions for producing the dosage forms described herein are described in the following documents, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004). Pharmaceutical formulation techniques may also be used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 23rd Ed., Elsevier (2020), or Remington's Pharmaceutical Sciences, 21st Edition, Mack Publishing, 2005. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, the entire contents of each of which are incorporated herein by reference.

[0326] The crystalline forms and compositions described herein may be provided in a suitable container and labeled for treatment of an indicated condition.

[0327] As described below, crystalline Form I of the compound of formula (I) can be administered in combination with additional active ingredients. In some embodiments, a pharmaceutical composition comprising crystalline Form I of the compound of formula (I) can include an additional therapeutic agent.

[0328] Treatment methods and uses As described herein, EBC-1013 (compound of formula (I)) is proposed for use in treating a variety of difficult-to-manage wounds, including chronic non-healing ulcers, traumatic acute wounds, and burns, reducing scarring, and treating conditions such as bacterial infections, psoriasis, and eczema. Accordingly, the crystalline forms of the present disclosure are used in the therapy of such conditions.

[0329] In another aspect, there is provided crystalline Form I of the compound of formula (I) as defined herein for use in therapy.

[0330] In another aspect, there is provided crystalline Form I of compound of formula (I) as defined herein, or a pharmaceutical composition comprising said crystalline form, for use in the treatment of wounds; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating bacterial infections; preventing or treating inflammatory skin disorders, such as psoriasis or eczema; treating ulcers; and / or treating burns.

[0331] In another aspect, there is provided a method for treating wounds; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating bacterial infections; preventing or treating inflammatory skin disorders, such as psoriasis or eczema; treating ulcers; and / or treating burns, the method comprising administering to a subject an effective amount of crystalline Form I of the compound of formula (I) as defined herein, or an effective amount of a pharmaceutical composition comprising said crystalline form.

[0332] In another aspect, there is provided the use of crystalline Form I of compound of formula (I) as defined herein for the manufacture of a medicament for the treatment of wounds; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating bacterial infections; preventing or treating inflammatory skin disorders, such as psoriasis or eczema; treating ulcers; and / or treating burns.

[0333] Any suitable route of administration can be employed to provide the crystalline forms of the present disclosure, or pharmaceutical compositions comprising the crystalline forms, to a human or non-human patient, such as oral, topical, rectal, parenteral, sublingual, buccal, intravenous, intraarticular, intramuscular, intradermal, subcutaneous, inhalation, intraocular, intraperitoneal, intracerebroventricular, transdermal, etc.

[0334] The subject of treatment can be any subject, including mammals, birds, fish, and reptiles. In some embodiments, the subject is a human, a companion animal, a laboratory animal, a farm or work animal, a domestic bird, a racing animal, or a captive wild animal such as those kept in a zoo. Examples of suitable subjects include, but are not limited to, humans, dogs, cats, rabbits, hamsters, guinea pigs, mice, rats, horses, cows, sheep, goats, deer, pigs, monkeys, marsupials, chickens, geese, canaries, budgerigars, crocodiles, snakes, lizards, and the like. In certain embodiments, the subject is a mammalian subject, such as a human, dog, cat, horse, cow, sheep, goat, pig, deer, rat, guinea pig, kangaroo, rabbit, or mouse.

[0335] In some embodiments, the subject is a human. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult.

[0336] In some other embodiments, the subject may be a non-human, such as a non-human animal or mammal.

[0337] By "effective amount" is meant the amount necessary to at least partially achieve the desired response, e.g., in the case of wound healing, the amount necessary to at least partially initiate wound healing or at least partially increase the rate of wound healing. Such amounts will vary depending on the health and physical condition of the individual being treated, the taxonomic group of the individual being treated, the formulation of the composition, an evaluation of the medical situation, and other relevant factors.

[0338] Any suitable dosage of crystalline Form I, or a pharmaceutical composition comprising said crystalline form, can be used.

[0339] Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, the therapy can be administered once daily or multiple times daily, or less frequently, such as once monthly or at other suitable time intervals.

[0340] In some embodiments, the crystalline form or a pharmaceutical composition comprising the crystalline form is used to treat wounds or promote wound healing.

[0341] As used herein, the term "wound" refers to a physical disruption of the continuity or integrity of a tissue structure. Wounds may be acute or chronic and may include cuts and lacerations, surgical incisions or wounds, puncture wounds, abrasions, scratches, pressure wounds, abrasions, friction wounds, decubitus ulcers (e.g., pressure ulcers or bed sores); thermal wounds (burns from cold sources), chemical wounds (e.g., burns from acids or alkalis), or pathogenic infections (e.g., viral, bacterial, or fungal), such as open or closed boils, skin rashes, age spots and acne, ulcers, chronic wounds (e.g., wounds associated with diabetes, e.g., leg and foot ulcers, venous leg ulcers and pressure ulcers), skin transplant / graft donor and recipient sites, immune response conditions, e.g., psoriasis and eczema, gastric or intestinal ulcers, intraoral wounds, e.g., oral ulcers, damaged cartilage or bone, amputation wounds, and corneal lesions.

[0342] As used herein, the term "chronic wound" refers to a wound that does not heal within the normal healing period in an otherwise healthy subject. A chronic wound can be a wound that does not heal due to the subject's health condition, for example, when the subject suffers from poor circulation or a disease, such as diabetes, or when the subject is taking a drug that inhibits the normal healing process. Healing can also be impaired by the presence of an infection, such as a bacterial infection, a fungal infection, or a parasitic infection. In some cases, a chronic wound may remain unhealed for weeks, months, or even years. Examples of chronic wounds include, but are not limited to, diabetic ulcers, pressure ulcers, and tropical ulcers.

[0343] The term "promoting wound healing" as used herein refers to improved wound healing compared to that observed in an untreated wound. Promoting wound healing includes increasing the rate at which the wound heals, e.g., the wound may heal at a rate that is hours, days, or weeks higher than if the wound were left untreated. Promoting wound healing may also include reducing scar tissue in a healing or healed wound compared to that expected if the wound were left untreated.

[0344] The term "wound healing" refers to the partial or total restoration of tissue integrity.

[0345] The wound to be healed can be in any organ or tissue, including an internal organ or tissue, or an external tissue, such as skin. The wound can be the result of an injury, bite, or burn. The organ or tissue can be any one or more of the following: skin, muscle, liver, kidney, lung, heart, pancreas, spleen, stomach, intestine, bladder, ovaries, testes, uterus, cartilage, tendon, ligament, bone, etc. In certain embodiments, the wound can be in skin and / or muscle.

