Microcrystalline polymorphs of LMP400 and uses thereof

Abstract

Disclosed herein are crystalline polymorphs of indotecan (LMP400) that can be used in the treatment of cancers associated with dysregulation of Topl and / or MYC activity, such as, for example, a sarcoma, (e.g., Ewing's sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a. glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

Attorney Docket No.38373.0001P1 MICROCRYSTALLINE POLYMORPHS OF LMP400 AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Provisional Application No.63 / 677,109, filed on July 30, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Topoisomerases are ubiquitous enzymes that resolve the topological problems associated with DNA supercoiling during replication, transcription, and other nuclear processes. Human topoisomerase I (Top1) cleaves a single DNA strand by nucleophilic attack of the enzyme on a DNA phosphodiester to form a “cleavage complex” in which the 3′ end of the broken DNA strand is covalently linked to the enzyme (Staker, B. L., et al., The Mechanism of Topoisomerase I Poisoning by a Camptothecin Analog, Proc. Natl. Acad. Sci. U.S.A.2002, 99, 15387-15392). The broken (scissile) strand then undergoes “controlled rotation” around the unbroken strand to relax the DNA superhelical tension and remove supercoils. The catalytic cycle ends when the 5′ end of the scissile strand carries out a nucleophilic attack on the phosphotyrosyl-DNA phosphodiester to religate the DNA and release the enzyme.

[0003] Top1 inhibitors are classified as Top1 suppressors, which inhibit the DNA cleavage reaction, and Top1 poisons, which inhibit the DNA religation reaction. Top1 is overexpressed in cancer cells and DNA damage responses are defective in some human tumors. Top1 poisons that stabilize the “cleavage complex” have therefore been developed as chemotherapeutic agents. The mechanism of cancer cell death produced by Top1 poisons involves collision of the DNA replication fork with the DNA cleavage site in the ternary DNA-drug-Top1 complex leading to double-strand breaks and cell death (Pommier, Y., Topoisomerase I Inhibitors: Camptothecins and Beyond, Nat. Rev. Cancer 2006, 6, 789-802).

[0004] Indotecan, also known as LMP400, is a novel selective and potent topoisomerase I inhibitor that has successfully completed Phase I clinical trials at the National Institutes of Health (Kummar, S., et. al., Pharmacokinetic and Pharmacodynamic Evaluation of Two Dosing Schedules of Indotecan (LMP400), a Novel Indenoisoquinoline, in Patients with Advanced Solid Tumors, Cancer Chemother. Pharmacol.2016, 78, 73-81. In October 2023, the U.S. Food and Drug Administration (FDA) granted orphan drug status to indotecan for use in patients with malignant glioma, a cancer of the brain that begins in glial cells (cells thatAttorney Docket No.38373.0001P1 surround and support nerve cells). Additionally, indotecan has shown promising activity for the treatment of pediatric cancers, such as Ewing’s sarcoma and solid tumors.

[0005] A limitation of the currently developed form of indotecan is its limited solubility inwater, which reduces its bioavailability and makes its practical application difficult. One strategy to resolve this problem is polymorphism. The higher solubility and bioavailability of polymorphous modifications are generally associated with the formation of crystals that change the properties of the original compound. Unfortunately, the controlled synthesis of polymorphous forms continues to be an ongoing challenge. Thus, there remains a need for more soluble forms of indotecan, such as soluble crystalline polymorph forms, as well as methods of making and using same. These needs and others are met by the disclosure herein. SUMMARY

[0006] In accordance with the purpose(s) of the invention, as embodied and broadlydescribed herein, the invention, in one aspect, relates to crystalline polymorphs of indotecan (LMP400), which can be useful in, for example, treating cancers associated with dysregulation of Top1 and / or MYC activity, such as, for example, a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

[0007] Thus, disclosed are crystalline polymorphs of a pharmaceutically acceptable salt of acompound having a structure:.

[0008] Also disclosed are pharmaceutical compositions comprising an effective amount of acrystalline polymorph as described herein and a pharmaceutically acceptable carrier.Attorney Docket No.38373.0001P1

[0009] Also disclosed are methods for modifying topoisomerase I (Top1) and / or MYCsignaling in a subject, the method comprising the step of administering to the subject an effective amount of a crystalline polymorph as described herein.

[0010] Also disclosed are methods for modifying topoisomerase I (Top1) and / or MYCsignaling in at least one cell, the method comprising the step of contacting the cell with an effective amount of a crystalline polymorph as described herein.

[0011] Also disclosed are methods of treating cancer in a subject in need thereof, the methodcomprising administering to the subject an effective amount of a crystalline polymorph as described herein. Examples of cancer include, but are not limited to, a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

[0012] Also disclosed are methods for making a crystalline polymorph as described herein,the method comprising: (a) suspending a compound having a structure:, or a pharmaceutically acceptable salt thereof, in a basic solution; (b) filtering; (c) adding an acid; and (d) filtering.

[0013] Also disclosed are kits comprising a crystalline polymorph as described herein andone or more selected from: (a) an agent associated with the treatment of cancer; (b) instructions for administering the crystalline polymorph in connection with treating cancer; and (c) instructions for treating cancer.

[0014] Additional aspects of the disclosed crystalline polymorphs, pharmaceuticalcompositions, and methods will be set forth, in part, in the detailed description, and claims which follow, and in part will be derived from the detailed description, or can be learned by practice of the disclosed crystalline polymorphs, pharmaceutical compositions, and methods. It is to be understood that both the foregoing general description and the following detailedAttorney Docket No.38373.0001P1 description are exemplary and explanatory only and are not restrictive of the disclosed crystalline polymorphs, pharmaceutical compositions, and methods. BRIEF DESCRIPTION OF THE FIGURES

[0015] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0016] These and other features of the aspects of the disclosed crystalline polymorphs, pharmaceutical compositions, and methods will become more apparent in the detailed description in which reference is made to the appended drawings wherein:

[0017] FIG.1 shows a representative1H NMR spectrum of Form A.

[0018] FIG.2 shows a representative high performance liquid chromatogram of Form A.

[0019] FIG.3A and FIG.3B show representative photographs of Form B produced via Method 1 (FIG.3A) and Method 2 (FIG.3B).

[0020] FIG.4 shows a representative high performance liquid chromatogram of Form B produced by Method 1.

[0021] FIG.5 shows a representative high performance liquid chromatogram of Form B produced by Method 2.

[0022] FIG.6 shows a representative1H NMR spectrum of Form B produced by Method 2.

[0023] FIG.7 shows representative data depicting the powder X-ray diffraction (XRD) pattern of Form B.

[0024] FIG.8 shows representative data depicting the powder XRD pattern of Form A.

[0025] FIG.9 shows representative data depicting the comparison of powder XRD patterns of Form A and Form B.

[0026] FIG.10 shows representative data depicting the powder XRD pattern of solid material recovered from a slurry formed of Form B.

[0027] FIG.11 shows representative data depicting the powder XRD pattern comparisons for solid material recovered from a slurry formed from Form B and Form B.

[0028] FIG.12 shows representative data depicting the powder XRD pattern comparisons for solid material recovered from a slurry formed from Form B and Form A.

[0029] FIG.13 shows representative data depicting the observed peaks for material recovered from a slurry prepared from Form B.

[0030] FIG.14 shows representative data depicting the observed peaks of Form B.Attorney Docket No.38373.0001P1

[0031] FIG.15 shows representative data depicting the observed peaks for Form A.

[0032] FIG.16 shows representative data depicting the particle size distribution for Form A as measured by laser diffraction.

[0033] FIG.17 shows representative data depicting the particle size distribution for Form B as measured by laser diffraction. DETAILED DESCRIPTION

[0034] The present invention can be understood more readily by reference to the following detailed description, examples, drawings, and claims, and their previous and following description. However, before the present crystalline polymorphs, pharmaceutical compositions, and / or methods are disclosed and described, it is to be understood that inventions described and claimed herein are not limited to the specific crystalline polymorphs, pharmaceutical compositions, and / or methods disclosed unless otherwise specified, as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0035] The following description of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods are provided as an enabling teaching of the invention in its best, currently known embodiment. To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various aspects of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods, while still obtaining the beneficial results of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods. It will also be apparent that some of the desired benefits of the present crystalline polymorphs, pharmaceutical compositions, and / or methods can be obtained by selecting some of the features of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods are possible and can even be desirable in certain circumstances and are a part of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods. Thus, the following description is provided as illustrative of the principles of the disclosed crystalline polymorphs, pharmaceutical compositions, and / or methods and not in limitation thereof.Attorney Docket No.38373.0001P1 A. DEFINITIONS

[0036] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural forms unless the context clearly dictates otherwise. Thus, for example, reference to “a peak,” “a pharmaceutically acceptable salt,” or “a pharmaceutically acceptable carrier” includes mixtures of two or more such peaks, pharmaceutically acceptable salts, or pharmaceutically acceptable carriers, and the like.

[0037] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0038] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0039] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated or some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0040] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship betweenAttorney Docket No.38373.0001P1 the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0041] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0042] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0043] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0044] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is aAttorney Docket No.38373.0001P1 mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0045] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0046] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0047] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0048] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in theAttorney Docket No.38373.0001P1 medical arts. For example, it is well within the skill of the art to start doses of a Form A at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0049] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage form can comprise a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0050] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kitAttorney Docket No.38373.0001P1 comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0051] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form, which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0052] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0053] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) andAttorney Docket No.38373.0001P1 poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0054] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Sigma-Aldrich Chemical Co. (Burlington, MA), Strem Chemicals (Newburyport, MA), or Fisher Scientific (Pittsburgh, PA.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1994); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 8th Edition, 2020); and Larock’s Comprehensive Organic Transformations (Wiley-VCH Publishers Inc., 2ndEdition, 1999).

[0055] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0056] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific referenceAttorney Docket No.38373.0001P1 of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the Form and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C- E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods.

[0057] As used herein, the term “microcrystalline” means a crystallized material in which the crystals are small in size. For example, in various aspects, the median particle diameter of the crystals, which can be determined by laser diffraction as is known in the art, can be about 200 microns or less, about 180 microns or less, about 160 microns or less, about 140 microns or less, about 120 microns or less, about 100 microns or less, about 80 microns or less, about 60 microns or less, about 40 microns or less, about 20 microns or less, or about 10 microns or less. In further aspects, the median particle diameter of the crystals is from about 10 microns to about 200 microns, such as about 10 microns to about 180 microns, about 10 microns to about 150 microns, about 10 microns to about 120 microns, about 10 microns to about 100 microns, about 10 microns to about 50 microns, about 20 microns to about 200 microns, about 20 microns to about 180 microns, about 20 microns to about 150 microns, about 20 microns to about 120 microns, about 20 microns to about 100 microns, about 20 microns to about 80 microns, about 50 microns to about 200 microns, or about 100 microns to about 200 microns.

[0058] As used herein, the term “polymorph form A” or “Form A” refers to a crystalline form of indotecan hydrochloride (LMP400 hydrochloride). In one aspect, Form A exhibits a powder X-ray diffraction (XRD) pattern substantially similar to that shown in FIG.15. In an alternative aspect, Form A has a powder XRD pattern that contains a peak at each of aboutAttorney Docket No.38373.0001P1 13.0 ± 0.2º 2θ and about 24.6 ± 0.2º 2θ. In an alternative aspect, Form A has a solubility in water that is less than about 5 mg / ml at 25 °C. In a yet further aspect, Form A has a solubility in water of about 0.5 mg / ml to about 5 mg / ml at 25 °C, such as about 0.5 mg / ml to about 4 mg / ml, about 0.5 mg / ml to about 3 mg / ml, about 0.5 mg / ml to about 2 mg / ml, about 1 mg / ml to about 5 mg / ml, about 1 mg / ml to about 4 mg / ml, about 1 mg / ml to about 3 mg / ml, or about 1 mg / ml to about 2 mg / ml at 25 °C. In a still further aSpect, Form A has a solubility in water of about 1.4 mg / ml at 25 °C.

