Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present disclosure relates generally to crystalline forms of 3-( ⁇ [(4R)-7-
• This first-in-class epigenetic-modifying compound shows promise for treatment of cancers, including gastric and colon cancers.
• Compound 1 has poor solubility in water and most common organic solvents, and tends to precipitate as an amorphous paste, making filtration at large scale difficult. As such, there is also a need to provide the compound in an alternate form, such as a salt, for ease of handling and further formulation.
• crystalline forms i. e. , polymorphs
• 3 -( ⁇ [(4R)-7 - ⁇ methyl [4-(propan-2-y l)phenyl] amino ⁇ -3 ,4-dihydro-2H- 1 -benzopyran-4- yl]methyl ⁇ amino)pyridine-4-carboxylic acid, L-lysine salt Compound 1-L-lysine
• pharmaceutical compositions comprising a crystalline form of Compound 1 -L-lysine.
• compositions comprising such crystalline forms.
• Embodiment 1 A crystalline form of 3-( ⁇ [(4R)-7- ⁇ methyl[4-(propan-2- yl)phenyl]amino ⁇ -3,4-dihydro-2H- 1 -benzopyran-4-yl]methyl ⁇ amino)pyridine-4-carboxylic acid, L-lysine salt, wherein the crystalline form is Form 1.
• Embodiment 2 The crystalline form of embodiment 1, having an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2°.
• Embodiment 3 The crystalline form of embodiment 1 or 2, wherein the X-ray powder diffraction exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2° and 7.6° ⁇ 0.2°.
• Embodiment 4 The crystalline form of any one of embodiments 1-3, wherein the X- ray powder diffraction exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2°, 7.6° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
• Embodiment 5 The crystalline form of any one of embodiments 1-4, wherein the X- ray powder diffraction exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2°, 7.6° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 14.5° ⁇ 0.2°.
• Embodiment 6 The crystalline form of any one of embodiments 1-5, wherein the X- ray powder diffraction exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2°, 7.6° ⁇ 0.2°, 23.5° ⁇ 0.2°, 14.5° ⁇ 0.2°, 4.9° ⁇ 0.2°, 6.9° ⁇ 0.2°, 8.5° ⁇ 0.2°, 9.4° ⁇ 0.2°, 10.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
• Embodiment 7 The crystalline form of any one of embodiments 1-6, having an X- ray powder diffraction substantially as shown in FIG. 9.
• Embodiment 8 The crystalline form of any one of embodiments 1-7, having a differential scanning calorimetry thermogram comprising an endotherm at about 239.4° ⁇ 5°.
• Embodiment 9. The crystalline form of any one of embodiments 1-8, having a differential scanning calorimetry thermogram substantially as shown in FIG. 11.
• Embodiment 10. The crystalline form of any one of embodiments 1-9, having no significant weight loss up to about 200 °C as determined by thermogravimetric analysis.
• Embodiment 11 The crystalline form of any one of embodiments 1-10, having a thermogravimetric analysis thermogram substantially as shown in FIG. 10.
• Embodiment 12 The crystalline form of any one of embodiments 1-11, having reversible sorption of about 1.4% up to 90% relative humidity as determined by dynamic vapor sorption.
• Embodiment 13 The crystalline form of any one of embodiments 1-12, having a dynamic vapor sorption profile substantially as shown in FIG. 14.
• Embodiment 14 A crystalline form of 3-( ⁇ [(4R)-7- ⁇ methyl[4-(propan-2- yl)phenyl]amino ⁇ -3,4-dihydro-2H- 1 -benzopyran-4-yl]methyl ⁇ amino)pyridine-4-carboxylic acid, L-lysine salt, wherein the crystalline form is Form 2.
• Embodiment 15 The crystalline form of embodiment 14, having an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2°.
• Embodiment 16 The crystalline form of embodiment 14 or 15, wherein the X-ray powder diffraction exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2° and 18.2° ⁇ 0.2°.
• Embodiment 17 The crystalline form of any one of embodiments 14-16, wherein the X-ray powder diffraction exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, and 21.5° ⁇ 0.2°.
• Embodiment 18 The crystalline form of any one of embodiments 14-17, wherein the X-ray powder diffraction exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 25.6° ⁇ 0.2°.
• Embodiment 19 The crystalline form of any one of embodiments 14-18, wherein the X-ray powder diffraction exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 21.5° ⁇ 0.2°, 25.6° ⁇ 0.2°, 8.6° ⁇ 0.2°, 13.8° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
• Embodiment 20 The crystalline form of any one of embodiments 14-19, having an X-ray powder diffraction substantially as shown in FIG. 5B.
• Embodiment 21 The crystalline form of any one of embodiments 14-20, having a differential scanning calorimetry thermogram comprising an endotherm at about 231.7° ⁇ 5°.