[0346] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, can be administered shortly after the wound has occurred. In other embodiments, the wound is a chronic wound that has not healed for days, weeks, months, or years. In yet other embodiments, the wound is a pre-existing wound that has not healed at a normal rate or has not responded to other therapies.

[0347] In some embodiments, administration of crystalline Form I, or a pharmaceutical composition comprising said crystalline form, promotes wound healing by increasing the rate at which the wound heals. In some embodiments, the administration promotes healing by reducing scarring or the amount of scar tissue that would form in the absence of treatment. In some embodiments, the treatment improves the cosmetic result or outcome or appearance of the healed wound, including, for example, improved skin pigmentation and / or improved hair regrowth compared to an untreated wound.

[0348] In certain embodiments of promoting wound healing, the therapy is preferably administered topically at or around the site or intralesionally to provide a localized effect.

[0349] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, is used to treat, prevent and / or reduce scarring.

[0350] The term "scar reduction" or "scar tissue reduction" as referred to herein relates to an improved cosmetic outcome and / or a reduction in abnormal tissue caused by wound healing compared to if the wound were left untreated. In some embodiments, the reduction in scar tissue includes a reduction or minimization of abnormal tissue, a reduction or minimization of skin pigmentation, and / or improved hair regrowth compared to if the wound were left untreated.

[0351] Crystalline Form I, or a pharmaceutical composition comprising said crystalline form, can be applied to, for example, healing or healed wounds with excessive scarring, such as wounds that are developing or have developed keloid or hypertrophic scars.

[0352] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, is used to prevent or treat an infection, such as a bacterial infection or a fungal infection.

[0353] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, is used to prevent or treat a bacterial infection, which may be caused by gram-positive or gram-negative bacteria, particularly gram-positive bacteria. Non-limiting examples of bacteria controlled by the crystalline morphology of the present disclosure include bacteria of the genus Bacillus, such as B. subtilis, B. anthracis, B. cereus, B. firmus, B. licheniformis, B. megaterium, B. pumilus, B. coagulans, B. pantothenticus, B. alvei, B. brevis, B. circubins, B. laterosporus, B. macerans, B. polymyxa, B. Staphylococcus species such as S. aureus, S. epidermidis, S. haemolyticus, S. saprophyticus; Streptococcus species such as S. pyogenes, S. pneumoniae, S. agalactiae, S. dysgalactiae, S. equisimilis, S. equi, S. equi), S. zooepidemicus, S. anginosus, S. salivarius, S. milleri, S. sanguis, S.S. mitior, S. mutans, S. faecalis, S. faecium, S. bovis, S. equinus, S. uberus, and S. avium; species of the genera Aerococcus, Gemella, Corynebacterium, Listeria, Kurthia, Lactobacillus, Erysipelothrix, Arachnia, Actinomyces, Propionibacterium, Roscommon, Examples of suitable bacteria include the genera Bacillus subtilis, Bifidobacterium, Clostridium, Eubacterium, Serratia, Klebsiella, Proteus, Enterococcus, Pseudomonas, Nocardia, and Mycobacterium.

[0354] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, is used to treat wounds infected with a bacterial infection.

[0355] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising the crystalline form, is used to prevent or treat a fungal infection. The fungal infection may be caused by, for example, a mold or yeast. Non-limiting examples of fungi controlled by the crystalline forms of the present disclosure include species of Aspergillus, Mucor, Trichophyton, Cladosporium, Ulocladium, Curvularia, Aureobasidium, Candida albicans, Candida, Cryptococcus, Malassezia pachydermatis, Malassezia, and Trichosporon.

[0356] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, is used to treat wounds infected with a fungal infection.

[0357] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, is used to treat wounds infected with both bacterial and fungal infections, including those in biofilms.

[0358] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising the crystalline form, is used to prevent or treat an inflammatory skin disorder. In some embodiments, the inflammatory skin disorder is psoriasis. In other embodiments, the inflammatory skin disorder is eczema.

[0359] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, is used to treat ulcers.

[0360] In some embodiments, crystalline Form I, or a pharmaceutical composition comprising said crystalline form, is used to treat burns.

[0361] In some embodiments, crystalline Form I of compound of formula (I) is administered in combination with an additional therapeutic agent, for example, another therapeutic agent useful for one or more of: treating wounds in a subject; promoting wound healing; treating, preventing, and / or reducing scarring; preventing or treating bacterial infections; preventing or treating inflammatory skin disorders, such as psoriasis or eczema; treating ulcers; and / or treating burns.

[0362] Crystalline Form I of the compound of formula (I) may, for example, be administered separately, simultaneously, or sequentially with the additional therapeutic agent.

[0363] For example, crystalline Form I of the compound of formula (I) can be administered in combination with antibiotics and / or anti-inflammatory agents. Suitable antibiotics include β-lactam antibiotics such as penicillin, ampicillin, amoxicillin, flucloxacillin, dicloxacillin, methacillin, carbenicillin, and norocillin; cephalosporins such as cephalexin, cephacetrile, cefadroxil, cephaloglycin, cephalonium, cephalorzidine, cefatrizine, ceachlor, cefproxil, cefzonam, cefmetozole, loracarbef, cefminox, cefdinir, cefpodoxime, and cefpirome; carbapenems such as imipenem, meropenem, ertapenem, daripenem, panipenem, and biapenem; Aminoglycosides such as gentamicin, streptomycin, neomycin, kanamycin, vancomycin, erythromycin and asthromycin; oxazolidinones such as linezolid and pocizolid, lincosamides such as clindamycin, quinolones such as oxolinic acid, ciprofloxacin, enoxacin, ofloxacin, lomefloxacin, levofloxacin and difloxacin; and sulfonamides such as sulfamethoxazole, sulfodiazine and sulfacetamide, or mixtures such as amoxiclav (amoxicillin and clavulic acid). Suitable anti-inflammatory agents include non-steroidal anti-inflammatory drugs such as meloxicam, piroxicam, oxicam, aspirin, diflunisal, ibuprofen, dexibuprofen, naproxen, ketoprofen, indomethacin, tolmetin, mefenamic acid, numisulide, and the like, and corticosteroids such as hydrocortisone, prednisolone, methylprednisolone, prednisone, budesonide, betamethasone, and dexamethasone.