[0059] As used herein, the term “polymorph form B” or “Form B” refers to an alternative crystalline form of indotecan hydrochloride (LMP400 hydrochloride). In one aspect, Form B exhibits a powder X-ray diffraction (XRD) pattern substantially similar to that shown in FIG. 14. In an alternative aspect, Form B has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ. In an alternative aspect, Form B has a solubility in water of at least about 25 mg / ml at 25 °C. In a yet further aspect, Form B has a solubility in water of about 25 mg / ml to about 200 mg / ml at 25 °C, such as about 25 mg / ml to about 180 mg / ml, about 25 mg / ml to about 150 mg / ml, about 25 mg / ml to about 120 mg / ml, about 25 mg / ml to about 100 mg / ml, about 30 mg / ml to about 200 mg / ml, about 30 mg / ml to about 180 mg / ml, about 30 mg / ml to about 150 mg / ml, about 30 mg / ml to about 120 mg / ml, about 30 mg / ml to about 100 mg / ml, or about 25 mg / ml to about 40 mg / ml. In a still further aspect, Form B has a solubility of about 31.8 mg / ml at 25 °C. In a yet further aspect, Form B has a solubility in water higher than a solubility in water of Form A. B. CRYSTALLINE POLYMORPHS

[0060] In one aspect, disclosed herein are crystalline polymorphs of indotecan (LMP400), which can be useful in, for example, treating cancers associated with dysregulation of Top1 and / or MYC activity, such as, for example, a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).Attorney Docket No.38373.0001P1

[0061] In one aspect, disclosed are crystalline polymorphs of a pharmaceutically acceptablesalt of a compound having a structure:.

[0062] In a further aspect, the pharmaceutically acceptable salt is selected from a halide salt,an acetate salt, an alginate salt, an ascorbate salt, a benzene sulfonate salt, a benzoate salt, a carbonate salt, a cinnamate salt, a citrate salt, a diphosphate salt, a fumarate salt, a gluconate salt, a lactate salt, a laurate salt, a malate salt, a maleate salt, a mesylate salt, a myristate salt, a nitrate salt, a palmitate salt, a perchlorate salt, a phenolate salt, a phosphate salt, a propionate salt, a sorbate salt, a succinate salt, a sulfate salt, and a tartrate salt. In a further aspect, the pharmaceutically acceptable salt is a halide salt. In a yet further aspect, the pharmaceutically acceptable salt is a hydrochloride salt.

[0063] In some aspects, the crystalline polymorph can be present as a crystalline particulatematerial, wherein the crystalline particulate material is a plurality of particles having a median particle diameter. The median particle diameter can be measured using any technique known in the art for measuring crystal size, such as, for example, light scattering, laser diffraction, and electron microscopy.

[0064] In some aspects, the median particle diameter is measured using laser diffraction. Anexemplary instrument that can be used to measure the median particle diameter is a Mastersizer, commercially produced by Malvern. This measurement calculates a volume distribution from the LASER diffraction pattern of a suspension of particles. The raw scatter data is processed using a complex algorithm and presented on the basis of equivalent spherical diameter. Dv(10), Dv(50), and Dv(90) are size values that indicate the median particle diameter in which 10%, 50%, or 90% of particles within the particle volume distribution, respectively, are smaller. A Dv(90) value of 140 μm, for example, indicates that 90% of the total volume of the sample is in particles smaller than 140 μm. 1. FORM A

[0065] In various aspects, the crystalline polymorph is Form A.Attorney Docket No.38373.0001P1

[0066] In a further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at each of about 13.0 ± 0.2º 2θ and about 24.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 12.8, 12.9, 13.0, 13.1, or 13.2º 2θ and also contains a peak at 24.4, 24.5, 24.6, 24.7, or 24.8º 2θ.

[0067] In a further aspect, the powder XRD pattern further contains a peak at each of about 13.9 ± 0.2º 2θ, about 26.1 ± 0.2º 2θ, and about 27.0 ± 0.2º 2θ. For example, the powder XRD pattern can further contain a peak at each of about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.8, 27.0, 27.1, or 27.2 º 2θ.

[0068] In a further aspect, the powder XRD pattern further contains a peak at each of about 6.9 ± 0.2º 2θ, about 8.9 ± 0.2º 2θ, about 13.9 ± 0.2º 2θ, about 16.7 ± 0.2º 2θ, about 19.9 ± 0.2º 2θ, about 26.1 ± 0.2º 2θ, and about 27.0 ± 0.2º 2θ. For example, the powder XRD pattern can further contain a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ.

[0069] In various aspects, the powder XRD pattern further contains two or more peaks at positions selected from about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6, 9.7, 9.8, 9.9, or 9.10º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 12.0, 12.1, 12.2, 12.3, or 12.4º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7,Attorney Docket No.38373.0001P1 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 17.1, 17.2, 17.3, 17.4, or 17.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 18.7, 18.8, 18.9, 19.0, or 19.1º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 24.2, 24.3, 24.4, 24.5, or 24.6º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 27.6, 27.7, 27.8, 27.9, or 28.0º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 29.1, 29.2, 29.3, 29.4, or 29.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 11.6, 11.7, 11.8, 11.9, or 12.0º 2θ, and about 15.7, 15.8, 15.9, 16.0, or 16.1º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and aboutAttorney Docket No.38373.0001P1 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 12.0, 12.1, 12.2, 12.3, or 12.4º 2θ, and about 20.1, 20.2, 20.3, 20.4, or 20.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 15.7, 15.8, 15.9, 16.0, or 16.1º 2θ, and about 18.7, 18.8, 18.9, 19.0, or 19.1º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 18.3, 18.4, 18.5, 18.6, or 18.7º 2θ, and about 24.2, 24.3, 24.4, 24.5, or 24.6º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and 20.1, 20.2, 20.3, 20.4, or 20.5º 2θ, and about 27.9, 28.0, 28.1, 28.2, or 28.3º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 27.6, 27.7, 27.8, 27.9, or 28.0º 2θ, and about 29.1, 29.2, 29.3, 29.4, or 29.5º 2θ.

[0070] In various aspects, the powder XRD pattern further contains five or more peaks at positions selected from about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6,Attorney Docket No.38373.0001P1 9.7, 9.8, 9.9, or 10.0º 2θ, and about 11.6, 11.7, 11.8, 11.9, or 12.0º 2θ, and about 12.0, 12.1, 12.2, 12.3, or 12.4º 2θ, and about 15.7, 15.8, 15.9, 16.0, or 16.1º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6, 9.7, 9.8, 9.9, or 10.0º 2θ, and about 11.6, 11.7, 11.8, 11.9, or 12.0º 2θ, and about 12.0, 12.1, 12.2, 12.3, or 12.4 º 2θ, and about 17.1, 17.2, 17.3, 17.4, or 17.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6, 9.7, 9.8, 9.9, or 10.0º 2θ, and about 11.6, 11.7, 11.8, 11.9, or 12.0º 2θ, and about 12.0, 12.1, 12.2, 12.3, or 12.4º 2θ, and about 20.1, 20.2, 20.3, 20.4, or 20.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6, 9.7, 9.8, 9.9, or 10.0º 2θ, and about 11.6, 11.7, 11.8, 11.9, or 12.0º 2θ, and about 20.1, 20.2, 20.3, 20.4, or 20.5º 2θ, and about 29.1, 29.2, 29.3, 29.4, or 29.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and 24.2, 24.3, 24.4, 24.5, or 24.6º 2θ, and about 27.6, 27.7, 27.8, 27.9, or 28.0º 2θ, and about 27.9, 28.0, 28.1, 28.2, or 28.3º 2θ, and about 28.5, 28.6, 28.7, 28.8, or 28.9º 2θ, and about 29.1, 29.2, 29.3, 29.4, or 29.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6, 9.7, 9.8, 9.9, or 10.0º 2θ, and about 20.1, 20.2, 20.3, 20.4, or 20.5º 2θ, and about 28.5, 28.6, 28.7, 28.8, or 28.9º 2θ, and about 29.1, 29.2, 29.3, 29.4, or 29.5º 2θ.Attorney Docket No.38373.0001P1

[0071] In various aspects, the powder XRD pattern further contains ten or more peaks at positions selected from about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6, 9.7, 9.8, 9.9, or 10.0º 2θ, and about 11.6, 11.7, 11.8, 11.9, or 12.0º 2θ. and about 12.0, 12.1, 12.2, 12.3, or 12.4º 2θ, and 15.7, 15.8, 15.9, 16.0, or 16.1º 2θ, or about 17.1, 17.2, 17.3, 17.4, or 17.5º 2θ, and about 17.7, 17.8, 17.9, 18.0, or 18.1º 2θ, and about 18.3, 18.4, 18.5, 18.6, or 18.7º 2θ, and about 18.7, 18.8, 18.9, 19.0, or 19.1º 2θ, and about 20.1, 20.2, 20.3, 20.4, or 20.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6, 9.7, 9.8, 9.9, or 10.0º 2θ, and about 11.6, 11.7, 11.8, 11.9, or 12.0º 2θ. and about 12.0, 12.1, 12.2, 12.3, or 12.4º 2θ, and 15.7, 15.8, 15.9, 16.0, or 16.1º 2θ, or about 17.1, 17.2, 17.3, 17.4, or 17.5º 2θ, and about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ, and about 23.1, 23.2, 23.3, 23.4, or 23.5º 2θ, and about 27.9, 28.0, 28.1, 28.2, or 28.3º 2θ, and about 28.5, 28.6, 28.7, 28.9, or 29.0º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 18.7, 18.8, 18.9, 19.0, or 19.1º 2θ, and about 20.1, 20.2, 20.3, 20.4, or 20.5º 2θ, and 21.4, 21.5, 21.6, 21.7, or 21.8º 2θ, and about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ, and about 23.1, 23.2, 23.3, 23.4, or 23.5º 2θ, and 24.2, 24.3, 24.4, 24.5, or 24.6º 2θ, and about 27.6, 27.7, 27.8, 27.9, or 28.0º 2θ, and about 27.9, 28.0, 28.1, 28.2, or 28.3º 2θ, and about 28.5, 28.6, 28.7, 28.8, or 28.9º 2θ, and about 29.1, 29.2, 29.3, 29.4, or 29.5º 2θ.

[0072] In various aspects, the powder XRD pattern further contains fifteen or more peaks at positions selected from about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, aboutAttorney Docket No.38373.0001P1 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 9.0, 9.1, 9.2, 9.3, or 9.4º 2θ, and about 9.6, 9.7, 9.8, 9.9, or 10.0º 2θ, and about 11.6, 11.7, 11.8, 11.9, or 12.0º 2θ, and about 12.0, 12.1, 12.2, 12.3, or 12.4º 2θ, and about 15.7, 15.8, 15.9, 16.0, or 16.1º 2θ, and about 17.1, 17.2, 17.3, 17.4, or 17.5º 2θ, and about 17.7, 17.8, 17.9, 18.0, or 18.1, and about 18.3, 18.4, 18.5, 18.6, or 18.7º 2θ, and about 18.7, 18.8, 18.9, 19.0, or 19.1º 2θ, and about 20.1, 20.2, 20.3, 20.4, or 20.5, and about 21.4, 21.5, 21.6, 21.7, or 21.8º 2θ, and about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ, and about 23.1, 23.2, 23.3, 23.4, or 23.5º 2θ, and about 24.2, 24.3, 24.4, 24.5, or 24.6º 2θ, and about 27.6, 27.7, 27.8, 27.9, or 28.0º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 6.7, 6.8, 6.9, 7.0, or 7.1 º 2θ, and about 8.7, 8.8, 8.9, 9.0, or 9.1º 2θ, and about 13.7, 13.8, 13.9, 14.0, or 14.1º 2θ, and about 16.5, 16.6, 16.7, 16.8, or 16.9º 2θ, and about 19.7, 19.8, 19.9, 20.0, or 20.1º 2θ, and about 25.9, 26.0, 26.1, 26.2, or 26.3º 2θ, and about 26.8, 26.9, 27.0, 27.1, or 27.2º 2θ, and about 12.0, 12.1, 12.2, 12.3, or 12.4 and about 15.7, 15.8, 15.9, 16.0, or 16.1 and about 17.1, 17.2, 17.3, 17.4, or 17.5º 2θ, and about 17.7, 17.8, 17.9, 18.0, or 18.1, and about 18.3, 18.4, 18.5, 18.6, or 18.7º 2θ, and about 18.7, 18.8, 18.9, 19.0, or 19.1º 2θ, and about 20.1, 20.2, 20.3, 20.4, or 20.5, and about 21.4, 21.5, 21.6, 21.7, or 21.8º 2θ, and about 21.6, 21.7, 21.8, 21.9, or 22.0º 2θ, and about 23.1, 23.2, 23.3, 23.4, or 23.5º 2θ, and about 24.2, 24.3, 24.4, 24.5, or 24.6º 2θ, and about 27.6, 27.7, 27.8, 27.9, or 28.0º 2θ, and about 27.9, 28.0, 28.1, 28.2, or 28.3º 2θ, and about 28.5, 28.6, 28.7, 28.8, or 28.9º 2θ, and about 29.1, 29.2, 29.3, 29.4, or 29.5º 2θ.