• Embodiment 22 The crystalline form of any one of embodiments 14-21, having no significant weight loss up to about 240 °C as determined by thermogravimetric analysis.
• Embodiment 23 The crystalline form of any one of embodiments 14-22, having reversible sorption of about 1.6% up to 90% relative humidity as determined by gravimetric vapor sorption.
• Embodiment 24 A method of preparing the crystalline form of any one of embodiments 1-23, comprising: combining 3 -( ⁇ [(4R)-7 - ⁇ methyl [4-(propan-2-y l)pheny 1] amino ⁇ -3 ,4-dihydro-2H- l-benzopyran-4-yl]methyl ⁇ amino)pyridine-4-carboxylic acid and methanol at about 50 °C to give a suspension; adding L-lysine to the suspension at about 50 °C to give a solution; cooling the solution; and isolating the crystalline form from the solution.
• Embodiment 25 A solid pharmaceutical composition comprising the crystalline form of any one of embodiments 1-23 and a pharmaceutically acceptable excipient.
• Embodiment 26 A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of the solid pharmaceutical composition of embodiment 25 to the subject.
• Embodiment 27 The method of embodiment 26, wherein the cancer is selected from colorectal cancer, esophageal cancer, gastric cancer, breast cancer, and lymphoma.
• FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of Compound 1.
• FIG. 2 shows both a thermogravimetric analysis (TGA) thermogram and a differential scanning calorimetry (DSC) thermogram of Compound 1.
• FIG. 3 shows predicted and measured pKas for Compound 1.
• FIG. 4 shows an overlay of X-ray powder diffraction (XRPD) patterns of crystalline forms of Compound 1 -sodium salt (Nal-Na6).
• FIG. 5 A shows an overlay of X-ray powder diffraction (XRPD) patterns of crystalline forms of Compound 1-L-lysine (LYS1 (Form 1) and LYS2 (Form 2)).
• XRPD X-ray powder diffraction
• FIG. 5B shows an X-ray powder diffraction (XRPD) pattern of Compound 1-L- lysine Form 2.
• FIG. 6 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of Compound 1 ethanolamine salt (EA1).
• FIG. 7 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of Compound 1 N-ethylglucamine salt (Negl).
• FIG. 8 shows a polarized light microscopy (PLM) micrograph of Compound 1-L- lysine Form 1.
• FIG. 9 shows an X-ray powder diffraction (XRPD) pattern of Compound 1-L-lysine Form 1.
• FIG. 10 shows a thermogravimetric analysis (TGA) thermogram of Compound 1-L- lysine Form 1.
• FIG. 11 shows a differential scanning calorimetry (DSC) thermogram of Compound 1-L-lysine Form 1.
• FIG. 12 shows a high-performance liquid chromatography (HPLC) chromatogram of Compound 1-L-lysine Form 1.
• FIG. 13 shows a NMR chromatogram of Compound 1-L-lysine Form 1.
• FIG. 14 shows a dynamic vapor sorption (DVS) sorption-desorption plot of
• FIG. 15 shows an overlay of X-ray powder diffraction (XRPD) patterns of Compound 1-L-lysine Form 1, before and after analysis by dynamic vapor sorption (DVS).
• XRPD X-ray powder diffraction
• the terms “comprising” and “including” can be used interchangeably.
• the terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.
• any concentration range, error range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
• any number range recited herein relating to any physical feature are to be understood to include any integer within the recited range, unless otherwise indicated.
• the terms “about” and “approximately” mean ⁇ 20%, ⁇ 10%, ⁇ 5%, or ⁇ 1% of the indicated range, value, or structure, unless otherwise indicated.
• “Treating” as used herein means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
• the disorder is a cancer, as described herein, or a symptom thereof.
• Preventing means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
• the disorder is a cancer, as described herein, or symptoms thereof.
• the term “effective amount” in connection with a compound disclosed herein means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.
• subject as used herein include an animal, including, but not limited to, a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig.
• the subject is a mammal.
• the mammal is a human.
• a subject is a human having or at risk for having a cancer.
• a crystalline form of Compound 1 -L-lysine is a crystalline form of Compound 1 -L-lysine.
• the crystalline form of Compound 1 -L-lysine is Form 1.
• the crystalline form of Compound 1-L-lysine is Form 2.
• crystalline forms of Compound 1-L-lysine described herein can be identified by their unique solid-state properties characterized by, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic vapour sorption (DSV), gravimetric vapor sorption (GVS), and other techniques.
• XRPD X-ray powder diffraction
• DSC differential scanning calorimetry
• TGA thermogravimetric analysis
• DSC differential scanning calorimetry
• DCV dynamic vapour sorption
• GVS gravimetric vapor sorption
• crystalline form of Compound 1-L-lysine wherein the crystalline form is Form 1.