[0364] Crystalline Form I of the compound of formula (I) can also be used in combination with other wound healing agents, such as dressings and ointments, lotions, and gels. For example, crystalline Form I of the compound of formula (I) can be used in combination with silver dressings and ointments, ointments, lotions, and gels containing therapeutic agents such as iodine, aloe vera, pawpaw, or medicinal active honeys, such as manuka honey, or other biologically or physiologically active ingredients, such as antiviral agents, antifungal agents, and vitamins, such as vitamins A, C, D, and E and their esters.

[0365] Crystalline Form I of the compound of formula (I) can also be used in conjunction with dressings that provide molecular structure to the wound, such as polymeric films and cross-linked polymeric films, such as hyaluronic acid and related structures, such as cross-linked hyaluronic acid.

[0366] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described, and the present disclosure is to be understood to include all such variations and modifications.

[0367] The present invention will now be described with reference to the following examples, which illustrate certain preferred embodiments of the invention. However, it should be understood that the specificity of the following description of the invention does not supersede the generality of the preceding description of the invention. [Example]

[0368] EBC-1013 EBC-1013 can be prepared, for example, as described in WO 2014 / 169356.

[0369] Analysis method X-ray powder diffraction (XRPD): Instrumentation: Diffraction patterns were recorded on a Bruker D8-Advance diffractometer. conditions: Tube anode: Cu Generator voltage (kV): 40 Generator current (mA): 40 Wavelengths α1 and α2 (Å): 1.54056, 1.54439 Intensity ratio (α2 / α1): 0.500 Spinner: Off Angle range (2θ°): 3.00~50.00 Step size (2θ°): 0.020 Time per step (seconds): 0.50

[0370] Solubility: Method: The solubility of EBC-1013 was determined in various solvents at room temperature according to European Pharmacopoeia (EP) section 5.11. For methanol, acetonitrile, and propylene glycol, approximately 20 mg of EBC-1013 was accurately weighed into an appropriate flask. For all other solvents, approximately 10 mg of EBC-1013 was accurately weighed into an appropriate flask.

[0371] Differential Scanning Calorimetry (DSC): Equipment: Mettler Toledo DSC1 and Mettler software STAR e Thermal Analysis System Method: Heat flow was recorded from 30 to 250 °C at a linear heating rate (10 °C / min) using a sealed aluminum crucible (volume 40 μl) with a pinhole under a nitrogen flow of 50 ml / min. Approximately 5 mg of powder was used for the measurements.

[0372] Thermogravimetry and Differential Scanning Calorimetry (TG / DSC) The analysis was performed using a Mettler-Toledo TGA / DSC3+ simultaneous system equipped with an autosampler, using sealed aluminum crucibles (100 μl volume) with pinholes. TG / DSC signals were recorded from 30 to 250 °C at a linear heating rate (10 °C / min) under a nitrogen flow of 150 ml / min. Approximately 10 mg of powder was used for each measurement.

[0373] Dynamic Vapor Sorption (DVS) Analysis: device: DVS Intrinsic1 system (Surface Measurement Systems Ltd UK) with Intrinsic Control Software and DVS Analysis Suite software for detailing method: The analysis was carried out at a constant temperature of 25±0.1°C.

[0374] The samples were dried under a continuous flow of dry air (relative humidity, RH<0.1%) for 6 hours to determine the dry mass (preconditioning step).

[0375] The relative humidity was then increased from 0% to 90% RH (in 10% RH steps) and then similarly decreased to 0% RH until two complete adsorption / desorption cycles were completed. The instrument was operated in dm / dt mode (mass change over time), and a fixed dm / dt value of 0.002% / min was selected to reach equilibrium at each step.

[0376] The maximum dm / dt stage time was chosen to be 3 hours, and the minimum dm / dt stability duration was chosen to be 1 hour. In the final step, the sample was kept under a dry air flow for 3 hours, which was required for weight equilibrium.

[0377] The moisture absorption of the sample is calculated by the following formula: Weight change = 100 x [(W2-W1) / W1] where: W1 = weight of the sample at the start of the experiment (25°C, 40% RH) W2 = weight of sample at 25°C and 80% RH in the first absorption cycle (See V. Murikipudi et al., Pharmaceutical Development and Technology, 2013; 18(2): 348-358).

[0378] [Table 1]

[0379] High-Performance Liquid Chromatography (HPLC): The purity of the reference material was determined by high performance liquid chromatography (HPLC).

[0380] Instrument: UHPLC Agilent 1290 Infinity II (retention volume <150 μl, maximum system pressure 18000 psi) equipped with a G7117A DAD Detector, a Thermostable Column Compartment, and a Cooling Sample Manager Compartment. Method reference: ARM / 79-8034 HPLC conditions:

[0381] [Table 2]

[0382] [Table 3]

[0383] Example 1: Amorphous EBC-1013 The starting point of the research program was amorphous EBC-1013. Briefly, the method for producing amorphous EBC-1013 involved combining column fractions containing EBC-1013, extracting them into an organic phase, concentrating the organic phase, scraping the dried EBC-1013 from the flask, and drying under vacuum at 40°C for 12 hours to yield the amorphous material.

[0384] A photograph of a batch of amorphous EBC-1013 is shown in Figure 1. This sample was a hard, glassy flake. A typical X-ray powder diffraction (XRPD) profile is shown in Figure 2, a typical differential scanning calorimetry (DSC) profile in Figure 3, and a typical thermogravimetric (TG) profile in Figure 4.

[0385] The XRPD profile was typical of an amorphous material. DSC analysis showed an endothermic peak with an onset at 37.8 °C and a peak at 46.8 °C. TG profile, performed at a rate of 10 K / min, showed a weight loss of 0.39% in the range 25-80 °C. Decomposition occurred above 260 °C.

[0386] The purity profile of a typical amorphous EBC-1013 batch is shown below:

[0387] [Table 4]

[0388] Disadvantages of this amorphous material and its preparation method include: - No final refining steps are performed; - Lack of standardization for impurities and limited batch-to-batch reproducibility; - Difficulty in recovering the product as it must be mechanically recovered from the container; - Poor particle size control; - a low glass transition temperature; and - Chemical and physical stability and limited hygroscopicity.

[0389] Example 2: Unsuccessful Attempt to Prepare Crystalline EBC-1013 The following experiment is an example of a failed attempt to produce a crystalline form of EBC-1013.