[0073] In various aspects, the powder XRD pattern further contains a peak at each of about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ.

[0074] In a further aspect, the crystalline polymorph has a powderXRD pattern as shown in FIG.15.Attorney Docket No.38373.0001P1

[0075] In various aspects, the solubility of the crystalline polymorph in water is from about 0.5 mg / ml to about 4.0 mg / ml at 25 °C. The solubility of the crystalline polymorph in water can be, for example, from about 0.5 mg / ml to about 1.0 mg / ml, about 0.5 mg / ml to about 1.4 mg / ml, about 0.5 mg / ml to about 2.0 mg / ml, about 0.5 mg / ml to about 3.0 mg / ml, about 0.5 mg / ml to about 4.0 mg / ml, about 1.0 mg / ml to about 2.0 mg / ml, about 1.0 mg / ml to about 3.0 mg / ml, about 1.0 mg / ml to about 4.0 mg / ml, about 1.4 mg / ml to about 4.0 mg / ml, about 1.4 mg / ml to about 3.0 mg / ml, about 1.4 mg / ml to about 2.0 mg / ml, about 2.0 mg / ml to about 4.0 mg / ml, or about 2.0 mg / ml to about 3.0 mg / ml at 25 °C. The solubility of the crystalline polymorph in water can be, for example, about 0.5 mg / ml, about 1.0 mg / ml, about 1.4 mg / ml, about 1.5 mg / ml, about 1.7 mg / ml, about 1.8 mg / ml, 2.0 mg / ml, about 2.5 mg / ml, about 2.8 mg / ml, about 3.0 mg / ml, about 3.5 mg / ml, or about 4.0 mg / ml at 25 °C. In a further aspect, the solubility of the crystalline polymorph in water at is about 1.4 mg / ml at 25 °C. In a further aspect, the solubility of the crystalline polymorph in water is about 2.8 mg / ml at 25 °C.

[0076] In some aspects, the crystalline polymorph is present as a crystalline particulate material being a plurality of particles, wherein the plurality of particles has a Dv(10) value of from about 0.1 μm to about 3 μm. The plurality of particles can have a Dv(10) value of, for example, from about 0.1 μm to about 2.5 μm, about 0.1 μm to about 2.0 μm, about 0.1 μm to about 1.5 μm, about 0.1 μm to about 1.0 μm, about 0.1 μm to about 0.5 μm, about 0.3 μm to about 3 μm, about 0.3 μm to about 2.5 μm, about 0.3 μm to about 2.0 μm, about 0.3 to about 1.5 μm, about 0.3 to about 1.0 μm, about 0.5 μm to about 3 μm, about 0.5 μm to about 2.5 μm, about 0.5 μm to about 2.0 μm, about 0.5 μm to about 1.5 μm, about 0.5 μm to about 1.0 μm, or about 1.0 μm to about 3 μm. The plurality of particles can have, for example, a Dv(10) value of about 0.1 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.8 μm, 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, or about 3 μm. In some aspects, the plurality of particles has a Dv(10) value of about 0.8 μm.

[0077] In some aspects, the plurality of particles has a Dv(50) value of from about 5 μm to about 20 μm. The plurality of particles can have a Dv(50) value of, for example, about 5 μm to about 18 μm, about 5 μm to about 15 μm, about 5 μm to about 13 μm, about 5 μm to about 10 μm, about 5 μm to about 8 μm, about 8 μm to about 20 μm, about 8 μm to about 18 μm, about 8 μm to about 15 μm, about 8 μm to about 13 μm, about 13 μm to about 20 μm, about 13 μm to about 18 μm, or about 10 μm to about 20 μm. The plurality of particles can have a Dv(50) value of, for example, about 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 15 μm, 18 μm, or about 20 μm. In some aspects, the plurality of particles has a Dv(50) value of about 13 μm.Attorney Docket No.38373.0001P1

[0078] In some aspects, the plurality of particles has a Dv(90) of from about 40 μm to about 120 μm. The plurality of particles can have a Dv(90) value of, for example, about 40 μm to about 100 μm, about 40 μm to about 90 μm, about 40 μm to about 80 μm, about 40 μm to about 60 μm, about 40 μm to about 50 μm, about 50 μm to about 120 μm, about 50 μm to about 100 μm, about 50 μm to about 90 μm, about 50 μm to about 80 μm, about 50 μm to about 70 μm, about 60 μm to about 120 μm, about 60 μm to about 100 μm, about 60 μm to about 90 μm, about 60 μm to about 80 μm, about 75 μm to about 120 μm, about 75 μm to about 100 μm, or about 75 μm to about 90 μm. The plurality of particles can have a Dv(90) of, for example, about 40 μm, 50 μm, 60 μm, 70 μm, 75 μm, 77 μm, 80 μm, 90 μm, 100 μm, 110 μm, or about 120 μm. In some aspects, the plurality of particles has a Dv(90) value of about 77 μm. 2. IN SOME ASPECTS, THE PLURALITY OF PARTICLES HAS A DV(10) VALUE OF FROM ABOUT 0.1 μM TO ABOUT 3 μM, A DV(50) VALUE OF FROM ABOUT 5 μM TO ABOUT 20 μM, AND A DV(90) OF FROM ABOUT 40 μM TO ABOUT 120 μM. FORM B

[0079] In one aspect, the crystalline polymorph is Form B.

[0080] In a further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 5.9, 6.0, 6.1, 6.2, or about 6.3º 2θ, about 6.2, 6.3, 6.4, 6.5, or about 6.6º 2θ, about 7.3, 7.4, 7.5, 7.6, or about 7.7º 2θ, about 14.3, 14.4, 14.5, 14.6, or about 14.7º 2θ, about 14.8, 14.9, 15.0, 15.1, or about 15.2º 2θ, and about 25.4, 25.5, 25.6, 25.7, or about 25.8º 2θ.

[0081] In a further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that further contains a peak at each of about 11.7 ± 0.2º 2θ, about 14.1 ± 0.2º 2θ, about 16.5 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 26.5 ± 0.2º 2θ, and about 27.3 ± 0.2º 2θ. For example, the crystalline polymorph can have a powder X-ray diffraction (XRD) pattern that further contains a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ.Attorney Docket No.38373.0001P1

[0082] In a further aspect, the powder XRD pattern further contains two or more peaks at positions selected from about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 9.9, 10.0, 10.1, 10.2, or about 10.3º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 15.5, 15.6, 15.7, 15.8, or about 15.9º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 17.1, 17.2, 17.3, 17.4, or about 17.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 19.3, 19.4, 19.5, 19.6, or about 19.7º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, orAttorney Docket No.38373.0001P1 about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 21.2, 21.3, 21.4, 21.5, or about 21.6º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 28.7, 28.8, 28.9, 29.0, or about 29.1º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 9.9, 10.0, 10.1, 10.2, or about 10.3º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 13.4, 13.5, 13.6, 13.7, or about 13.8º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 15.5, 15.6, 15.7, 15.8, or about 15.9º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 17.1, 17.2, 17.3, 17.4, or about 17.5. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 18.3, 18.4, 18.5, 18.6, or about 18.7º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, orAttorney Docket No.38373.0001P1 about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 20.5, 20.6, 20.7, 20.8, or about 20.9º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 23.0, 23.1, 23.2, 23.3, or about 23.5º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 9.9, 10.0, 10.1, 10.2, or about 10.3º 2θ, and about 13.4, 13.5, 13.6, 13.7, or about 13.8º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 11.9, 12.0, 12.1, 12.2, or about 12.3º 2θ and about 18.3, 18.4, 18.5, 18.6, or about 18.7º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 15.5, 15.6, 15.7, 15.8, or about 15.9º 2θ, and about 20.5, 20.6, 20.7, 20.8, or about 20.9º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 18.3, 18.4, 18.5, 18.6, or about 18.7º 2θ, and about 23.0, 23.1, 23.2, 23.3, or about 23.4º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, orAttorney Docket No.38373.0001P1 about 27.5º 2θ, and about 23.9, 24.0, 24.1, 24.2, or about 24.3º 2θ, and about 28.7, 28.8, 28.9, 29.0, or about 29.1º 2θ.

[0083] In various aspects, the powder XRD pattern further contains five or more peaks at positions selected from about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 9.9, 10.0, 10.1, 10.2, or about 10.3º 2θ, and about 11.9, 12.0, 12.1, 12.2, or about 12.3, and about 13.4, 13.5, 13.6, 13.7, or about 13.8º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 15.5, 15.6, 15.7, 15.8, or about 15.9º 2θ, and about 16.9, 17.0, 17.1, 17.2, or about 17.3º 2θ, and about 17.1, 17.2, 17.3, 17.4, or about 17.5º 2θ, and about 18.3, 18.4, 18.5, 18.6, or about 18.7º 2θ, and about 18.6, 18.7, 18.8, 18.9, or about 19.0º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 19.3, 19.4, 19.5, 19.6, or about 19.7º 2θ, and about 20.5, 20.6, 20.7, 20.8, or about 20.9º 2θ, and about 21.2, 21.3, 21.4, 21.5, or about 21.6º 2θ, and about 23.0, 23.1, 23.2, 23.3, or about 23.4º 2θ, and about 23.9, 24.0, 24.1, 24.2, or about 24.3º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 9.9, 10.0, 10.1, 10.2, or about 10.3º 2θ, and about 18.6, 18.7, 18.8, 18.9, orAttorney Docket No.38373.0001P1 about 19.0º 2θ, and about 27.9, 28.0, 28.1, 28.2, or about 28.3º 2θ, and about 28.7, 28.8, 28.9, 29.0, or about 29.1º 2θ.

[0084] In various aspects, the powder XRD pattern further contains ten or more peaks at positions selected from about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 9.9, 10.0, 10.1, 10.2, or about 10.3º 2θ, and about 11.9, 12.0, 12.1, 12.2, or about 12.3º 2θ, and about 13.4, 13.5, 13.6, 13.7, or about 13.8º 2θ, and about 15.5, 15.6, 15.7, 15.8, or about 15.9º 2θ, and about 16.9, 17.0, 17.1, 17.2, or about 17.3, and about 17.1, 17.2, 17.3, 17.4, or about 17.5, and about 18.3, 18.4, 18.5, 18.6, or about 18.7º 2θ, and about 18.6, 18.7, 18.8, 18.9, or about 19.0º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, or about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 9.9, 10.0, 10.1, 10.2, or about 10.3º 2θ, and about 11.9, 12.0, 12.1, 12.2, or about 12.3º 2θ, and about 13.4, 13.5, 13.6, 13.7, or about 13.8º 2θ, and about 21.2, 21.3, 21.4, 21.5, or about 21.6º 2θ, and about 23.0, 23.1, 23.2, 23.3, or about 23.4º 2θ, and about 23.9, 24.0, 24.1, 24.2, or about 24.3º 2θ, and about 27.9, 28.0, 28.1, 28.2, or about 28.3º 2θ, and about 28.7, 28.8, 28.9, 29.0, or about 29.1º 2θ.