• Compound 1-L-lysine Form 1 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2°. In some embodiments, Compound 1-L-lysine Form 1 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2° and 7.6° ⁇ 0.2°. In some embodiments, Compound 1-L-lysine Form 1 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2°, 7.6° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
• Compound 1-L-lysine Form 1 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2°, 7.6° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 14.5° ⁇ 0.2°.
• Compound 1-L-lysine Form 1 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.0° ⁇ 0.2°, 7.6° ⁇ 0.2°, 23.5° ⁇ 0.2°, 14.5° ⁇ 0.2°, 4.9° ⁇ 0.2°, 6.9° ⁇ 0.2°, 8.5° ⁇ 0.2°, 9.4° ⁇ 0.2°, 10.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
• Compound 1-L-lysine Form 1 has an X-ray powder diffraction substantially as shown in FIG. 9.
• Compound 1-L-lysine Form 1 has a differential scanning calorimetry thermogram comprising an endotherm at about 239.4° ⁇ 5°. In some embodiments, Compound 1-L-lysine Form 1 has a differential scanning calorimetry thermogram comprising an endotherm at about 239.4° ⁇ 4°, 239.4° ⁇ 3°, or 239.4° ⁇ 2°.
• Compound 1-L-lysine Form 1 has a differential scanning calorimetry thermogram comprising an endotherm at about 239.4° ⁇ 10°, such as at about 239.4° ⁇ 9°, 239.4° ⁇ 8°, 239.4° ⁇ 7°, or 239.4° ⁇ 6°. In some embodiments, Compound 1-L-lysine Form 1 has a differential scanning calorimetry thermogram substantially as shown in FIG. 11.
• Compound 1-L-lysine Form 1 has no significant weight loss up to about 200 °C as determined by thermogravimetric analysis. In some embodiments, Compound 1-L-lysine Form 1 has a thermogravimetric analysis thermogram substantially as shown in FIG. 10.
• Compound 1-L-lysine Form 1 has reversible sorption of about 1.4% up to 90% relative humidity as determined by dynamic vapor sorption. In some embodiments, Compound 1-L-lysine Form 1 has a dynamic vapor sorption profile substantially as shown in FIG. 14.
• crystalline form of Compound 1-L-lysine wherein the crystalline form is Form 2.
• Compound 1-L-lysine Form 2 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2°. In some embodiments, Compound 1-L-lysine Form 2 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2° and 18.2° ⁇ 0.2°. In some embodiments, Compound 1-L-lysine Form 2 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, and 21.5° ⁇ 0.2°.
• Compound 1-L-lysine Form 2 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 25.6° ⁇ 0.2°. In some embodiments, Compound 1-L-lysine Form 2 has an X-ray powder diffraction which exhibits characteristic scattering angles (20) at least at: 20.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 21.5° ⁇ 0.2°, 25.6° ⁇ 0.2°, 8.6° ⁇ 0.2°, 13.8° ⁇ 0.2°, and 19.3° ⁇ 0.2°. In some embodiments, Compound 1-L-lysine Form 2 has an X-ray powder diffraction substantially as shown in FIG. 5B.
• Compound 1-L-lysine Form 2 has a differential scanning calorimetry thermogram comprising an endotherm at about 231.7° ⁇ 5°. In some embodiments, Compound 1-L-lysine Form 2 has a differential scanning calorimetry thermogram comprising an endotherm at about 231.7° ⁇ 4°, 231.7° ⁇ 3°, or 231.7° ⁇ 2°. In some embodiments, Compound 1-L-lysine Form 2 has a differential scanning calorimetry thermogram comprising an endotherm at about 231.7° ⁇ 10°, such as about 231.7° ⁇ 9°, 231.7° ⁇ 8°, 231.7° ⁇ 7°, or 231.7° ⁇ 6°.
• Compound 1-L-lysine Form 2 has no significant weight loss up to about 240 °C as determined by thermogravimetric analysis.
• Compound 1-L-lysine Form 2 has having reversible sorption of about 1.6% up to 90% relative humidity as determined by gravimetric vapor sorption.
• the method of preparing a crystalline form of Compound 1 comprises: combining Compound 1 and a solvent (such as methanol) at an elevated temperature (for example, about 50 °C) to give a suspension; adding a base or acid to the suspension at the elevated temperature to give a solution; cooling the solution; and isolating the crystalline form from the solution.
• a solvent such as methanol
• a method of preparing a crystalline form of Compound 1-L-lysine comprising: combining Compound 1 and methanol at about 50 °C to give a suspension; adding L-lysine to the suspension at about 50 °C to give a solution; cooling the solution; and isolating the crystalline form from the solution.