[0390] a) 95:5 v / v heptane / ethyl acetate slurry at room temperature 50 mg of amorphous EBC-1013 was added to 1 mL of a 95:5 v / v solvent mixture of heptane and ethyl acetate. After the solid was added, the sample appeared to dissolve, with only a few particles remaining in the suspension; however, after 15 minutes, gel formation was observed. The gel was broken up using a spatula and stirred magnetically at room temperature for 12 days. The product was filtered under vacuum. A sticky compound was recovered, which after prolonged drying reached a powder-like consistency. XRPD analysis revealed an amorphous phase, exhibiting a broad signal at 4.8° 2-theta.

[0391] b) 90:10 v / v heptane / ethyl acetate room temperature slurry 50 mg of amorphous EBC-1013 was added to 1 mL of a 90:10 v / v solvent mixture of heptane and ethyl acetate. After the solid was added, the sample appeared to dissolve, with only a few particles remaining in the suspension; however, after 15 minutes, gel formation was observed. The gel was broken up using a spatula and stirred magnetically at room temperature for 12 days. The product was filtered under vacuum. A sticky compound was recovered, which after prolonged drying reached a powder-like consistency. XRPD analysis revealed an amorphous phase, exhibiting a broad signal at 4.8° 2-theta and a smaller broad signal between 8.3 and 11.4° 2-theta.

[0392] c) 90:10 v / v water / acetonitrile slurry at room temperature 50 mg of amorphous EBC-1013 was added to 1 mL of a 90:10 v / v solvent mixture of water / acetonitrile. After the solid was added, a sticky / gummy yellowish sample was observed. A stir bar was attached to the solid. The mixture was stirred at room temperature with magnetic stirring for 4 days. The supernatant was removed and evaporated at room temperature under 100 mbar vacuum, and the remaining rubbery / sticky solid was dried at room temperature under 100 mbar vacuum for 18 hours. No recovery was obtained from the mother liquor. The dried solid appeared to be part glassy and part rubbery. XRPD analysis revealed an amorphous phase.

[0393] d) 90:10 v / v water / tetrahydrofuran room temperature slurry 50 mg of amorphous EBC-1013 was added to 1 mL of a 90:10 v / v solvent mixture of water and tetrahydrofuran. After the solid was added, a sticky / gummy yellowish sample was observed. The stir bar initially adhered to the solid. After several hours, an off-white solid was observed at the bottom of the vial while stirring with a magnetic stir bar was possible. The mixture was stirred at room temperature for 12 days with magnetic stirring. The supernatant was removed and evaporated at room temperature under 100 mbar vacuum, and the remaining rubbery / sticky solid was dried at room temperature under 100 mbar vacuum for 18 hours. No recovery was obtained from the mother liquor. The dried solid appeared to be partially sticky. XRPD analysis revealed an amorphous phase.

[0394] e) Hot 90:10 v / v heptane / ethyl acetate 50 mg of amorphous EBC-1013 was added to 1 mL of a 90:10 v / v solvent mixture of heptane / ethyl acetate. The sample was then heated at 50°C. After a few minutes at 50°C, dissolution occurred. The mixture was cooled to room temperature, resulting in a gel-like precipitate. The mixture was then heated again to 50°C, resulting in a clear solution. Water was added dropwise to induce precipitation. At the end of the water addition, the supernatant appeared slightly milky. Different temperature conditions were applied to induce precipitation: - 1 hour at 50°C under stirring - 1 hour at room temperature.

[0395] No precipitate was observed. The material was stored at low temperature (8-10°C) over the weekend. Two distinct phases were observed: a clear vial bottom and a gel-like top. The gel was broken up by vigorous agitation. After a few minutes, a slightly milky solution was observed. This was evaporated at low temperature and 60°C. The product was glassy and no recovery was obtained.

[0396] f) Water as the sole solvent at high temperatures 50 mg of amorphous EBC-1013 was added to 1 mL of water and heated to 90°C with stirring at 600 rpm. After 2 hours, a slightly milky suspension was observed with yellowish solid droplets at the bottom of the vial. The mixture was left at 90°C for 18 hours. After this time, an off-white suspension with yellowish solid droplets at the bottom of the vial was observed. The supernatant was removed and evaporated at room temperature under 100 mbar vacuum, and the remaining yellowish solid droplets were dried at room temperature under 100 mbar vacuum for 4 days. No recovery was obtained from the mother liquor. The dried solid droplets appeared glassy. The dried solid droplets were manipulated with a spatula to yield a white powder. XRPD analysis revealed that the material was amorphous.

[0397] Example 3: Preparation of Form I A) Preparation on a 50 mg scale 50 mg of EBC-1013 was added to 1 mL of a water / acetone (90 / 10 v / v) solvent mixture, which had been prepared by stirring the mixture for 5 minutes. After the solid was added, a yellowish sample was observed that appeared sticky / rubbery. A magnetic stir bar adhered to the sample, while the supernatant was clear. When checked after several hours, the stir bar remained attached to the material, except for a few particles present on the wall of the vial. When the experiment was checked after one day, the stir bar was still attached to the sticky / rubbery solid. The mixture was left for an additional 3 days.

[0398] This mixture was treated as follows: the supernatant was removed and evaporated under 100 mbar vacuum at room temperature and the remaining sticky / gummy solid was dried under 100 mbar vacuum at room temperature for 18 hours.

[0399] No recovery was observed from evaporation of the mother liquor.

[0400] The dried solid was a white solid that was not sticky / gummy and yielded a fine powder when manipulated with a spatula. XRPD analysis revealed that a crystalline polymorph with high crystallinity (designated Form I) was obtained.

[0401] B) Preparation on a 500 mg scale In the EasyMax102 System, 20 mL of a water / acetone (95 / 5 v / v) solvent mixture was added to a 100 mL glass reactor. Next, 500 mg of amorphous EBC-1013 was added to the reactor, resulting in a concentration of 25 mg / mL. Immediately, semi-clear aggregates were observed at the bottom of the reactor. The aggregates were stirred with an anchor blade at 400 rpm at 25°C (reactor jacket set point). After one day, the semi-clear solid at the bottom of the reactor appeared whiter than the starting material, and a small amount of off-white solid was observed on the wall in the center of the reactor. The experiment was left under the same conditions for an additional six days.

[0402] The supernatant was removed and evaporated at room temperature at 100 mbar. After 7 days, the supernatant solvent mixture was completely evaporated. A small amount of particles was observed, but these particles were not further analyzed.