[0085] In various aspects, the powder XRD pattern further contains fifteen or more peaks at positions selected from about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ. The powder XRD pattern can contain, for example, a peak at each of about 11.5, 11.6, 11.7, 11.8, or about 11.9º 2θ, and about 13.9, 14.0, 14.1, 14.2, or about 14.3º 2θ, and about 16.3, 16.4, 16.5, 16.6, or about 16.7º 2θ, and about 21.6, 21.7, 21.8, 21.9, orAttorney Docket No.38373.0001P1 about 22.0º 2θ, and about 26.3, 26.4, 26.5, 26.6, or about 26.7º 2θ, and about 27.1, 27.2, 27.3, 27.4, or about 27.5º 2θ, and about 6.8, 6.9, 7.0, 7.1, or about 7.2º 2θ, and about 9.1, 9.2, 9.3, 9.4, or about 9.5º 2θ, and about 9.9, 10.0, 10.1, 10.2, or about 10.3º 2θ, and about 11.9, 12.0, 12.1, 12.2, or about 12.3º 2θ, and about 13.4, 13.5, 13.6, 13.7, or about 13.8º 2θ, and about 15.5, 15.6, 15.7, 15.8, or about 15.9º 2θ, and about 16.9, 17.0, 17.1, 17.2, or about 17.3, and about 17.1, 17.2, 17.3, 17.4, or about 17.5, and about 18.3, 18.4, 18.5, 18.6, or about 18.7º 2θ, and about 18.6, 18.7, 18.8, 18.9, or about 19.0º 2θ, and about 19.3, 19.4, 19.5, 19.6, or about 19.7º 2θ, and about 20.5, 20.6, 20.7, 20.8, or about 20.9º 2θ, and about 21.2, 21.3, 21.4, 21.5, or about 21.6º 2θ, and about 23.0, 23.1, 23.2, 23.3, or about 23.4º 2θ, and about 23.9, 24.0, 24.1, 24.2, or about 24.3º 2θ.

[0086] In a further aspect, the powder XRD pattern further contains a peak at each of about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ.

[0087] In a further aspect, the crystalline polymorph has a powder XRD pattern as shown in FIG.14.

[0088] In various aspects, the solubility of the crystalline polymorph in water is from about 25 mg / ml to 100 mg / ml at 25 °C. The solubility of the crystalline polymorph in water can be, for example, from about 25 mg / ml to about 90 mg / ml, about 25 mg / ml to about 75 mg / ml, about 25 mg / ml to about 40 mg / ml, about 25 mg / ml to about 35 mg / ml, about 30 mg / ml to about 100 mg / ml, about 30 mg / ml to about 90 mg / ml, about 30 mg / ml to about 75 mg / ml, about 30 mg / ml to about 50 mg / ml, about 40 mg / ml to about 100 mg / ml, about 40 mg / ml to about 75 mg / ml, or about 30 mg / ml to about 75 mg / ml at 25 °C. The solubility of the crystalline polymorph in water can be, for example, about 25 mg / ml, about 30 mg / ml, about 31.8 mg / ml, about about 35 mg / ml, about 40 mg / ml, about 50 mg / ml, about 60 mg / ml, about 70 mg / ml, about 74.8 mg / ml, about 90 mg / ml, or about 100 mg / ml at 25 °C. In a further aspect, the solubility of the crystalline polymorph in water is about 31.8 mg / ml at 25 °C. In a still further aspect, the solubility of the crystalline polymorph in water is about 74.8 mg / ml at 25 °C.

[0089] In some aspects, the crystalline polymorph is present as a crystalline particulate material being a plurality of particles, wherein the plurality of particles has a Dv(10) value of from about 0.5 μm to about 5 μm. The plurality of particles can have a Dv(10) value, of for example, from about 0.5 μm to about 4.5 μm, about 0.5 μm to about 4.0 μm, about 0.5 μm toAttorney Docket No.38373.0001P1 about 3.5 μm, about 0.5 μm to about 3.0 μm, about 0.5 μm to about 2.5 μm, about 0.5 μm to about 2.0 μm, about 0.5 μm to about 1.5 μm, about 0.5 μm to about 1.0 μm, about 1.0 μm to about 4.5 μm, about 1.0 μm to about 4.0 μm, about 1.0 μm to about 3.5 μm, about 1.0 μm to about 3.0 μm, about 1.0 μm to about 2.5 μm, about 1.0 μm to about 2.0 μm, about 1.0 μm to about 1.5 μm, about 1.5 μm to about 5.0 μm, about 1.5 μm to about 4.5 μm, about 1.5 μm to about 4.0 μm, about 1.5 μm to about 3.5 μm, about 1.5 μm to about 3.0 μm, about 1.5 μm to about 2.5 μm, about 1.5 μm to about 2.0 μm, about 2.0 μm to about 4.0 μm, about 2.5 to μm about 3.5 μm, or about 3.0 μm to about 5.0 μm. The plurality of particles can have, for example, a Dv(10) value of about 1.0 μm, 1.2 μm, 1.3 μm, 1.4 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, 3.5 μm, 4.0 μm, 4.5 μm, or about 5.0 μm. In some aspects, the plurality of particles has a Dv(10) value of about 1.5 μm.

[0090] In some aspects, the plurality of particles has a Dv(50) value of from about 5 μm to about 25 μm. The plurality of particles can have a Dv(50) value of, for example, from about 5 μm to about 20 μm, about 5 μm to about 18 μm, about 5 μm to about 16 μm, about 8 μm to about 25 μm, about 8 μm to about 20 μm, about 8 μm to about 18 μm, about 8 μm to about 16 μm, about 10 μm to about 25 μm, about 10 μm to about 20 μm, about 10 μm to about 18 μm, about 10 μm to about 16 μm, about 12 μm to about 25 μm, about 12 μm to about 20 μm, about 12 μm to about 18 μm, about 15 μm to about 25 μm, or from about 15 μm to about 20 μm. The plurality of particles can have a Dv(50) value of, for example, about 5 μm, 8 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 18 μm, 20 μm, or about 25 μm. In some aspects, the plurality of particles has a Dv(50) value of about 16 μm.

[0091] In some aspects, the plurality of particles has a Dv(90) of from about 30 μm to about 100 μm. The plurality of particles can have a Dv(90) value, of for example, from about 30 μm to about 90 μm, about 30 μm to about 80 μm, about 30 μm to about 70 μm, about 30 μm to about 60 μm, about 40 μm to about 100 μm, about 40 μm to about 90 μm, about 40 μm to about 80 μm, about 40 μm to about 70 μm, about 40 μm to about 60 μm, about 50 μm to about 100 μm, about 50 μm to about 90 μm, about 50 μm to about 80 μm, about 50 μm to about 70 μm, about 50 μm to about 60 μm, about 60 μm to about 100 μm, or about 70 μm to about 100 μm. The plurality of particles can have a Dv(90) value of, for example, about 30 μm, 40 μm, 50 μm, 58 μm, 60 μm, 70 μm, 80 μm, 90 μm, or about 100 μm. In some aspects, the plurality of particles has a Dv(90) value of about 58 μm.

[0092] In some aspects, the plurality of particles has a Dv(10) value of from about 0.5 μm to about 5 μm, a Dv(50) value of from about 5 μm to about 25 μm, and a Dv(90) value, of from about 30 μm to about 90 μm.Attorney Docket No.38373.0001P1C. PHARMACEUTICAL COMPOSITIONS

[0093] In one aspect, disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of a disclosed crystalline polymorph or a pharmaceutically acceptable salt thereof.

[0094] In a further aspect, disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of a crystalline polymorph of a compound having a structure:.

[0095] In a further aspect, disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of of a crystalline polymorph being Form A, or a pharmaceutically acceptable salt thereof.

[0096] In a further aspect, disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of of a crystalline polymorph being Form B, or a pharmaceutically acceptable salt thereof:

[0097] In various aspects, the compounds and compositions can be administered inpharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, intravenous, topical, or oral administration.

[0098] The nature of the pharmaceutical compositions for administration is dependent on themode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The crystalline polymorphs disclosedAttorney Docket No.38373.0001P1 herein can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0099] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed crystalline polymorphs (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0100] In various aspects, the pharmaceutical compositions can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the crystalline polymorphs described herein. The crystalline polymorphs, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0101] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0102] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsulesAttorney Docket No.38373.0001P1 are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0103] A tablet containing the composition can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0104] The pharmaceutical compositions comprise a crystalline polymorph disclosed herein (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0105] Pharmaceutical compositions suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0106] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0107] Pharmaceutical compositions can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouthwashes, gargles, andAttorney Docket No.38373.0001P1 the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a crystalline polymorph as described herein, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0108] Pharmaceutical compositions can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0109] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a crystalline polymorph, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0110] In various aspects, the effective amount is a therapeutically effective amount. In a further aspect, the effective amount is a prophylactically effective amount.

[0111] In various aspects, the pharmaceutical composition is administered to a mammal. In a further aspect, the mammal is a human. In yet further aspect, the human is a patient.

[0112] In a further aspect, the pharmaceutical composition is used to treat cancer. In a yet further aspect, the cancer is associated with dysregulation of Top1 and / or MYC activity. In a still further aspect, the cancer is selected from a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In yet a further aspect, the cancer is Ewing’s sarcoma. In an even further aspect, the cancer is glioblastoma.Attorney Docket No.38373.0001P1

[0113] It is understood that the disclosed compositions can be prepared from thedisclosed crystalline polymorphs. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.D. METHODS FOR MODIFYING TOPOISOMERASE I AND / OR MYC SIGNALING IN ASUBJECT

[0114] In one aspect, disclosed are methods for modifying topoisomerase I (Top1)and / or MYC signaling in a subject, the method comprising the step of administering to the subject an effective amount of a crystalline polymorph as described herein. In a further aspect, the crystalline polymorph is a pharmaceutically acceptable salt of a compound having a structure:.

[0115] In a further aspect, the crystalline polymorph is Form A. In a still furtheraspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at each of about 13.0 ± 0.2º 2θ and about 24.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 12.8, 12.9, 13.0, 13.1, or 13.2º 2θ and also contains a peak at 24.4, 24.5, 24.6, 24.7, or 24.8º 2θ.

[0116] In a further aspect, the crystalline polymorph is Form B. In a still furtheraspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 5.9, 6.0, 6.1, 6.2, or about 6.3º 2θ, about 6.2, 6.3, 6.4, 6.5, or about 6.6º 2θ, about 7.3, 7.4, 7.5, 7.6, or about 7.7º 2θ, about 14.3, 14.4, 14.5, 14.6, or about 14.7º 2θ, about 14.8, 14.9, 15.0, 15.1, or about 15.2º 2θ, and about 25.4, 25.5, 25.6, 25.7, or about 25.8º 2θ.

[0117] In a further aspect, modifying topoisomeraise I (Top1) and / or MYC signalingin a subject is decreasing Top1 and / or MYC signaling in a subject. In a still further aspect,Attorney Docket No.38373.0001P1 modifying topoisomerase I (Top1) and / or MYC signaling in a subject is inhibiting Top1 and / or MYC signaling in a subject.

[0118] In various aspects, the subject has been diagnosed with a need for modifyingTop1 and / or MYC signaling prior to the administering step.

[0119] In a further aspect, the subject has been diagnosed with a need for treatment ofa disease or disorder associated with Top1 signaling dysfunction prior to the administering step. In a yet still further aspect, the method comprises the step of identifying a subject in need of treatment of a disease or disorder associated with Top1 and / or MYC signaling dysfunction. In an even further aspect, the disease or disorder is a cancer such as, for example, a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

[0120] In some aspects, the subject has been diagnosed with cancer prior to theadministering step.E. METHODS FOR MODIFYING TOPOISOMERASE I AND / OR MYC SIGNIALING IN ACELL

[0121] In one aspect, disclosed are methods for modifying topoisomerase I (Top1)and / or MYC signaling in at least one cell, the method comprising the step of contacting the cell with an effective amount of the crystalline polymorph as described herein. In a further aspect, the crystalline polymorph is a pharmaceutically acceptable salt of a compound having a structure:.

[0122] In a further aspect, the crystalline polymorph is Form A. In a still furtheraspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that containsAttorney Docket No.38373.0001P1 a peak at each of about 13.0 ± 0.2º 2θ and about 24.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 12.8, 12.9, 13.0, 13.1, or 13.2º 2θ and also contains a peak at 24.4, 24.5, 24.6, 24.7, or 24.8º 2θ.

[0123] In a further aspect, the crystalline polymorph is Form B. In a still further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 5.9, 6.0, 6.1, 6.2, or about 6.3º 2θ, about 6.2, 6.3, 6.4, 6.5, or about 6.6º 2θ, about 7.3, 7.4, 7.5, 7.6, or about 7.7º 2θ, about 14.3, 14.4, 14.5, 14.6, or about 14.7º 2θ, about 14.8, 14.9, 15.0, 15.1, or about 15.2º 2θ, and about 25.4, 25.5, 25.6, 25.7, or about 25.8º 2θ.