• the crystalline form of Compound 1-L-lysine is Form 1.
• the crystalline form of Compound 1-L-lysine is Form 2. Phannaceutical Compositions
• the crystalline forms provided herein can be administered to a subject in the form of a pharmaceutical composition.
• the pharmaceutical composition comprises a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2, and one or more pharmaceutically acceptable excipients.
• the pharmaceutical composition can be administered to the subject orally, topically, or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.
• the pharmaceutical composition comprises a solid formulation, such as capsules, microcapsules, tablets, granules, powder, pills, or suppositories.
• the crystalline forms disclosed herein can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.
• preparations such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions.
• Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder
• the effective amount of the crystalline forms of Compound 1 in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject’s body weight to about 10 mg/kg of a subject’s body weight in unit dosage for both oral and parenteral administration.
• the dose of a crystalline form described herein to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner.
• the compounds disclosed herein can be administered one to four times a day in a dose of about 0.001 mg/kg of a subject’s body weight to about 10 mg/kg of a subject’s body weight, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration.
• the dose is about 0.001 mg/kg of a subject’s body weight to about 5 mg/kg of a subject’s body weight, about 0.01 mg/kg of a subject’s body weight to about 5 mg/kg of a subject’s body weight, about 0.05 mg/kg of a subject’s body weight to about 1 mg/kg of a subject’s body weight, about 0.1 mg/kg of a subject’s body weight to about 0.75 mg/kg of a subject’s body weight or about 0.25 mg/kg of a subject’s body weight to about 0.5 mg/kg of a subject’s body weight.
• one dose is given per day. In any given case, the amount of the crystalline form administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
• a crystalline form described herein is administered to a subject at a dose of about 0.01 mg/day to about 750 mg/day, about 0.1 mg/day to about 375 mg/day, about 0.1 mg/day to about 150 mg/day, about 0.1 mg/day to about 75 mg/day, about 0.1 mg/day to about 50 mg/day, about 0.1 mg/day to about 25 mg/day, or about 0.1 mg/day to about 10 mg/day.
• unit dosage formulations that comprise between about 0.1 mg and 500 mg, about 1 mg and 250 mg, about 1 mg and about 100 mg, about 1 mg and about 50 mg, about 1 mg and about 25 mg, or between about 1 mg and about 10 mg of a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2.
• unit dosage formulations comprising about 0.1 mg or 100 mg of a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2.
• unit dosage formulations that comprise 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2.
• a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2 can be administered once, twice, three, four or more times daily. In a particular embodiment, doses of 100 mg or less are administered as a once daily dose and doses of more than 100 mg are administered twice daily in an amount equal to one half of the total daily dose.
• a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2 can be administered orally for reasons of convenience.
• the crystalline form when administered orally, is administered with a meal and water.
• the crystalline form is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or a suspension.
• the crystalline forms of Compound 1 disclosed herein can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin.
• the mode of administration is left to the discretion of the health-care practitioner, and can depend in part upon the site of the medical condition.
• compositions comprising an effective amount of a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2, and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
• the pharmaceutical compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.
• Pharmaceutical compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid.
• all of the pharmaceutical compositions are prepared according to known methods in pharmaceutical chemistry.
• Capsules can be prepared by mixing a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2, with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
• the usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
• Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
• Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium
• a lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye.
• the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
• Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, com and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet.
• the compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation
• a crystalline form of Compound 1 such as Compound 1-L-lysine Form 1 or Form 2
• typical bases can be used.
• Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly.
• Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use.
• the effect of the crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2, can be delayed or prolonged by proper formulation.
• a slowly soluble pellet of the crystalline form can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device.
• the technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the crystalline form of Compound 1 in oily or emulsified vehicles that allow it to disperse slowly in the serum.
• Compound 1 and salts thereof, including the crystalline forms described herein, Compound 1-L-lysine Form 1 or Form 2, are useful in selectively inhibiting the KDM4 family of histone demethylases and for treating a cancer associated with KDM4 activity.
• provided herein is a method of treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a crystalline form of Compound 1-L-lysine as described herein, such as Compound 1-L-lysine Form 1 or Form 2, to the subject.
• a method of treating a cancer in a subject in need thereof comprising administering a therapeutically effective amount of a solid pharmaceutical composition comprising Compound 1-L-lysine Form 1 to the subject.
• provided herein is a method of treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a solid pharmaceutical composition comprising Compound 1-L-lysine Form 2 to the subject. In some embodiments, provided herein is a method of treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of Compound 1-L-lysine Form 1 to the subject. In some embodiments, provided herein is a method of treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of Compound 1-L- lysine Form 2 to the subject.