[0403] A white solid with a slight pale yellow center was attached to the bottom of the vial.

[0404] A semi-clear, slightly glassy solid was observed at the solvent reactor interface. The reactor was left at room temperature under 100 mbar vacuum for 40 hours. The white solid was removed from the reactor with a spatula. The resulting powder was analyzed by XRPD and compared with a reference pattern, revealing it to be crystalline Form I with a high degree of crystallinity. The recovered yield was 107.5 mg.

[0405] The glassy solid that had deposited on the walls of the reactor was also collected and analyzed by XRPD, which showed it to be crystalline Form I. The recovered yield was 84.9 mg.

[0406] The reactor walls and bottom were covered with a significant amount of powder, primarily as a result of solid handling. A washing step was performed to recover the powder. 10 mL of water was added to the reactor, and the powder was removed with a spatula and then recovered by vacuum filtration. This procedure was repeated three times. The combined powder was evaporated at room temperature under 100 mbar vacuum for 18 hours and then analyzed by XRPD, which also showed it to be crystalline Form I. The recovered yield was 102.3 mg.

[0407] FIG. 5 shows the XRPD diffractogram of a batch of crystalline Form I of EBC-1013 obtained from the 500 mg scale-up procedure (bottom line) and the XRPD diffractogram of a reference batch of Form I (top line).

[0408] Example 4: Properties of EBC-1013: Form I exterior Crystalline Form I of EBC-1013 is a fine powder with soft agglomerates, as shown in FIG.

[0409] X-ray powder diffraction method (XRPD) Figure 7 shows the XRPD diffractogram of a typical batch of crystalline Form I of EBC-1013. A list of the 2θ peaks and their intensities is provided in the table below. Crystalline Form I of EBC-1013 was characterized by an X-ray powder diffraction (X-RPD) pattern obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å, which was found to be crystalline and contained characteristic reflections, expressed as values ​​in degrees 2θ, at 5.1, 6.5, 9.7, and 15.9 degrees 2θ ± 0.3 2θ, as well as at 8.9, 10.2, 11.0, 12.1, 13.1, 17.1, 18.3, and 18.5 degrees 2θ ± 0.3 2θ.

[0410] [Table 5]

[0411] Dynamic Vapor Sorption (DVS) A batch of crystalline Form I of EBC-1013 was subjected to DVS analysis as shown in Figure 8. The results are summarized below:

[0412] [Table 6]

[0413] Thermogravimetry (TG) / Differential Scanning Calorimetry (DSC) DSC and TG analyses were performed on a representative batch of crystalline Form I of EBC-1013, and the results are shown in Figure 9. Differential scanning calorimetry (DSC) analysis showed a peak with an onset of 77.0°C and a peak at 86.8°C. TG showed a weight loss of less than 0.01%. This information confirms that crystalline Form I of EBC-1013 is not a solvate.

[0414] Crystal habit: Polarized light microscope (PLM) PLM analysis revealed that crystalline Form I of EBC-1013 contained small crystals, as shown in FIG.

[0415] solubility A 10 mg batch of crystalline Form I of EBC-1013 was analyzed for solubility in various solvents, and the results are summarized in the table below.

[0416] [Table 7]

[0417] Crystalline Form I of EBC-1013 is a highly crystalline form of the molecule that can be prepared as a fine powder, which is unhydrated, unsolvated, and non-hygroscopic.

[0418] Example 5: Preparation of EBC-1013 Form I: 1 g Scale 1 g of amorphous EBC-1013 was added to a 90:10 v / v water / acetone mixture at a concentration of 50 mg / mL and slurried for 7 days. The supernatant was then removed and the resulting material was a sticky solid that adhered to the reaction flask. The sticky solid was dried in the reaction flask and then analyzed by XRPD.

[0419] XRPD analysis showed that crystalline Form I was obtained, but the formation of a sticky solid that adhered to the reaction flask was not optimal for scale-up to manufacturing plant size.

[0420] Example 6: Preparation of EBC-1013 Form II from acetone:water Amorphous EBC-1013 was dissolved in acetone (10 volumes based on the HPLC assay of EBC-1013). Water (10 volumes based on the HPLC assay of EBC-1013) was added dropwise to the mixture with stirring at 20-25°C. The resulting suspension was then cooled to 5°C over 2 hours and then stirred at 0-5°C for an additional 2 hours.

[0421] The resulting mixture was filtered and the solid was washed with water (2 volumes relative to the HPLC assay of EBC-1013).

[0422] XRPD analysis reveals the presence of a different crystalline polymorph, which is designated crystalline Form II.

[0423] Example 7: Characterization of Form II of EBC-1013 produced from acetone:water X-ray powder diffraction (XRPD) Figure 11 shows the XRPD diffractogram of a typical batch of crystalline Form II of EBC-1013 prepared from acetone:water. A list of the 2θ peaks and their intensities is provided in the table below. Crystalline Form II of EBC-1013 was characterized by an X-ray powder diffraction (X-RPD) pattern obtained using copper wavelengths λ1 and λ2 = 1.54056 Å and 1.54439 Å, which was found to be crystalline and contained characteristic reflections, expressed as values ​​in degrees 2θ, at 6.6, 13.3, and 20.0 degrees 2θ ± 0.2 2θ, as well as at 7.4, 9.4, 16.9, 17.9, 18.6, 20.9, and 22.5 degrees 2θ ± 0.2 2θ.

[0424] [Table 8]

[0425] Dynamic Vapor Sorption (DVS) Crystalline Form II of EBC-1013 produced from acetone:water was subjected to DVS analysis as shown in Figure 12. The results are summarized below.

[0426] [Table 9]

[0427] Thermogravimetry (TG) / Differential Scanning Calorimetry (DSC) DSC and TG analyses were performed on a typical batch of crystalline Form II of EBC-1013 prepared from acetone:water, and the results are shown in Figure 13. Differential scanning calorimetry (DSC) analysis revealed a peak with an onset at 75.1°C and a peak at 81.0°C. TG revealed a 2.22% weight loss associated with this change at approximately 80°C.

[0428] Crystalline Form II of EBC-1013 prepared from acetone:water was found to be a crystalline solid partially solvated by acetone (the molar ratio of EBC-1013 to acetone is 3:1).

[0429] The material is a processable and filterable solid that can be easily obtained from acetone:water crystallization, and its manufacturing method facilitates the removal / reduction of impurities.