[0124] In a further aspect, modifying topoisomeraise I (Top1) and / or MYC signaling in a subject is decreasing Top1 and / or MYC signaling in at least one cell. In a still further aspect, modifying topoisomerase I (Top1) and / or MYC signaling in a subject is inhibiting Top1 and / or MYC signaling in at least one cell.

[0125] In a further aspect, the cell is a human cell. In a still further aspect, the cell has been isolated from a human prior to the administering step.

[0126] In a further aspect, contacting the cell is via administration to a subject.

[0127] In a further aspect, the subject has been diagnosed with a need for modification of Top1 and / or MYC signaling prior to the administering step.

[0128] In a further aspect, the subject has been diagnosed with a need for treatment of a disease or disorder associated with Top1 and / or MYC signaling dysfunction. In a still further aspect, the disease or disorder is a cancer such as, for example, a sarcoma (e.g., Ewing’s sarcoma), a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).Attorney Docket No.38373.0001P1F. METHODS FOR TREATING CANCER IN A SUBJECT

[0129] In one aspect, disclosed are methods of treating cancer in a subject in needthereof, the method comprising administering to the subject an effective amount of a crystalline polymorph described herein. In a further aspect, the crystalline polymorph is a pharmaceutically acceptable salt of a compound having a structure:.

[0130] In a further aspect, the crystalline polymorph is Form A. In a still furtheraspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at each of about 13.0 ± 0.2º 2θ and about 24.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 12.8, 12.9, 13.0, 13.1, or 13.2º 2θ and also contains a peak at 24.4, 24.5, 24.6, 24.7, or 24.8º 2θ.

[0131] In a further aspect, the crystalline polymorph is Form B. In a still furtheraspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 5.9, 6.0, 6.1, 6.2, or about 6.3º 2θ, about 6.2, 6.3, 6.4, 6.5, or about 6.6º 2θ, about 7.3, 7.4, 7.5, 7.6, or about 7.7º 2θ, about 14.3, 14.4, 14.5, 14.6, or about 14.7º 2θ, about 14.8, 14.9, 15.0, 15.1, or about 15.2º 2θ, and about 25.4, 25.5, 25.6, 25.7, or about 25.8º 2θ.

[0132] In a further aspect, the subject is a mammal. In a still further aspect, themammal is a human.

[0133] In a further aspect, the subject has been diagnosed with a need for treatment ofcancer prior to the administering step.

[0134] In a further aspect, the method further comprises the step of identifying asubject in need of treatment of cancer.

[0135] In various aspects, the effective amount is a therapeutically effective amount.In a further aspect, the effective amount is a prophylactically effective amount.Attorney Docket No.38373.0001P1

[0136] In various aspects, the cancer is associated with dysregulation of Top1 and / or MYC activity. In a further aspect, the cancer is associated with an increase in Top1 and / or MYC activity.

[0137] In a further aspect, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In a still further aspect, the cancer is a solid tumor or a lymphoma. In a yet still further aspect, the cancer is a glioma. In a yet still further aspect, the cancer is leukemia.

[0138] In various aspects, the cancer is a pediatric cancer. In a further aspect, the pediatric cancer is a Ewing’s sarcoma or a solid tumor.

[0139] In various aspects, the crystalline polymorph is administered at a dose of from about 10 mg / m2to about 100 mg / m2. The crystalline polymorph can be administered, for example, at a dose of from about 10 mg / m2to about 90 mg / m2, about mg / m2, about 10 mg / m2to about 70 mg / m2, about 10 mg / m2to about mg / m2to about 50 mg / m2, about 10 mg / m2to about 40 mg / m2, aboutmg / m2, about 10 mg / m2to about 20 mg / m2, about 20 mg / m2to about 100 mg / m2, about 20 mg / m2to about 90 mg / m2, about 20 mg / m2to about 80 mg / m2, about 20 mg / m2to about 70 mg / m2, about 20 mg / m2to about 60 mg / m2, about 20 mg / m2to about 50 mg / m2, about 20 mg / m2to about 40 mg / m2, about 20 mg / m2, about 30 mg / m2to about 100 mg / m2, about 30 mg / m2to about 90 mg / m2, about 30 mg / m2to about 80 mg / m2, about 30 mg / m2to about 70 mg / m2, about 30 mg / m2to about 60 mg / m2, about 30 mg / m2to about 50 mg / m2, about 30 mg / m2to about 40 mg / m2, about 40 mg / m2to about 100 mg / m2, about 40 mg / m2to about 90 mg / m2, about 40 mg / m2to about 80 mg / m2, about 40 mg / m2to about 70 mg / m2, about 40 mg / m2to about 60 mg / m2, about 40 mg / m2to about 50 mg / m2, about 50 mg / m2to about 100 mg / m2, about 50 mg / m2to about 90 mg / m2, about 50 mg / m2to about 80 mg / m2, about 50 mg / m2to about 70 mg / m2, about 50 mg / m2to about 60 mg / m2, about 60 mg / m2to about 100 mg / m2, about 60 mg / m2to about 90 mg / m2, about 60 mg / m2to about 80 mg / m2, about 60 mg / m2to about 70 mg / m2, about 70 mg / m2to about 100 mg / m2, about 70 mg / m2to about 90 mg / m2, about 70 mg / m2to about 80 mg / m2, about 80 mg / m2to about 100 mg / m2, about 80 mg / m2to about 90 mg / m2, or about 90 mg / m2to about 100 mg / m2. The crystalline polymorph can be administered, for example, at a dose of about 10 mg / m2, about 20 mg / m2, about 30Attorney Docket No.38373.0001P1 mg / m2, about 40 mg / m2, about 50 mg / m2, about 60 mg / m2, about 70 mg / m2, about 80 mg / m2, about 90 mg / m2, or about 100 mg / m2. In a further aspect, the crystalline polymorph is administered once daily at a dose of from 10 mg / m2to about 60 mg / m2. In a still further aspect, the crystalline polymorph is administered once daily at a dose of about 60 mg / m2.

[0140] In various aspects, the crystalline polymorph is administered once daily at a dose of from 10 mg / m2to about 60 mg / m2for a time period of from 1 to 7 days. The crystalline polymorph can be administered once daily at a dose of from 10 mg / m2to about 60 mg / m2for a time period of from 1 to 6 days, 1 to 5 days, 1 to 4 days, 1 to 3 days, 1 to 2 days, 2 to 7 days, 2 to 6 days, 2 to 5 days, 2 to 4 days, 2 to 3 days, 3 to 7 days, 3 to 6 days, 3 to 5 days, 3 to 4 days, 4 to 7 days, 4 to 6 days, 4 to 5 days, 5 to 7 days, 5 to 6 days, or from 6 to 7 days. In a further aspect, the crystalline polymorph is administered once daily at a dose of from about 10 mg / m2to about 60 mg / m2for a time period of 1 to 5 days.

[0141] In various aspects, the crystalline polymorph is administered once daily at a dose of from 80 mg / m2to about 100 mg / m2. The crystalline polymorph can be administered once daily at a dose of, for example, about 80 mg / m2to about 95 mg / m2, about 80 mg / m2to about 90 mg / m2, about 80 mg / m2to about 85 mg / m2, about 85 mg / m2to about 100 mg / m2, about 85 mg / m2to about 95 mg / m2, about 85 mg / m2to about 90 mg / m2, about 90 mg / m2to about 100 mg / m2, about 90 mg / m2to about 95 mg / m2, or about 95 mg / m2to about 100 mg / m2. The crystalline polymorph can be administered once daily at a dose of, for example, about 80 mg / m2, about 85 mg / m2, about 90 mg / m2, about 95 mg / m2, or about 100 mg / m2. In a further aspect, the crystalline polymorph is administered at a dose of about 90 mg / m2.

[0142] In various aspects, the crystalline polymorph is administered once a week at a dose of from about 80 mg / m2to about 100 mg / m2. The crystalline polymorph can be administered once a week at a dose of, for example, about 80 mg / m2to about 95 mg / m2, about 80 mg / m2to about 90 mg / m2, about 80 mg / m2to about 85 mg / m2, about 85 mg / m2to about 100 mg / m2, about 85 mg / m2to about 95 mg / m2, about 85 mg / m2to about 90 mg / m2, about 90 mg / m2to about 100 mg / m2, about 90 mg / m2to about 95 mg / m2, or about 95 mg / m2to about 100 mg / m2. The crystalline polymorph can be administered once a week at a dose of, for example, about 80 mg / m2, about 85 mg / m2, about 90 mg / m2, about 95 mg / m2, or about 100 mg / m2.Attorney Docket No.38373.0001P1G. METHODS OF MAKING A CRYSTALLINE POLYMORPH

[0143] In one aspect, disclosed are methods for making a crystalline polymorphdescribed herein, the method comprising: (a) suspending a compound having a structure:

[0144] or a pharmaceutically acceptable salt thereof, in a basic solution; (b) filtering;(c) adding an acid; and (d) filtering.

[0145] In various aspects, the basic solution can be any suitable solution with a pHvalue higher than 7. In some aspects, the basic solution has a pH of from about 7 to about 14, such as about 7 to about 13, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 14, about 8 to about 13, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 14, about 9 to about 13, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 14, about 10 to about 13, about 10 to about 12, about 10 to about 11, about 11 to about 14, about 11 to about 13, about 11 to about 12, about 12 to about 14, about 12 to about 13, or about 13 to about 14. In further aspects, the basic solution has a pH of about 7, about 8, about 9, about 10, about 11, about 12, about 13, or about 14. In some aspects, the basic solution is a sodium bicarbonate solution. In a further aspect, the basic solution is a 10% aqueous sodium bicarbonate solution.

[0146] In a further aspect, the suspending step (a) is for a time period of from about10 minutes to about 1.5 hours. The suspending step (a) can be, for example, for a time period of from about 10 minutes to about 1.0 hour, about 10 minutes to about 50 minutes, about 10 minutes to about 40 minutes, about 10 minutes to about 30 minutes, about 10 minutes to about 20 minutes, about 20 minutes to about 1.5 hours, about 20 minutes to about 1.0 hour, about 20 minutes to about 50 minutes, about 20 minutes to about 40 minutes, about 20 minutes to about 30 minutes, about 30 minutes to about 1.5 hours, about 30 minutes to about 1.0 hour, about 30 minutes to about 50 minutes, about 30 minutes to about 40 minutes, about 40 minutes to about 1.5 hours, about 40 minutes to about 1.0 hour, about 40 minutes to about 50 minutes, about 50 minutes to about 1.5 hours, about 50 minutes to about 1.0 hour, or aboutAttorney Docket No.38373.0001P1 1.0 hour to about 1.5 hours. The suspending step (a) can be, for example, for a time period of about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1.0 hour, or about 1.5 hours. In a still further aspect, the suspending step (a) is for a time period of about 1.0 hour.

[0147] In various aspects, the suspending step (a) further comprises adding an organic solvent. In such aspects, the suspension can form a two-phase mixture comprising an aqueous layer and an organic layer. In a further aspect, the solvent is chloroform. In a still further aspect, the suspending step (a) further comprises stirring the two-phase mixture for a time period of about 1.5 hours to about 2.5 hours after the organic solvent is added. The suspending step (a) can further comprise stirring the two-phase mixture for a time period of, for example, about 1.5 hours, about 2.0 hours, or about 2.5 hours after the organic solvent is added. In a yet still further aspect, the suspending step (a) further comprises stirring the two- phase mixture for about 2.0 hours after the organic solvent is added.

[0148] In various aspects, filtering step (b) comprises isolating the organic layer, drying the organic layer over a drying agent, and filtering the organic layer through a filter to produce a filtrate and remove the drying agent. In some aspects, the drying agent is Na2SO4. In some aspects, the filter is a celite pad. In further aspects, the filter is washed with an organic solvent.

[0149] In a further aspect, the filtering step (b) produces a filtrate.

[0150] In some aspects, following the filtering step (b) but prior to the adding step (c), the filtrate is cooled. In a yet still further aspect, the filtrate is cooled to a temperature of from about 1 °C to about 10 °C. The filtrate can be cooled, for example, to a temperature of from about 1 °C to about 9 °C, about 1 °C to about 8 °C, about 1 °C to about 7 °C, about 1 °C to about 6 °C, about 1 °C to about 5 °C, about 1 °C to about 4 °C, about 1 °C to about 3 °C, about 1 °C to about 2 °C, about 2 °C to about 10 °C, about 2 °C to about 8 °C, about 2 °C to about 6 °C, about 2 °C to about 4 °C, about 4 °C to about 10 °C, about 4 °C to about 8 °C, about 4 °C to about 6 °C, about 6 °C to about 10 °C, about 6 °C to about 8 °C, or about 8 °C to about 10 °C. The filtrate can be cooled, for example, to a temperature of about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, or about 10 °C. In a yet still further aspect, the filtrate is cooled to temperature of about 5 °C.