• a crystalline form of Compound 1-L-lysine as described herein such as Compound 1-L-lysine Form 1 or Form 2, in the manufacture of a medicament for treating a cancer.
• a crystalline form of Compound 1-L-lysine as described herein such as Compound 1-L-lysine Form 1 or Form 2, for treating a cancer in a subject in need thereof.
• Embodiments of the present disclosure provide a method for inhibiting the KDM4 family of histone demethylases in a subject in need thereof, the method comprising administering to the subject an effective amount of a crystalline form of Compound 1, such as Compound 1-L-lysine Form 1 or Form 2.
• Inhibition of the KDM4 family of histone demethylases can be assessed and demonstrated by a wide variety of ways known in the art. Kits and commercially available assays can be utilized for determining whether and to what degree the KDM4 family of histone demethylases has been inhibited.
• a method of inhibiting the KDM4 family of histone demethylases comprising contacting the KDM4 family of histone demethylases with an effective amount of a crystalline form of Compound 1.
• the crystalline form is Compound 1-L-lysine Form 1.
• the crystalline form is Compound 1-L- lysine Form 2.
• the crystalline form described herein inhibits the KDM4 family of histone demethylases by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
• the crystalline form described herein inhibits the KDM4 family of histone demethylases by about 1- 100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45- 100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90- 100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40- 60%.
• a method for treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline form described herein, such as Compound 1-L-lysine Form 1 or Form 2.
• a method for preventing a cancer such as a cancer associated with KDM4 activity, in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline form described herein, such as Compound 1-L-lysine Form 1 or Form 2.
• a cancer for treatment include gastric cancer, or colon cancer.
• the cancer is gastric cancer.
• the cancer is colon cancer.
• the cancer is colorectal cancer.
• the cancer is esophageal cancer.
• the cancer is breast cancer.
• the cancer is lymphoma.
• administering a crystalline form disclosed herein to a subject that is predisposed to a cancer prevents the subject from developing any symptoms of the cancer. In some embodiments, administering a crystalline form disclosed herein to a subject that does not yet display symptoms of a cancer prevents the subject from developing any symptoms of the cancer. In some embodiments, administering a crystalline form disclosed herein to a subject in need thereof diminishes the extent of the cancer in the subject. In some embodiments, administering the crystalline form disclosed herein to a subject in need thereof stabilizes the cancer (prevents or delays the worsening of the cancer).
• administering a crystalline form disclosed herein to a subject in need thereof delays the occurrence or recurrence of the cancer. In some embodiments, administering a crystalline form disclosed herein to a subject in need thereof slows the progression of the cancer. In some embodiments, administering a crystalline form disclosed herein to a subject in need thereof provides a partial remission of the cancer. In some embodiments, administering a crystalline form disclosed herein to a subject in need thereof provides a total remission of the cancer. In some embodiments, administering a crystalline form disclosed herein to a subject in need thereof decreases the dose of one or more other medications required to treat the cancer.
• administering a crystalline form disclosed herein to a subject in need thereof enhances the effect of another medication used to treat the cancer. In some embodiments, administering a crystalline form disclosed herein to a subject in need thereof delays the progression of the cancer. In some embodiments, administering a crystalline form disclosed herein to a subject in need thereof increases the quality of life of the subject having a cancer. In some embodiments, administering a crystalline form disclosed herein to a subject in need thereof prolongs survival of a subject having a cancer. [00104] In one aspect, provided herein is method of preventing a subject that is predisposed to a cancer from developing any symptoms of the cancer, the method comprising administering a crystalline form disclosed herein to the subject. In some embodiments, provided herein is a method of preventing a subject that does not yet display symptoms of a cancer from developing any symptoms of the cancer, the method comprising administering a crystalline form disclosed herein to the subject.
• provided herein is a method of diminishing the extent of a cancer in a subject, the method comprising administering a crystalline form disclosed herein to the subject.
• a method of stabilizing a cancer in a subject the method comprising administering a crystalline form disclosed herein to the subject.
• the method prevents the worsening of the cancer.
• the method delays the worsening of the cancer.
• a method of delaying the occurrence or recurrence of a cancer in a subject comprising administering a crystalline form disclosed herein to the subject.
• provided herein is a method of slowing the progression of a cancer in a subject, the method comprising administering a crystalline form disclosed herein to the subject.
• the method provides a partial remission of the cancer.
• the method provides a total remission of the cancer.
• provided herein is a method of decreasing the dose of one or more other medications required to treat a cancer in a subject, the method comprising administering a crystalline form disclosed herein to the subject.
• a method of enhancing the effect of another medication used to treat a cancer in a subject the method comprising administering a crystalline form disclosed herein to the subject.