[0430] The typical amount of acetone present in crystalline Form II of EBC-1013 prepared from acetone:water is about 1.5 wt %, which is above the optimum value.

[0431] Example 8: Preparation of EBC-1013 Form I from EBC-1013 Form II It has been found that crystalline Form I of EBC-1013 can be produced from crystalline Form II of EBC-1013. Batches of crystalline Form II of EBC-1013 produced from water:acetone were dried at 30°C ± 2°C for 16 hours under vacuum pressures ranging from 0 to 50 mbar. XRPD analysis of the resulting product revealed that a solid-solid transformation from Form II to Form I had occurred.

[0432] Another batch of crystalline Form II of EBC-1013 produced from water:acetone was also dried under vacuum for 16 hours at 35° C. XRPD analysis of the resulting product again revealed conversion to crystalline Form I.

[0433] Example 9: Preparation of EBC-1013 Form I from amorphous EBC-1013 via EBC-1013 Form II on a 20 g scale Amorphous EBC-1013 (20 g) was dissolved in acetone (200 ml, 10 volumes based on EBC-1013 HPLC assay). Water (200 ml, 10 volumes based on EBC-1013 HPLC assay) was added dropwise to the mixture with stirring at 20-25°C. The resulting suspension was then cooled to 5°C over 2 hours and then stirred at 5°C for an additional 2 hours.

[0434] The resulting mixture was filtered and the solid was washed with 40 mL of water (2 volumes relative to EBC-1013 HPLC assay). XRPD analysis showed that crystalline Form II of EBC-1013 had formed.

[0435] Crystalline Form II of EBC-1013 was then dried at 30° C.±2° C. under vacuum pressures ranging from 0 to 50 mbar for 16 hours. XRPD analysis of the resulting product revealed that the material was crystalline Form I of EBC-1013.

[0436] The yield of Form I was 17.6 g (88%).

[0437] The purity profile of crystalline Form I of EBC-1013 produced from a 20 g scale experiment is shown below, with the HPLC chromatogram shown in Figure 14:

[0438] [Table 10]

[0439] The process for preparing crystalline Form I of EBC-1013 via Form II facilitates obtaining highly pure crystalline Form I of EBC-1013, and this process is more easily scalable than the process for preparing crystalline Form I of EBC-1013 directly from amorphous EBC-1013.

[0440] Example 10: Accelerated Stability Study with Form I of EBC-1013 EBC-1013 crystalline Form I and amorphous EBC-1013 were subjected to accelerated stability testing, which evaluated them after one month of storage at 2-8°C, 25°C and 60% relative humidity, and 40°C and 75% relative humidity. Three-month data was also collected for EBC-1013 crystalline Form I. The results are shown in the table below:

[0441] [Table 11]

[0442] [Table 12]

[0443] As shown in the table, crystalline Form I of EBC-1013 is stable for up to 3 months of storage, including higher temperatures and higher relative humidity.

[0444] Example 11: Forms IIA, IIB, IIC and IID Additional crystalline forms of EBC-1013 were produced by preparation from various solvent systems, in which acetone was replaced with another organic solvent, i.e., isopropanol, tert-butanol, methyl ethyl ketone, or THF. The products had slight variations in XRPD from crystalline Form II of EBC-1013 produced from acetone:water. These products are considered variants or pseudopolymorphs, given the similarity of their XRPD profiles. These products are also solvates containing the respective organic solvents. These products are designated Forms IIA, IIB, IIC, and IID, respectively.

[0445] Amorphous EBC-1013 was dissolved in an organic solvent (2-10 volumes based on EBC-1013 HPLC assay). Water (10-40 volumes based on EBC-1013 HPLC assay) was added dropwise to the mixture with stirring at 20-25°C. The resulting suspension was stirred for the period indicated in the table below. The resulting mixture was filtered and the solid was washed with water (2 volumes based on EBC-1013 HPLC assay).

[0446] [Table 13]

[0447] Form IIA of EBC-1013 produced from isopropanol:water A representative XRPD of a batch of crystalline Form IIA of EBC-1013 prepared from isopropanol and water is shown in Figure 15. A listing of the 2θ peaks and their intensities for crystalline Form IIA of EBC-1013 prepared from isopropanol:water is provided in the table below.

[0448] [Table 14]

[0449] DSC and TG analyses were performed on a typical batch of crystalline Form IIA of EBC-1013 prepared from isopropanol:water, and the results are shown in Figure 16. DSC analysis revealed a peak with an onset at 61.0°C and a peak at 67.5°C. TG revealed a weight loss of 1.64% associated with this change.

[0450] Form IIB of EBC-1013 produced from tert-butanol:water A representative XRPD of a batch of crystalline Form IIB of EBC-1013 prepared from tert-butanol and water is shown in Figure 17. A list of the 2θ peaks and their intensities for crystalline Form IIB of EBC-1013 prepared from tert-butanol:water is provided in the table below.

[0451] [Table 15]

[0452] Form IIC of EBC-1013 produced from methyl ethyl ketone:water A representative XRPD of a batch of crystalline Form IIC of EBC-1013 prepared from methyl ethyl ketone and water is shown in Figure 18. A listing of the 2θ peaks and their intensities for crystalline Form IIC of EBC-1013 prepared from methyl ethyl ketone:water is provided in the table below.

[0453] [Table 16]

[0454] Thermogravimetry (TG) / Differential Scanning Calorimetry (DSC) DSC and TG analyses were performed on a typical batch of crystalline Form IIC of EBC-1013 prepared from methyl ethyl ketone and water, and the results are shown in Figure 19. Differential scanning calorimetry (DSC) analysis revealed a peak with an onset at 53.7°C and a peak at 62.4°C. TG revealed a weight loss of 1.40% associated with this change.

[0455] Form IID of EBC-1013 produced from tetrahydrofuran:water A representative XRPD of a batch of crystalline Form IID of EBC-1013 prepared from tetrahydrofuran and water is shown in Figure 20. A listing of the 2θ peaks and their intensities for crystalline Form IID of EBC-1013 prepared from tetrahydrofuran:water is provided in the table below.

[0456] [Table 17]

[0457] Example 12: Conversion of EBC-1013 Forms IIA, IIB, IIC, and IID to Form I It has also been found that drying crystalline Forms IIA, IIB, IIC, and IID of EBC-1013 under appropriate conditions can convert batches of these materials back to crystalline Form I of EBC-1013.