[0151] In some aspects, step (c) comprises adding ethanolic hydrochloric acid to the filtrate, thereby producing a solid salt. In such aspects, step (d) can comprise filtering the solid salt. In further aspects, following step (d), the solid salt can be washed with ethanol to remove organic solvent. In yet further aspects, following washing with ethanol, the solid saltAttorney Docket No.38373.0001P1 can be dried. In various aspects, the method produces a microcrystalline polymorph of Form B.

[0152] In various aspects, the filtering step (b) produces a filtrate, wherein following the filtering step (b) but prior to the adding step (c), the filtrate is concentrated, thereby forming a concentrated filtrate. In a still further aspect, the concentrated filtrate is diluted with a protic solvent, thereby providing a suspension. Non-limiting examples of suitable protic solvents include methanol, ethanol, isopropyl alcohol, water, and acetic acid. In a yet still further aspect, the protic solvent is ethanol.

[0153] In a further aspect, the suspension is filtered and washed with ethanol to provide a solid free base. In a still further aspect, the solid free base is suspended in a protic solvent, thereby providing a second suspension. Non-limiting examples of suitable protic solvents include methanol, ethanol, isopropyl alcohol, water, and acetic acid. In a yet still further aspect, the protic solvent is ethanol.

[0154] In a further aspect, the second suspension is cooled. In a further aspect, the second suspension is cooled to a temperature of from about 1 °C to about 10 °C. The second suspension can be cooled, for example, to a temperature of from about 1 °C to about 9 °C, about 1 °C to about 8 °C, about 1 °C to about 7 °C, about 1 °C to about 6 °C, about 1 °C to about 5 °C, about 1 °C to about 4 °C, about 1 °C to about 3 °C, about 1 °C to about 2 °C, about 2 °C to about 10 °C, about 2 °C to about 8 °C, about 2 °C to about 6 °C, about 2 °C to about 4 °C, about 4 °C to about 10 °C, about 4 °C to about 8 °C, about 4 °C to about 6 °C, about 6 °C to about 10 °C, about 6 °C to about 8 °C, or about 8 °C to about 10 °C. The second suspension can be cooled, for example, to a temperature of about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, or about 10 °C. In a yet still further aspect, the second suspension is cooled to temperature of about 5 °C.

[0155] In a further aspect, the acid is added dropwise in step (c). Non-limiting examples of suitable acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, and citric acid. In a still further aspect, the acid is a hydrochloric acid. In a yet still further aspect, the acid is an ethanolic hydrochloric acid solution.

[0156] In a further aspect, the adding step (c) further comprises stirring for a time period of from about 30 minutes to about 1.5 hours following addition of the acid. The adding step (c) can further comprise stirring for a time period of, for example, from about 30 minutes to about 1 hour, from about 30 minutes to about 45 minutes, from about 45 minutes to about 1.5 hours, from about 45 minutes to about 1 hour, or from about 1 hour to about 1.5 hoursAttorney Docket No.38373.0001P1 following addition of the acid. The adding step (c) can further comprise stirring for a time period of, for example, about 30 minutes, about 45 minutes, about 1 hour, or about 1.5 hours following addition of the acid. In a still further aspect, the adding step (c) further comprises stirring for a time period of about 1 hour following addition of the acid.

[0157] In a further aspect, the adding step (c) further comprises stirring at a temperature of from about 1 °C to about 15 °C following addition of the acid. The adding step (c) can further comprise stirring at a temperature of, for example, from about 1 °C to about 10 °C, about 1 °C to about 8 °C, about 1 °C to about 5 °C, about 1 °C to about 3 °C, about 3 °C to about 15 °C, about 3 °C to about 10 °C, about 3 °C to about 8 °C, about 3 °C to about 5 °C, about 5 °C to about 15 °C, about 5 °C to about 10 °C, about 5 °C to about 8 °C, about 8 °C to about 15 °C, about 8 °C to about 10 °C, or about 10 °C to about 15 °C following addition of the acid. The adding step (c) can further comprise stirring at a temperature of, for example, about 1 °C, about 3 °C, about 5 °C, about 8 °C, about 10 °C, or about 15 °C following addition of the acid. In a still further aspect, the adding step (c) further comprises stirring at a temperature of from about 5 °C to about 10 °C following addition of the acid.

[0158] In a further aspect, the filtering step (d) provides a solid.In such aspects, the method can further comprise filtering and / or drying the solid. In a still further aspect, the solid is dried at a temperature of from about 40 °C to about 50 °C. In a yet still further aspect, the solid is dried at a temperature of about 45 °C. In a yet still further aspect, the solid is dried for a time period of from about 3 hours to about 7 hours. The solid can be dried, for example, for a time period of from about 3 hours to about 6 hours, about 3 hours to about 5 hours, about 3 hours to about 4 hours, about 4 hours to about 7 hours, about 4 hours to about 6 hours, about 4 hours to about 5 hours, about 5 hours to about 7 hours, about 5 hours to about 6 hours, or about 6 hours to about 7 hours. The solid can be dried, for example, for a time period of about 3 hours, about 4 hours, about 5 hours, about 6 hours, or about 7 hours. In a yet still further aspect, the solid is dried for a time period of about 5 hours. In various aspects, the method produces a microcrystalline polymorph of Form A.

[0159] In one aspect, the method comprises: (a) suspending a compound having a structure:Attorney Docket No.38373.0001P1, or a pharmaceutically acceptable salt thereof, in a sodium bicarbonate solution for a time period of from about 30 minutes to about 1.5 hours, thereby providing a suspension, and adding a water-insoluble solvent to the suspension and stirring for a time period of from about 1.5 hours to about 2.5 hours, thereby forming an aqueous layer and an organic layer; (b) separating the organic layer from the aqueous layer and filtering the organic layer to obtain a filtrate and cooling the filtrate to a temperature of from about 1 °C to about 10 °C; (c) adding an ethanolic hydrochloric acid solution dropwise to the filtrate and stirring the filtrate for a time period of from about 30 minutes to about 1.5 hours at a temperature of from about 1 °C to about 15 °C, thereby providing a second suspension; (d) filtering the second suspension to obtain a solid; and (e) drying the solid hydrochloride at a temperature of from about 40 °C to about 50 °C for a time period of from about 3 hours to about 7 hours, and recrystallizing the solid hydrochloride from ethanol to remove residual chloroform.

[0160] In a further aspect, the suspending step (a) is for a time period of about 1.0hour.

[0161] In a further aspect, in step (a) stirring is for a time period of about 2.0 hours.

[0162] In a further aspect, in step (b), the filtrate is cooled to a temperature of about 5°C.

[0163] In a further aspect, in step (b), prior to cooling, the filtrate is concentrated,thereby forming a concentrated filtrate.

[0164] In a further aspect, the concentrated filtrate is diluted with a protic solvent,thereby providing a third suspension.

[0165] In a further aspect, the protic solvent is ethanol.

[0166] In a further aspect, the third suspension is filtered to provide a solid.

[0167] In a further aspect, the solid is suspended in a protic solvent, thereby providinga fourth suspension, and wherein the fourth suspension is cooled to the temperature of from about 1 °C to about 10 °C.

[0168] In a further aspect, the protic solvent is ethanol.

[0169] In a further aspect, in step (c) stirring is for a time period of about 1 hour.Attorney Docket No.38373.0001P1

[0170] In a further aspect, in step (c) stirring is at a temperature of from about 5 °C toabout 10 °C.

[0171] In a further aspect, in step (e) the solid is dried at a temperature of about 45°C.

[0172] In a further aspect, in step (e) the solid is dried for a time period of about 5hours.

[0173] In a further aspect, the crystalline polymorph has a powder X-ray diffraction(XRD) pattern that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ.

[0174] In a further aspect, the powder XRD pattern further contains a peak at each ofabout 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ.H. KITS

[0175] In one aspect, disclosed are kits comprising a crystalline polymorph asdescribed herein and one or more selected from: (a) an agent associated with the treatment of cancer; (b) instructions for administering the crystalline polymorph in connection with treating cancer; and (c) instructions for treating cancer. In a further aspect, the crystalline polymorph is a pharmaceutically acceptable salt of a compound having a structure:.

[0176] In a further aspect, the crystalline polymorph is Form A. In a still furtheraspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at each of about 13.0 ± 0.2º 2θ and about 24.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at 12.8, 12.9, 13.0, 13.1, or 13.2º 2θ and also contains a peak at 24.4, 24.5, 24.6, 24.7, or 24.8º 2θ.Attorney Docket No.38373.0001P1

[0177] In a further aspect, the crystalline polymorph is Form B. In a still further aspect, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ. For example, the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 5.9, 6.0, 6.1, 6.2, or about 6.3º 2θ, about 6.2, 6.3, 6.4, 6.5, or about 6.6º 2θ, about 7.3, 7.4, 7.5, 7.6, or about 7.7º 2θ, about 14.3, 14.4, 14.5, 14.6, or about 14.7º 2θ, about 14.8, 14.9, 15.0, 15.1, or about 15.2º 2θ, and about 25.4, 25.5, 25.6, 25.7, or about 25.8º 2θ.

[0178] In various aspects, the agent is a chemotherapeutic agent. In a further aspect, the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a PARP inhibitor, and an mTOR inhibitor agent.

[0179] In various aspects, the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

[0180] In various aspects, the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0181] In various aspects, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

[0182] In various aspects, the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[0183] In various aspects, the PARP inhibitor is selected from olaparib, niraparib, and rucaparib.

[0184] In various aspects, the mTOR inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0185] In a further aspect, the crystalline polymorph and the agent are co-packaged.Attorney Docket No.38373.0001P1

[0186] All publications and patent applications cited in this specification are hereinincorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.I. EXAMPLES

[0187] The following examples are put forth so as to provide those of ordinary skill inthe art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods described and aspected herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions. 1. CONVERSION OF FORM A POLYMORPH TO FORM B POLYMORPH

[0188] Two methods were implemented to convert Form A to Form B.Attorney Docket No.38373.0001P1 a. METHOD 1

[0189] A representativeNMR spectrum of the Form A hydrochloride salt in DMSO-d6is shown in FIG.1. A High Performance Liquid Chromatrogram (HPLC) Form A salt is shown in FIG.2, and retention times are presented in Table 1 below. TABLE 1.

[0190] Pure Form A hydrochloride salt (5.0 g), which has a solubility of 1.4 mg / mL in water, was stirred in 10% aq NaHCO3solution (150.0 mL) for 1.0 h. Chloroform (150.0 mL) was added at room temperature. The reaction mixture was stirred for 2.0 h at room temperature. Both layers were separated, and the aqueous layer was extracted with chloroform (3 x 50.0 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered through a pad of celite, and the filter pad was washed with chloroform (20.0 mL).

[0191] The chloroform filtrate was placed in a dry, clean round-bottomed flask and cooled to 0 ˚C. Ethanolic HCl solution (10.0 eq) was added dropwise, and the solution was stirred for 1 h. The solid was filtered and washed with ethanol (20 mL) and dried at 45 °C for 5 h to afford the solid salt (3.6 g).

[0192] To remove chloroform, the salt (3.5 g) was suspended in ethanol (105 mL) and heated to 60 °C for 1 h. The reaction mixture was cooled to room temperature and filtered and dried to give Form B hydrochloride salt (2.8.g), which was found to have a higher solubility in water, 31.8 mg / mL, relative to Form A hydrochloride salt, which has a solubilityAttorney Docket No.38373.0001P1 in water of 1.4 mg / mL. The Form B hydrochloride salt obtained by Method 1 is shown in FIG.3A. A representative HPLC trace is shown in FIG.4, and retention times are shown in Table 2 below. HPLC: 99.21%, retention time: 15.11 min. The NMR spectrum was recorded with DMSO-d6as the solvent. The chloride content of the product was 6.45% as determined by elemental analysis. TABLE 2.b. METHOD 2

[0193] Pure Form A hydrochloride salt (5.0 g), which has a solubility in water of 1.4 mg / mL, was stirred in 10% aq NaHCO3solution (150.0 mL) for 1.0 h. Chloroform (150.0 mL) was added at room temperature. The reaction mixture was stirred for 2.0 h at room temperature. The layers were separated and the aqueous layer was extracted with chloroform (3 x 50.0 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered through a pad of celite, and the filter pad was washed with chloroform (20.0 mL).