• Also provided here is a method of delaying the progression of a cancer in a subject, the method comprising administering a crystalline form disclosed herein to the subject.
• the method increases the quality of life of the subject having a cancer.
• the method prolongs survival of the subject having a cancer.
• X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector.
• X-ray optics consists of a single Gdbel multilayer mirror coupled with a pinhole collimator of 0.3 mm. A weekly performance check is carried out using a certified standard NIST 1976 Corundum (flat plate).
• the beam divergence i.e., the effective size of the X-ray beam on the sample, was approximately 4 mm.
• a 0-0 continuous scan mode was employed with a sample - detector distance of 20 cm which gives an effective 20 range of 3.2° - 29.7°.
• the sample would be exposed to the X-ray beam for 120 seconds.
• the software used for data collection was GADDS for XP/2000 4.1.43 and the data were analyzed and presented using Diffrac Plus EVA V15.0.0.0.
• Non-ambient conditions Samples run under non-ambient conditions were mounted on a silicon wafer with heatconducting compound. The sample was then heated to the appropriate temperature at 10 °C/min and subsequently held isothermally for 1 minute before data collection was initiated.
• NMR spectra were collected on a Bruker 400MHz instrument equipped with an auto-sampler and controlled by a DRX400 console. Automated experiments were acquired using ICON-NMR v4.0.7 running with Topspin vl.3 using the standard Bruker loaded experiments. For non-routine spectroscopy, data were acquired through the use of Topspin alone. Samples were prepared in DMSO-cfc, unless otherwise stated. Off-line analysis was carried out using ACD Spectrus Processor 2012.
• X-Ray Powder Diffraction patterns were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA), 0 - 20 goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector. The instrument is performance checked using a certified Corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and the data were analyzed and presented using Diffrac Plus PNN vl 5.0.0.0.
• DSC data were collected on a TA Instruments Q2000 equipped with a 50 position autosampler. The calibration for thermal capacity was carried out using sapphire and the calibration for energy and temperature was carried out using certified indium. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminum pan, was heated at 10 °C/min from 25 °C to 300 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample. Modulated temperature DSC was carried out using an underlying heating rate of 2 °C/min and temperature modulation parameters of ⁇ 0.636 °C (amplitude) every 60 seconds (period). The instrument control software was Advantage for Q Series v2.8.0.394 and Thermal Advantage v5.5.3 and the data were analyzed using Universal Analysis v4.5A.
• TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position autosampler. The instrument was temperature calibrated using certified Alumel and Nickel. Typically, 5-10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 ml/min was maintained over the sample.
• the instrument control software was Advantage for Q Series v2.5.0.256 and Thermal Advantage v5.5.3 and the data were analyzed using Universal Analysis v4.5A.
• Samples were studied on a Leica LM/DM polarised light microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide, mounted in immersion oil and covered with a glass slip, the individual particles being separated as well as possible. The sample was viewed with appropriate magnification and partially polarized light, coupled to a X false-color filter.
• Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyzer, controlled by DVS Intrinsic Control software vl.0.1.2 (or v 1.0.1.3).
• the sample temperature was maintained at 25 °C by the instrument controls.
• the humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min.
• the relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0-100 %RH), located near the sample.
• the weight change (mass relaxation) of the sample as a function of %RH was constantly monitored by the microbalance (accuracy ⁇ 0.005 mg).
• Salt Screen - Evaporation of Solutions Any solutions obtained from the paragraph described above titled “Salt Screen - General Procedure (Cooling)” were concentrated by evaporation at ambient conditions and solid residues were analyzed initially by XRPD. Gums were subject to the procedure detailed in the following paragraph.
• Salt Screen - Anti-solvent Additions Any gums, oils, or amorphous solids obtained from the paragraph described above titled “Salt Screen - General Procedure (Cooling)” were stirred with TBME (10 volumes) overnight at 30°C. Any solids were analyzed by XRPD.
• Compound 1 was characterized as a dark yellow amorphous solid. A representative XRPD pattern of Compound 1 is shown in FIG. 1. When this material was stored for 13 days at 40 °C/75%RH and 25 °C/97%RH, evidence of partial deliquescence on the edges of the sample was observed. Thermal analysis showed a water loss of 4.8%, which corresponds to a broad unresolved endothermic event by DSC (FIG. 2).
• the material showed low solubility in both aqueous ( ⁇ 5 mg/ml in water at 25 °C) and organic solvents (difficulty in preparing NMR samples using deuterated methanol and DMSO, and pKa/ion chromatography samples in acetonitrile).
• the pKa was determined using Compound 1 sodium salt. The low solubility of Compound 1 made it unsuitable for these determinations. The predicted and measured pKas are illustrated in FIG. 3. LogP measurement was not possible due to the insolubility of the compound. Two LogP experiments were attempted but precipitation was observed on both occasions. The compound exists as a cation, zwitterion and anion at different pHs. The neutral form is the minor species.