[0458] A batch of crystalline Form IIA of EBC-1013 prepared from isopropanol:water was dried under vacuum for 16 hours at 40° C. XRPD analysis revealed the presence of crystalline Form I of EBC-1013 (FIG. 21).

[0459] A batch of crystalline Form IIB of EBC-1013 prepared from tert-butanol:water was dried under vacuum, and XRPD analysis revealed the presence of crystalline Form I of EBC-1013 (Figure 24).

[0460] A batch of crystalline Form IIC of EBC-1013 prepared from methyl ethyl ketone:water was dried under vacuum, and XRPD analysis revealed the presence of crystalline Form I of EBC-1013 (Figure 22).

[0461] A batch of crystalline Form IID of EBC-1013 prepared from tetrahydrofuran:water was dried under vacuum, and XRPD analysis revealed the presence of crystalline Form I of EBC-1013 (Figure 23).

Claims

1. Formula (I): 【Chemistry 1】 A crystalline form (Form I) of the compound of The crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 5.1, 6.5, 9.7, and 15.9 degrees 2θ±0.3 degrees 2θ as determined by X-ray powder diffraction.

2. 10. The crystalline form of claim 1, wherein the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 8.9, 10.2, 11.0, 12.1, 13.1, 17.1, 18.3, and 18.5 degrees 2θ±0.3 2θ.

3. 3. The crystalline form of claim 2, wherein the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 5.1, 6.5, 8.9, 9.7, 10.2, 11.0, 12.1, 13.1, 15.9, 17.1, 18.3, and 18.5 degrees 2θ±0.3 2θ.

4. 4. The crystalline form of any one of claims 1 to 3, wherein the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in Figure 7.

5. 5. The crystalline form of any one of claims 1 to 4, wherein the crystalline form has a differential scanning calorimetry profile that exhibits an endothermic peak with an onset at 77°C ± 5°C and a peak at 87°C ± 5°C.

6. 6. The crystalline form of any one of claims 1 to 5, wherein the crystalline form exhibits a mass loss of 0.3% or less upon heating to 100°C when subjected to thermogravimetric analysis.

7. 7. The crystalline form of any one of claims 1 to 6, wherein the crystalline form is substantially unsolvated.

8. 8. The crystalline form of any one of claims 1 to 7, wherein the compound of formula (I) has a purity of at least 98% by weight.

9. Formula (I): 【Chemistry 2】 (Form II) of the compound of The crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.6, 13.3, and 20.0 degrees 2θ±0.2° as determined by X-ray powder diffraction.

10. 10. The crystalline form of claim 9, wherein the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.4, 9.4, 16.9, 17.9, 18.6, 20.9, and 22.5 degrees 2θ±0.2 2θ.

11. 11. The crystalline form of claim 10, wherein the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.6, 7.4, 9.4, 13.3, 16.9, 17.9, 18.6, 20.0, 20.9, and 22.5 degrees 2θ±0.2 2θ.

12. 12. The crystalline form of claim 11, wherein the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in Figure 11.

13. 13. The crystalline form of any one of claims 9 to 12, wherein the crystalline form has a differential scanning calorimetry profile that exhibits an endothermic peak with an onset at 75°C ± 5°C and a peak at 81°C ± 5°C.

14. 14. The crystalline form of any one of claims 9 to 13, wherein the crystalline form exhibits a mass loss of at least 1.5% upon heating to 100°C when subjected to thermogravimetric analysis.

15. The crystalline form of any one of claims 9 to 14, wherein the crystalline form is a solvate.

16. 16. The crystalline form of claim 15, wherein the solvate is an acetone solvate.

17. 17. The crystalline form of any one of claims 9 to 16, wherein the compound of formula (I) has a purity of at least 97.5% by mass.

18. Formula (I): 【Transformation 3】 A crystalline form of the compound of formula (Form IIA), The crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.7, 9.5, 13.3, 18.8, and 19.9 degrees 2θ±0.2° as determined by X-ray powder diffraction.

19. 20. The crystalline form of claim 18, wherein the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.6, 11.3, 16.9, 17.8, 21.1, and 22.5 degrees 2θ±0.2 2θ.

20. 20. The crystalline form of claim 19, wherein the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.7, 7.6, 9.5, 11.3, 13.3, 16.9, 17.8, 18.8, 19.9, 21.1, and 22.5 degrees 2θ±0.2 2θ.

21. 19. The crystalline form of claim 18, wherein the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in Figure 15.

22. 22. The crystalline form of any one of claims 18 to 21, wherein the crystalline form has a differential scanning calorimetry profile that exhibits an endothermic peak with an onset at 61°C ± 5°C and a peak at 68°C ± 5°C.

23. 23. The crystalline form of any one of claims 18 to 22, wherein the crystalline form exhibits a mass loss of at least 1.5% upon heating to 100°C when subjected to thermogravimetric analysis.

24. 24. The crystalline form of any one of claims 18 to 23, wherein the crystalline form is a solvate.

25. 25. The crystalline form of claim 24, wherein the solvate is an isopropanol solvate.

26. 26. The crystalline form of any one of claims 18 to 25, wherein the compound of formula (I) has a purity of at least 97.5% by weight.

27. Formula (I): 【Chemistry 4】 (Form IIB) of the compound of The crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.4, 9.3, 13.1, and 17.7 degrees 2θ±0.2° as determined by X-ray powder diffraction.

28. 28. The crystalline form of claim 27, wherein the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.3, 11.1, 16.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.2 2θ.

29. 30. The crystalline form of claim 28, wherein the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.4, 7.3, 9.3, 11.1, 13.1, 16.7, 17.7, 18.4, 18.7, 19.0, 19.7, 19.8, 20.9, 21.6, 22.0, and 22.2 degrees 2θ±0.2 2θ.

30. 28. The crystalline form of claim 27, wherein the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in Figure 17.

31. 31. The crystalline form of any one of claims 27 to 30, wherein the crystalline form is a solvate.

32. 32. The crystalline form of claim 31, wherein the solvate is a tert-butanol solvate.

33. 33. The crystalline form of any one of claims 27 to 32, wherein the compound of formula (I) has a purity of at least 97.5% by mass.

34. Formula (I): 【Transformation 5】 A crystalline form (Form IIC) of the compound of The crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.5, 9.4, and 13.1 degrees 2θ±0.2° as determined by X-ray powder diffraction.