[0194] The chloroform layer was concentrated under vacuum and diluted with ethanol (100.0 mL). The suspension was filtered and washed with ethanol (20.0 mL) and dried to afford the solid free base (4.4 g).

[0195] The free base (4.3 g) was suspended in ethanol (100 mL) and the suspension was cooled to 5 °C. Ethanolic HCl solution (10 equiv) was then added dropwise, and the suspension was stirred for 1.0 h at 5 to 10 °C. The solid was filtered and washed with ethanolAttorney Docket No.38373.0001P1 (20.0 mL), followed by drying at 45 °C for 5 h to afford the salt (4.2 g). The Form B hydrochloride salt obtained by Method 2 is shown in FIG.3B. A representative HPLC trace is shown in FIG.5, and retention times are shown in Table 3 below. HPLC: 98.69%, Retention time: 15.11 min. The NMR spectrum, recorded with DMSO-d6as the solvent, is shown in FIG.6. The chloride content of the product was 6.73% as determined by elemental analysis. TABLE 3.2. X-RAY POWDER DIFFRACTION (XRPD) PATTERNS

[0196] Powder XRD patterns were collected on a PANalytical Empyreandiffractometer using a Cu K incident beam of radiation generated at 45 kV / 40 mA. Asilicon standard was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST-certified position. Powder samples were sandwiched between 3- m-thick Etnom films and analyzed in transmission geometry. The X-ray source wasconfigured with Soller slits of 0.02 radians, a fixed anti-scatter slit of 1 / 2 , a mask of 10 mm,and a fixed divergence slit of 1 / 2 . The diffracted beam passed through a 3.0 mm anti-scatterextension and Soller slits of 0.02 radians to the detector. A beam-stop was used to minimize the background generated by air. The diffraction pattern was collected with Data CollectorAttorney Docket No.38373.0001P1 software using a PIXcel3D-Medipix3 detector located 240 mm from the specimen. The datawas acquired using one scan from 2-40 2θ with the sample spinning at a revolution time of 2seconds.

[0197] The powder XRD pattern obtained on Form B is shown in FIG. 7. The pattern shows predominately broad peaks indicative of crystalline material(s) comprised of very small particles (possibly sub-micron) or highly strained crystals. The powder XRD pattern obtained on Form A is shown in FIG.8. The pattern shows somewhat sharper peaks indicative of a crystalline material(s). This material may contain slightly larger particles which still appear to be of insufficient size and quality for structure determination.

[0198] Comparison of the two patterns is provided in FIG.9. Both patterns display peak positions that are remarkably similar, especially below 25 °2θ. However, each pattern also contains additional peaks that have distinctly different positions. 3. SLURRY STUDY AND OBSERVED PEAKS LISTS

[0199] A saturated solution of the polymorph was prepared by adding excess solid to solvent and stirring at room temperature for ~24 hours. Form B was used and DMSO and HPLC grade water were initially evaluated as the solvents. The DMSO solution became a rusty brown color and was not used further. The aqueous solution became a dark purple color and the initial amount of solid fully dissolved. Additional solid was added and the mixture was stirred at room temperature for 24 hours, and this procedure was repeated two more times until a saturated solution was achieved. The saturated solution was then filtered through a 0.2-μm nylon filter, and the saturated solution was used to prepare a slurry. Approximately 40 mg of Form B was weighed into a 20-mL vial along with approximately 1000 μL of the filtered, saturated solution and a stir bar. The suspension was stirred at room temperature for 12 days. The suspension was filtered through a 0.2-μm PTFE Swinnex filter giving a clear, nearly colorless solution and a dark purple solid. The solid was dried under vacuum for approximately 30 minutes and analyzed by powder X-ray diffraction (XRD).

[0200] The powder XRD pattern obtained on the solid material recovered from the slurry is shown in FIG.10. The pattern shows relatively sharp peaks indicative of crystalline material(s) possibly comprised of very small particles (sub-micron) or highly strained crystals. The powder XRD pattern is compared to the patterns of Form B and Form A, in FIG.11 and FIG.12, respectively. FIG.11 shows that the starting crystalline material(s) changed form(s) during the aqueous slurry. FIG.12 shows that the powder XRD patternAttorney Docket No.38373.0001P1 obtained on the solid recovered from the slurry is identical to the pattern obtained on Form A indicating that these materials are composed of the same crystalline form(s). 4. OBSERVED PEAKS

[0201] The peak picking data presented contains X-ray diffraction patterns with labeled peaks and tables with peak lists. Under most circumstances, peaks within the range of up to about 30º 2θ were selected. The observed peak location was obtained “manually” by selecting the peak apex along the x-axis (º 2θ) using measurement data viewer software. Peak positions were rounded to the nearest 0.01º 2θ. Peak position variabilities are generally expected to be within ±0.2º 2θ based upon recommendations outlined in the USP discussion of variability in powder XRD. The accuracy and precision associated with any measurement reported herein has not been determined. Per USP guidelines, variable hydrates and solvates may display peak variances greater than 0.2º 2θ and therefore peak variances of 0.2º 2θ are not applicable to these materials.

[0202] The observed peaks for material recovered from the slurry prepared from Form B are shown in Table 4 below and FIG.13. TABLE 4.Attorney Docket No.38373.0001P1

[0203] The observed peaks for Form B are shown in Table 5 below and FIG.14. TABLE 5.Attorney Docket No.38373.0001P1served peaks for Form A are shown in Table 6 below and FIG.15. TABLE 6.Attorney Docket No.38373.0001P15. SOLUBILITY STUDY

[0205] The solubilities of Form A and Form B in water were analyzed using HPLC and an external standard calibration curve. Stock solutions of Form A and Form B were prepared at 1 mg / mL concentration in water, and a series of dilutions ranging from 0.01 to 0.2 mg / mL were prepared in acetonitrile to generate a calibration curve.

[0206] A saturated solution of Form A was prepared with about 50 mg of sample in water, which was then filtered through a 0.22 μm Nylon syringe filter. The solution was diluted by taking 0.3 mL into 100 mL of acetonitrile. Using the external standard quantification method, the solubility of Form A was found to be 1.4 mg / mL.

[0207] A saturated solution of Form B was prepared using about 100 mg of sample in water, which was then filtered through a 0.22 μm Nylon syringe filter. The solution was diluted by taking 0.4 mL into 100 mL of acetonitrile. Using the external standard quantification method, the solubility of Form A was found to be 31.8 mg / mL.Attorney Docket No.38373.0001P1 6. PARTICLE SIZE ANALYSIS

[0208] Particle size analysis was performed using a Malvern Panalytical Mastersizer 3000 using LASER Diffraction – Liquid Dispersion in a non-aqueous carrier with a Hydro MV accessory. The system default values were set as detailed in Table 7 below. TABLE 7.

[0209] The analysis settings were set according to Table 8. TABLE 8.

[0210] A plot showing the distribution of the crystals for Form A is shown in FIG. 16. The Dv(10), Dv(50), and Dv(90) were determined to be 0.813, 12.7, and 77.3 μm, respectively. The full table of results is shown below in Table 9. TABLE 9.Attorney Docket No.38373.0001P1Attorney Docket No.38373.0001P1Attorney Docket No.38373.0001P1Attorney Docket No.38373.0001P1

[0211] A plot showing the distribution of the crystals for Form B is shown in FIG. 17. The Dv(10), Dv(50), and Dv(90) were determined to be 1.53, 15.8, 57.6 μm, respectively. The full table of results is shown below in Table 10. TABLE 10.Attorney Docket No.38373.0001P1Attorney Docket No.38373.0001P1Attorney Docket No.38373.0001P1

[0212] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other aspects of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

Attorney Docket No.38373.0001P1 CLAIMS What is claimed is:

1. A crystalline polymorph of a pharmaceutically acceptable salt of a compound havinga structure:.

2. The crystalline polymorph of claim 1, wherein the crystalline polymorph has apowder X-ray diffraction (XRD) pattern that contains a peak at each of about 13.0 ± 0.2º 2θ and about 24.6 ± 0.2º 2θ.

3. The crystalline polymorph of claim 2, wherein the powder XRD pattern furthercontains a peak at each of about 13.9 ± 0.2º 2θ, about 26.1 ± 0.2º 2θ, and about 27.0 ± 0.2º 2θ.

4. The crystalline polymorph of claim 2, wherein the powder XRD pattern furthercontains a peak at each of about 6.9 ± 0.2º 2θ, about 8.9 ± 0.2º 2θ, about 13.9 ± 0.2º 2θ, about 16.7 ± 0.2º 2θ, about 19.9 ± 0.2º 2θ, about 26.1 ± 0.2º 2θ, and about 27.0 ± 0.2º 2θ.

5. The crystalline polymorph claim 4, wherein the powder XRD pattern further containstwo or more peaks at positions selected from about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ.

6. The crystalline polymorph of claim 4, wherein the powder XRD pattern furthercontains five or more peaks at positions selected from about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, aboutAttorney Docket No.38373.0001P1 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ.

7. The crystalline polymorph of claim 4, wherein the powder XRD pattern further contains ten or more peaks at positions selected from about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ.

8. The crystalline polymorph of claim 4, wherein the powder XRD pattern further contains fifteen or more peaks at positions selected from about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ.

9. The crystalline polymorph of claim 4, wherein the powder XRD pattern further contains a peak at each of about 9.2 ± 0.2º 2θ, about 9.8 ± 0.2º 2θ, about 11.8 ± 0.2º 2θ, about 12.2 ± 0.2º 2θ, about 15.9 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 17.9 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.9 ± 0.2º 2θ, about 20.3 ± 0.2º 2θ, about 21.6 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 23.3 ± 0.2º 2θ, about 24.4 ± 0.2º 2θ, about 27.8 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, about 28.7 ± 0.2º 2θ, and about 29.3 ± 0.2º 2θ.

10. The crystalline polymorph of claim 2, wherein the crystalline polymorph has a powder XRD pattern as shown in FIG.

15.

11. The crystalline polymorph of claim 1, wherein the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ.

12. The crystalline polymorph of claim 11, wherein the powder XRD pattern further contains a peak at each of about 11.7 ± 0.2º 2θ, about 14.1 ± 0.2º 2θ, about 16.5 ± 0.2º 2θ, about 21.8 ± 0.2º 2θ, about 26.5 ± 0.2º 2θ, and about 27.3 ± 0.2º 2θ.Attorney Docket No.38373.0001P1 13. The crystalline polymorph claim 12, wherein the powder XRD pattern further contains two or more peaks at positions selected from about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ.

14. The crystalline polymorph of claim 12, wherein the powder XRD pattern further contains five or more peaks at positions selected from about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ.

15. The crystalline polymorph of claim 12, wherein the powder XRD pattern further contains ten or more peaks at positions selected from about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ.

16. The crystalline polymorph of claim 12, wherein the powder XRD pattern further contains fifteen or more peaks at positions selected from about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ.

17. The crystalline polymorph of claim 12 wherein the powder XRD pattern further contains a peak at each of about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ± 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ.Attorney Docket No.38373.0001P1 18. The crystalline polymorph of claim 11, wherein the crystalline polymorph has a powder XRD pattern as shown in FIG.

14.

19. The crystalline polymorph of claim 1, wherein the pharmaceutically acceptable salt is selected from a halide salt, an acetate salt, an alginate salt, an ascorbate salt, a benzene sulfonate salt, a benzoate salt, a carbonate salt, a cinnamate salt, a citrate salt, a diphosphate salt, a fumarate salt, a gluconate salt, a lactate salt, a laurate salt, a malate salt, a maleate salt, a mesylate salt, a myristate salt, a nitrate salt, a palmitate salt, a perchlorate salt, a phenolate salt, a phosphate salt, a propionate salt, a sorbate salt, a succinate salt, a sulfate salt, and a tartrate salt.