• Methanol, acetone/10%water, and THF were chosen for the main screen based on the above results and their diversity.
• the salt screen was performed in three solvent systems, using the procedures described above. Anti-solvent additions were carried out where necessary. Crystalline salts were obtained with sodium, L-lysine, ethanolamine, and N-ethylglucamine. Crystalline solids were obtained from the experiments using tromethamine and ammonium, although the absence of the counterions was proven by NMR or ion chromatography. Data is summarized in Table 7. The recovery of these processes was low, although not quantified at this stage.
• FIGS. 4-7 Representative XRPD patterns for the various crystalline forms of Compound 1 sodium salt, Compound 1’L-lysine salt, Compound 1 ethanolamine salt, and Compound 1 N- ethylglucamine are shown in FIGS. 4-7.
• Crystalline salts were obtained with sodium, L-lysine, ethanolamine and N- ethylglucamine. Crystalline free form materials were also obtained via unsuccessful salt formation experiments with ammonium and tromethamine.
• the mono sodium salt, Na2 is crystalline and is likely to be a mono-hydrate based on water content.
• the water loss is observed by TGA and corresponds to multiple endothermic events by DSC.
• the salt was stable upon storage at 40°C/75%RH for one week but showed deliquescence after a total of 36 days storage.
• the mono L-lysine salt (Compound 1-L-lysine), LYS1 (Form 1), is crystalline and anhydrous, and shows a melting endotherm (associated with decomposition) at 233 °C. This material was stable upon storage at 40°C/75%RH for 36 days.
• NEG1 N-ethylglucamine salt
• NEG1 N-ethylglucamine salt
• NMR N-ethylglucamine salt
• N-ethylglucamine salt shows an endothermic event (possible melt) at 110 °C. Insufficient material was available for TGA analysis at this stage. This material was stable upon storage at 40°C/75%RH for 36 days.
• the ethanolamine salt, EA1 is also crystalline, and the mono stoichiometry was confirmed by NMR.
• This salt shows an endothermic event (possible melt) at 143 °C. Insufficient material was available for TGA analysis at this stage. This material was stable upon storage at 40°C/75%RH for 7 days.
• the sodium, L-lysine, and N- ethylglucamine salts were chosen for the scale-up phase.
• N-Ethylglucamine Salt Compound 1 (-300 mg) was suspended in methanol (17 volumes) at 65°C. N-ethylglucamine (1 M in water, 1.1 equivalents) was added at 65°C. Full dissolution was not observed after 30 minutes, and the solution was filtered. A ramp was then set up at 0.1°C/minute to 5 °C. Seeds of NEG 1 (material from screen) were added ( ⁇ 10 mg) at 63 °C. A clear solution was still observed at 5 °C, so TBME was added as an anti-solvent (10 volumes). The solution was concentrated by opening the vial cap at room temperature. Further seeds were added, and the vial was placed at -20°C overnight, which did not aid crystallization.
• the sodium salt was crystallized as form Na2. However, after 10 days storage at room conditions in a closed vial, a form change was observed to Na4. The sodium salt is hydrated, and the diffractograms show slight changes depending on the amount of hydration water. Also, these slight changes may be due to differences in ambient humidity on the date of analysis. The ion chromatography shows 0.8 equivalents of sodium. The DSC showed multiple endothermic events, related to water loss by TGA. The material was subjected to VT-XRPD. The starting material was checked prior to starting this analysis, and a change to Na4 had been observed.
• Na4 showed two form changes upon heating (Nal and a new form Na5) and a further change upon cooling at the end of the experiment (to a new form denoted as Na6, suspected anhydrous).
• a representative XRPD pattern of the different sodium salt forms is shown in FIG. 4. It is possible that some of these XRPD patterns are mixtures of different forms.
• the GVS analysis also confirmed the multiple steps of hydration. The starting material showed 5.7% water (1.5 eqs), as opposed to the material at the end of the experiment, showing 4.4% water (1 eq, Na4 by XRPD). A total of 9.7% water was uptaken at 90%RH on the first cycle (2.5 eqs) and 16.0% on the second cycle (4.5 eqs).
• NEG2 salt deliquesced at 40°C/75%RH and 25°C/97%RH after two days.
• GVS a reversible moisture uptake of 22.5% w/w was observed between 0- 90%RH, after which a gummy solid with low crystallinity was recovered (denoted as NEG3).
• TGA showed a small water loss (1.1 % below 125 °C) after which an endotherm was observed by DSC (106 °C).
• any salt formed with N-ethylglucamine has a poor thermal profile and is not recommended for further development.