35. 35. The crystalline form of claim 34, wherein the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.3, 11.3, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ±0.2 2θ.

36. 36. The crystalline form of claim 35, wherein the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.5, 7.3, 9.4, 11.3, 13.1, 13.4, 16.5, 18.1, 18.8, 19.6, 20.3, 20.9, and 21.9 degrees 2θ±0.2 2θ.

37. 35. The crystalline form of claim 34, wherein the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in Figure 18.

38. 38. The crystalline form of any one of claims 34 to 37, wherein the crystalline form has a differential scanning calorimetry profile that exhibits an endothermic peak with an onset at 54°C ± 5°C and a peak at 62°C ± 5°C.

39. 39. The crystalline form of any one of claims 34 to 38, wherein the crystalline form exhibits a mass loss of at least 1.25% upon heating to 100°C when subjected to thermogravimetric analysis.

40. 40. The crystalline form of any one of claims 34 to 39, wherein the crystalline form is a solvate.

41. 41. The crystalline form of claim 40, wherein the solvate is a methyl ethyl ketone solvate.

42. 42. The crystalline form of any one of claims 34 to 41, wherein the compound of formula (I) has a purity of at least 97.5% by mass.

43. Formula (I): 【Transformation 6】 A crystalline form (Form IID) of the compound of The crystalline form exhibits an X-ray powder diffraction pattern having peaks at each of 6.4, 9.3, and 13.1 degrees 2θ±0.2° as determined by X-ray powder diffraction.

44. 43. The crystalline form of claim 42, wherein the crystalline form exhibits an X-ray powder diffraction pattern with one or more peaks at 7.3, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.2 2θ.

45. 44. The crystalline form of claim 43, wherein the crystalline form exhibits an X-ray powder diffraction pattern with peaks at each of 6.4, 7.3, 9.3, 13.1, 13.2, 16.6, 17.8, 19.6, 20.1, 20.9, and 22.1 degrees 2θ±0.2 2θ.

46. 43. The crystalline form of claim 42, wherein the crystalline form exhibits an X-ray powder diffraction pattern substantially as shown in Figure 20.

47. 46. ​​The crystalline form of any one of claims 42 to 45, wherein the crystalline form is a solvate.

48. 48. The crystalline form of claim 47, wherein the solvate is a tetrahydrofuran solvate.

49. 49. The crystalline form of any one of claims 42 to 48, wherein the compound of formula (I) has a purity of at least 97.5% by mass.

50. A process for preparing crystalline form II, IIA, IIB, IIC or IID of compound of formula (I) according to any one of claims 9 to 49, comprising the steps of: slowly adding water to a solution of the compound of formula (I) in an organic solvent selected from the group consisting of acetone, isopropanol, methyl ethyl ketone, THF, and tert-butanol; forming a solid precipitate; separating the solid precipitate from the water:organic solvent mixture; A method comprising:

51. 51. The method of claim 50, wherein the crystalline form is Form II and the organic solvent is acetone.

52. 52. The method of claim 50 or 51, wherein the water is added to the solution of the compound of formula (I) in the organic solvent at a temperature in the range of 20 to 30°C.

53. 53. A process according to any one of claims 50 to 52, wherein following the addition of water the mixture is cooled to a temperature in the range of 0 to 5°C.

54. 54. The method of claim 53, wherein the mixture is cooled over a period ranging from about 90 minutes to 3 hours, optionally about 2 hours.

55. 55. The method of claim 53 or 54, wherein following cooling, the mixture is held at the cooled temperature for a period ranging from about 90 minutes to 3 hours, optionally about 2 hours.

56. 56. The method of any one of claims 50 to 55, wherein the amount of organic solvent in which the compound of formula (I) is dissolved ranges from 2 to 15 volumes, optionally about 10 volumes.

57. 57. The method of any one of claims 50 to 56, wherein the amount of water added to the solution of the compound of formula (I) in the organic solvent is in the range of 5 to 40 volumes, optionally about 10 volumes.

58. 58. The method of any one of claims 50 to 57, wherein the solid precipitate is separated from the water:organic solvent mixture by filtration.

59. 59. A method according to any one of claims 50 to 58, wherein the separated solid precipitate is washed with water, optionally with an amount of water in the range of 1 to 5 volumes, optionally with an amount of water of about 2 volumes.

60. A method for preparing crystalline form I of the compound of formula (I) according to any one of claims 1 to 8, comprising the steps of:

50. The method of claim 49, wherein said crystalline form II, IIA, IIB, IIC or IID of the compound of formula (I) is subjected to vacuum conditions at a temperature of up to 70° C. to produce said crystalline form I. A method comprising:

61. 61. The method of claim 60, wherein crystalline form II, IIA, IIB, IIC or IID is obtained by carrying out the method of any one of claims 50 to 59.

62. 62. The method of claim 60 or 61, wherein crystalline Form II, IIA, IIB, IIC or IID is subjected to vacuum conditions at a temperature in the range of 30 to 60°C.

63. 63. The method of any one of claims 60 to 62, wherein crystalline Form II, IIA, IIB, IIC or IID is subjected to vacuum conditions for a period in the range of from 6 to 120 hours.

64. 64. The method of claim 63, wherein crystalline Form II, IIA, IIB, IIC, or IID is subjected to vacuum conditions for a period ranging from 12 to 18 hours.

65. A pharmaceutical composition comprising crystalline Form I of the compound of formula (I) according to any one of claims 1 to 8 and a pharmaceutically acceptable excipient.

66. 10. Crystalline Form I of compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutical composition comprising said crystalline form, for use in the treatment of wounds; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating bacterial infections; preventing or treating inflammatory skin disorders, such as psoriasis or eczema; treating ulcers; and / or treating burns.

67. 10. A method for treating a wound in a subject; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating a bacterial infection; preventing or treating an inflammatory skin disorder, such as psoriasis or eczema; treating an ulcer; and / or treating a burn, said method comprising administering to said subject an effective amount of crystalline Form I of the compound of formula (I) according to any one of claims 1 to 8, or an effective amount of a pharmaceutical composition comprising said crystalline form.

68. 10. Use of crystalline form I of compound of formula (I) according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of wounds; promoting wound healing; treating, preventing and / or reducing scarring; preventing or treating bacterial infections; preventing or treating inflammatory skin disorders, such as psoriasis or eczema; treating ulcers; and / or treating burns.

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