20. The crystalline polymorph of claim 1, wherein the pharmaceutically acceptable salt is a halide salt.

21. The crystalline polymorph of claim 20, wherein the halide salt is a hydrochloride salt.

22. A pharmaceutical composition comprising an effective amount of the crystalline polymorph of claim 1 and a pharmaceutically acceptable carrier.

23. A method for modifying topoisomerase I (Top1) and / or MYC signaling in a subject, the method comprising the step of administering to the subject an effective amount of the crystalline polymorph of claim 1.

24. The method of claim 23, wherein modifying is decreasing.

25. The method of claim 23, wherein modifying is inhibiting.

26. The method of claim 23, wherein the subject has been diagnosed with a need for modifying Top1 and / or MYC signaling prior to the administering step.

27. The method of claim 23, wherein the subject has been diagnosed with a need for treatment of a disease or disorder associated with Top1 signaling dysfunction prior to the administering step.

28. The method of claim 27, further comprising the step of identifying a subject in need of treatment of a disease or disorder associated with Top1 and / or MYC signaling dysfunction.Attorney Docket No.38373.0001P1 29. The method of claim 23, wherein the subject has been diagnosed with cancer prior to the administering step.

30. A method for modifying topoisomerase I (Top1) and / or MYC signaling in at least one cell, the method comprising the step of contacting the cell with an effective amount of the crystalline polymorph of claim 1.

31. The method of claim 30, wherein modifying is decreasing.

32. The method of claim 30, wherein modifying is inhibiting.

33. The method of claim 30, wherein the cell is human.

34. The method of claim 33, wherein the cell has been isolated from a human prior to the administering step.

35. The method of claim 30, wherein contacting is via administration to a subject.

36. The method of claim 35, wherein the subject has been diagnosed with a need for modification of Top1 and / or MYC signaling prior to the administering step.

37. The method of claim 35, wherein the subject has been diagnosed with a need for treatment of a disease or disorder associated with Top1 and / or MYC signaling dysfunction.

38. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the crystalline polymorph of claim 1.

39. The method of claim 38, wherein the subject is a mammal.

40. The method of claim 39, wherein the mammal is a human.

41. The method of claim 38, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

42. The method of claim 38, further comprising the step of identifying a subject in need of treatment of cancer.

43. The method of claim 38, wherein the effective amount is a therapeutically effective amount.Attorney Docket No.38373.0001P1 44. The method of claim 38, wherein the effective amount is a prophylactically effective amount.

45. The method of claim 38, wherein the cancer is associated with dysregulation of Top1 and / or MYC activity.

46. The method of claim 38, wherein the cancer is associated with an increase in Top1 and / or MYC activity.

47. The method of claim 38, wherein the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, a melanoma, a glioma, leukemia, a lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

48. The method of claim 38, wherein the cancer is a solid tumor or a lymphoma.

49. The method of claim 38, wherein the cancer is a glioma.

50. The method of claim 49, wherein the glioma is a malignant glioma.

51. The method of claim 38, wherein the cancer is leukemia.

52. The method of claim 38, wherein the cancer is a pediatric cancer.

53. The method of claim 52, wherein the pediatric cancer is a Ewing’s sarcoma or a solid tumor.

54. The method of claim 38, wherein the crystalline polymorph is administered at a dose of from about 10 mg / m2to about 100 mg / m2.

55. The method of claim 54, wherein the crystalline polymorph is administered once daily at a dose of from about 10 mg / m2to about 60 mg / m2.

56. The method of claim 54, wherein the crystalline polymorph is administered once daily at a dose of about 60 mg / m2.Attorney Docket No.38373.0001P157. The method of claim 54, wherein the crystalline polymorph is administered once dailyat a dose of from about 10 mg / m2to about 60 mg / m2for a time period of from 1 to 7 days.

58. The method of claim 54, wherein the crystalline polymorph is administered once dailyat a dose of from about 10 mg / m2to about 60 mg / m2for a time period of from 1 to 5 days.

59. The method of claim 54, wherein the crystalline polymorph is administered once dailyat a dose of from about 80 mg / m2to about 100 mg / m2.

60. The method of claim 54, wherein the crystalline polymorph is administered at a doseof about 90 mg / m2.

61. The method of claim 54, wherein the crystalline polymorph is administered once aweek at a dose of from about 80 mg / m2to about 100 mg / m2.

62. A method for making the crystalline polymorph of claim 1, the method comprising:(a) suspending a compound having a structure:, or a pharmaceutically acceptable salt thereof, in a basic solution; (b) filtering;(c) adding an acid; and(d) filtering.

63. The method of claim 62, wherein the basic solution is a sodium bicarbonate solution.

64. The method of claim 62, wherein the basic solution is a 10% aqueous sodiumbicarbonate solution.

65. The method of claim 62, wherein the suspending step (a) is for a time period of fromabout 30 minutes to about 1.5 hours.Attorney Docket No.38373.0001P1 66. The method of claim 62, wherein the suspending step (a) is for a time period of about 1.0 hour.

67. The method of claim 62, wherein the suspending step (a) further comprises adding a solvent.

68. The method of claim 67, wherein the solvent is chloroform.

69. The method of claim 67, wherein the suspending step (a) further comprises stirring for a time period of from about 1.5 hours to about 2.5 hours after the solvent is added.

70. The method of claim 67, wherein the suspending step (a) further comprises stirring for a time period of about 2.0 hours after the solvent is added.

71. The method of claim 62, wherein the filtering step (b) produces a filtrate, and wherein, following the filtering step (b) but prior to the adding step (c), the filtrate is cooled.

72. The method of claim 71, wherein the filtrate is cooled to a temperature of from about 1 °C to about 10 °C.

73. The method of claim 71, wherein the filtrate is cooled to a temperature of about 5 °C.

74. The method of claim 62, wherein the filtering step (b) produces a filtrate, and wherein, following the filtering step (b) but prior to the adding step (c), the filtrate is concentrated, thereby forming a concentrated filtrate.

75. The method of claim 74, wherein the concentrated filtrate is diluted with a protic solvent, thereby providing a suspension.

76. The method of claim 75, wherein the protic solvent is ethanol.

77. The method of claim 75, wherein the suspension is filtered to provide a solid.

78. The method of claim 77, wherein the solid is suspended in a protic solvent, thereby providing a second suspension.

79. The method of claim 78, wherein the protic solvent is ethanol.

80. The method of claim 78, wherein the second suspension is cooled.Attorney Docket No.38373.0001P1 81. The method of claim 80, wherein the second suspension is cooled to a temperature of from about 1 °C to about 10 °C.

82. The method of claim 80, wherein the second suspension is cooled to a temperature of about 5 °C.

83. The method of claim 62, wherein the acid is added dropwise.

84. The method of claim 62, wherein the acid is a hydrochloric acid.

85. The method of claim 62, wherein the acid is an ethanolic hydrochloric acid solution.

86. The method of claim 62, wherein the adding step (c) further comprises stirring for a time period of from about 30 minutes to about 1.5 hours following addition of the acid.

87. The method of claim 62, wherein the adding step (c) further comprises stirring for a time period of about 1 hour following addition of the acid.

88. The method of claim 62, wherein the adding step (c) further comprises stirring at a temperature of from about 1 °C to about 15 °C following addition of the acid.

89. The method of claim 62, wherein the adding step (c) further comprises stirring at a temperature of from about 5 °C to about 10 °C following addition of the acid.

90. The method of claim 62, wherein the filtering step (d) provides a solid, and wherein the method further comprises drying the solid.

91. The method of claim 90, wherein the solid is dried at a temperature of from about 40 °C to about 50 °C.

92. The method of claim 90, wherein the solid is dried at a temperature of about 45 °C.

93. The method of claim 90, wherein the solid is dried for a time period of from about 3 hours to about 7 hours.

94. The method of claim 90, wherein the solid is dried for a time period of about 5 hours.

95. The method of claim 62, wherein the method comprises: (a) suspending a compound having a structure:Attorney Docket No.38373.0001P1, or a pharmaceutically acceptable salt thereof, in a sodium bicarbonate solution for a time period of from about 30 minutes to about 1.5 hours, thereby providing a suspension, and adding a water-insoluble solvent to the suspension and stirring for a time period of from about 1.5 hours to about 2.5 hours, thereby forming an aqueous layer and an organic layer; (b) separating the organic layer from the aqueous layer, filtering the organic layerto obtain a filtrate, and cooling the filtrate to a temperature of from about 1 °C to about 10 °C; (c) adding an ethanolic hydrochloric acid solution dropwise and stirring for a timeperiod of from about 30 minutes to about 1.5 hours at a temperature of from about 1 °C to about 15 °C, thereby providing a second suspension; (d) filtering the second suspension to obtain a solid; and(e) drying the solid hydrochloride at a temperature of from about 40 °C to about50 °C for a time period of from about 3 hours to about 7 hours, and recrystallizing the solid hydrochloride from ethanol to remove residual chloroform.

96. The method of claim 95, wherein the suspending step (a) is for a time period of about1.0 hour.

97. The method of claim 95, wherein in step (a) stirring is for a time period of about 2.0hours.

98. The method of claim 95, wherein in step (b) the filtrate is cooled to a temperature ofabout 5 °C.Attorney Docket No.38373.0001P1 99. The method of claim 95, wherein in step (b), prior to cooling, the filtrate is concentrated, thereby forming a concentrated filtrate.

100. The method of claim 99, wherein the concentrated filtrate is diluted with a protic solvent, thereby providing a third suspension.

101. The method of claim 100, wherein the protic solvent is ethanol.

102. The method of claim 100, wherein the third suspension is filtered to provide a solid.

103. The method of claim 102, wherein the solid is suspended in a protic solvent, thereby providing a fourth suspension, and wherein the fourth suspension is cooled to the temperature of from about 1 °C to about 10 °C.

104. The method of claim 103, wherein the protic solvent is ethanol.

105. The method of claim 95, wherein in step (c) stirring is for a time period of about 1 hour.

106. The method of claim 95, wherein in step (c) stirring is at a temperature of from about 5 °C to about 10 °C.

107. The method of claim 95, wherein in step (e) the solid is dried at a temperature of about 45 °C.

108. The method of claim 95, wherein in step (e) the solid is dried for a time period of about 5 hours.

109. The method of claim 62, wherein the crystalline polymorph has a powder X-ray diffraction (XRD) pattern that contains a peak at positions selected from about 6.1 ± 0.2º 2θ, about 6.4 ± 0.2º 2θ, about 7.5 ± 0.2º 2θ, about 14.5 ± 0.2º 2θ, about 15.0 ± 0.2º 2θ, and about 25.6 ± 0.2º 2θ.

110. The method of claim 62, wherein the powder XRD pattern further contains a peak at each of about 7.0 ± 0.2º 2θ, about 9.3 ± 0.2º 2θ, about 10.1 ± 0.2º 2θ, about 12.1 ± 0.2º 2θ, about 13.6 ± 0.2º 2θ, about 15.7 ± 0.2º 2θ, about 17.1 ± 0.2º 2θ, about 17.3 ± 0.2º 2θ, about 18.5 ± 0.2º 2θ, about 18.8 ± 0.2º 2θ, about 19.5 ± 0.2º 2θ, about 20.7 ± 0.2º 2θ, about 21.4 ±Attorney Docket No.38373.0001P1 0.2º 2θ, about 23.2 ± 0.2º 2θ, about 24.1 ± 0.2º 2θ, about 28.1 ± 0.2º 2θ, and about 28.9 ± 0.2º 2θ.

111. A kit comprising the crystalline polymorph of claim 1 and one or more selected from: (a) an agent associated with the treatment of cancer; (b) instructions for administering the crystalline polymorph in connection with treating cancer; and (c) instructions for treating cancer.

112. The kit of claim 111, wherein the agent is a chemotherapeutic agent.

113. The kit of claim 112, wherein the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a PARP inhibitor, and an mTOR inhibitor agent.

114. The kit of claim 113, wherein the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

115. The kit of claim 113, wherein the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

116. The kit of claim 113, wherein the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

117. The kit of claim 113, wherein the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.Attorney Docket No.38373.0001P1 118. The kit of claim 113, wherein the PARP inhibitor is selected from olaparib, niraparib, and rucaparib.

119. The kit of claim 113, wherein the mTOR inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

120. The kit of claim 111, wherein the crystalline polymorph and the agent are co- packaged.

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