• the L-lysine salt, LYS2 (Form 2), is also anhydrous and stable upon storage at 40°C/75%RH and 25 °C/97% RH for 8 days, and during the GVS experiment. Thermal analysis showed a melt and decomposition at 231 °C. The 'H NMR spectrum confirmed the mono stoichiometry. Slight changes in multiplicity were observed in several peaks in the aromatic area, whose nature is unknown. Aqueous solubility was assessed for LYS2, which showed a turbid yellow solution at 5 mg/mL.
• a polymorph screen was conducted with the goal of identifying new solid-state forms of Compound 1 -L-lysine.
• Experiments consisted of solvent mediated solid-state form transformations, temperature cycling, anti-solvent vapor diffusion, solvent drop grinding, pH swings, cooling crystallizations, and anti-solvent addition to solutions.
• the solid-state properties of Compound 1 -L-lysine, Form 1 were also fully characterized.
• DSC Differential Scanning Calorimetry
• Thermogravimetric Analysis was collected with a TA Discovery series TGA. A few milligrams of material were analyzed in an aluminum sample pan. The data was collected from room temperature to 300 °C with a 10 °C per minute scan rate.
• Dynamic Vapor Sorption (DVS). Dynamic vapor sorption experiments were performed on a DVS Intrinsic system by Surface Measurement Systems. Samples were exposed to relative humidities cycling from 0% RH to 90% RH, with the weight equilibrated and measured at each humidity step. Temperature was set and held constant at 25 °C during the entire experiment.
• Anti-Solvent Vapor Diffusion Approximately 25 to 30 mg of material was weighed out into 4 mL vials. About 2 mL of solvent was added and the vials were sonicated in an attempt to make solutions. Any slurries were filtered into clean 4 mL vials to generate solutions for all experiments. These uncapped 4 mL vials were then placed inside larger 20 mL vials containing anti-solvent. The 20 mL vials were capped to allow anti-solvent vapor to slowly diffuse into the solutions in the uncapped 4 mL vials. All experiments were kept at ambient conditions. A summary of experiments and results is provided in Table 14. No crystalline solids were obtained.
• pH Swing Experiments to generate new solid-state forms of Compound 1-L-lysine were conducted by changing the pH of aqueous solutions. Four experiments were conducted consisting of (1) adding base to an acidic solution of Compound 1-L-lysine; (2) adding acid to a basic solution of Compound 1-L-lysine; (3) adding an acidic solution of Compound 1-L-lysine to base; or (4) adding a basic solution of Compound 1-L-lysine to acid.
• Experiment 1 Approximately 30 mg of Compound 1-L-lysine was weighed out into a 4 mL amber glass vial and 1.5 mL of 0.1 M HC1 was added. The suspension was filtered to obtain a clear solution with a pH of 1.7. While stirring on a 25 °C stir plate, 1.5 mL of 0.1 M NaOH was slowly added to give a final pH of 12.0. No solids were observed.
• Experiment 2 Approximately 30 mg of Compound 1-L-lysine was weighed out into a 4 mL amber glass vial and 1.5 mL of 0.1 M NaOH was added. A solution was obtained with a pH of 12.2. While stirring on a 25 °C stir plate, 1.5 mL of 0.1 M HC1 was slowly added to give a pH of 9.6. An additional 0.5 mL of 0.1 M HC1 was added resulting in formation of a gel with a pH of 3.0.
• Experiment 3 Approximately 30 mg of Compound 1-L-lysine was weighed out into a 4 mL amber glass vial and 1.5 mL of 0.1 M HC1 was added. The suspension was filtered to obtain a clear solution with a pH of 1.6. This solution was slowly added to a 4 mL amber glass vial containing 1.5 mL of a stirring 0.1 M NaOH solution on a 25 °C stir plate. The final pH was 12.1. No solids were observed.
• Solubility was determined gravimetrically in the solvents used for the solvent mediated solid-state form transformation experiments described above. Each slurry sample was centrifuged at 2000 rpm for 5 minutes, ambient, then the supernatant was transferred to a microcentrifuge tube and centrifuged again for 30 minutes, 16400 rpm, 21 °C. A 0.500 mL aliquot of the final supernatant solution was transferred to a pre-tared vial and the solvent was removed by evaporation. The vials were reweighed to calculate the final weight. Solubility values are listed in Table 18.
• a polymorph screen was conducted with the goal of identifying new solid-state forms of Compound 1-L-lysine. Experiments consisted of solvent-mediated solid-state form transformations, temperature cycling, anti-solvent vapor diffusion, solvent drop grinding, pH swings, cooling crystallizations, and anti-solvent addition to solutions. No new crystalline forms were discovered in the screen as all crystalline forms corresponded to Form 1.

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