Polymorphs of Levodopa Tyrosine

Abstract

This disclosure is directed in part to crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-A-tyrosine and pharmaceutical compositions thereof.

Description

Related Applications

[0001] cross reference

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 321,202, filed March 18, 2022, the entire disclosure of which is incorporated herein by reference. [Background technology]

[0002]

[0002] Parkinson's disease is a degenerative condition characterized by a decrease in the concentration of the neurotransmitter dopamine in the brain. Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine), a direct metabolic precursor of dopamine that, unlike dopamine, can cross the blood-brain barrier, is the most commonly used to restore dopamine concentration in the brain. Although levodopa remains an effective therapy for treating Parkinson's disease, some patients may become less responsive to levodopa and experience reduced efficacy after about three or four years of treatment. Furthermore, the preparation of liquid formulations of levodopa can be difficult. Thus, there remains a need for additional therapeutic agents to treat degenerative disorders such as Parkinson's disease.

[0003]

[0003] Polymorphism is the ability of a substance to crystallize in more than one crystal lattice arrangement. Crystallization or polymorphism can affect many aspects of the solid-state properties of a drug substance. A crystalline substance can be significantly different from an amorphous form, and different crystalline modifications of a substance can differ significantly from each other in many ways, including solubility, dissolution rate, and / or bioavailability. In general, it is difficult to predict whether a given compound will form crystalline solid state forms. It is even more difficult to predict the physical properties of these crystalline solid state forms. Therefore, it can be advantageous for certain formulations and / or manufacturing methods for a therapeutic agent to have a crystalline form. Summary of the Invention

[0004]

[0004] This disclosure is directed, at least in part, to crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, as well as crystalline anhydrates, hydrates and solvates thereof.

[0005]

[0005] Disclosed herein are crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine characterized, for example, by a powder X-ray diffraction pattern having characteristic peaks at about 20.1 degrees 2θ; characterized, for example, by a powder X-ray diffraction pattern having characteristic peaks at about 12.6, 16.3, and 20.1 degrees 2θ; characterized, for example, by a powder X-ray diffraction pattern having characteristic peaks at about 7.7, 8.7, 12.6, 16.3, 20.1, and 25.7 degrees 2θ; characterized, for example, by a powder X-ray diffraction pattern having characteristic peaks at about 7.7, 8.7, 8.8, 12.6, 16.2, 16.3, 17.3, 20.1, 25.7, 29.8, 30.0, and 34.2 degrees 2θ.

[0006] ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine has the following chemical structure:

[0007] [ka]

[0008] has.

[0007] Further contemplated herein is a pharmaceutical composition comprising the disclosed crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine and a pharma- ceutically acceptable excipient. Further contemplated herein is a drug substance comprising at least a detectable amount of the disclosed forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. For example, disclosed herein is a drug substance comprising a substantially pure crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 is an illustration of the X-ray powder diffraction (XRPD) pattern of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form N). [Diagram 2] FIG. 2 is a differential scanning calorimetry (DSC) profile of Form N. [Diagram 3]

[0010] FIG. 3 is a thermogravimetric analysis (TGA) profile of Form N. [Figure 4]

[0011] FIG. 4 is an X-ray powder diffraction (XRPD) pattern of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine form A (top), form B (middle), and form C (bottom). [Diagram 5]

[0012] FIG. 5 is a differential scanning calorimetry (DSC) profile and a thermogravimetric analysis (TGA) profile of Form B. [Figure 6]

[0013] FIG. 6 is a diagram of the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of Form C. [Figure 7]

[0014] FIG. 7 is an X-ray powder diffraction (XRPD) pattern of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine form D (top), form E (middle), and form G (bottom). [Figure 8]

[0015] FIG. 8 is a diagram of the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of Form D. [Figure 9]

[0016] FIG. 9 is a diagram of the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) profiles of Form G. [Figure 10]

[0017] FIG. 10 is an X-ray powder diffraction (XRPD) pattern of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine form H (top), form I (middle), and form J (bottom). [Figure 11]

[0018] FIG. 11 is an X-ray powder diffraction (XRPD) pattern of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine form K (top), form L (middle), and form M (bottom). [Figure 12]

[0019] FIG. 12 is a thermogravimetric analysis (TGA) profile of Form K. [Figure 13]

[0020] FIG. 13 is a thermogravimetric analysis (TGA) profile of Form M. [Figure 14]

[0021] FIG. 14 is an X-ray powder diffraction (XRPD) pattern of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine form N (top) and form O (bottom). [Figure 15]

[0022] FIG. 15 is an X-ray powder diffraction (XRPD) pattern of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine form P (top) and form Q (bottom). [Figure 16]

[0023] FIG. 16 is an X-ray powder diffraction (XRPD) pattern of amorphous ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. [Figure 17]

[0024] FIG. 17 is a diagram of the thermogravimetric analysis (TGA) profile of the amorphous form. [Figure 18]

[0025] FIG. 18 is a differential scanning calorimetry (DSC) profile of the amorphous form. [Figure 19]

[0026] FIG. 19 is a representation of the X-ray single crystal structure of crystalline form N. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010]

[0027] The features and other details of the present disclosure will now be described in more detail.Before the present disclosure is further described, the specific terms used in the present specification, examples and appended claims will now be summarized.These definitions should be read in the context of the remainder of the present disclosure and as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0011] definition

[0028] The term "crystalline form" refers to a crystalline form or crystalline modification that can be characterized by analytical methods such as, for example, X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in solvated and unsolvated forms with solvents such as water, ethanol, etc. Unless otherwise indicated or implied, the crystalline compounds disclosed herein are intended to include both solvated and unsolvated forms.

[0012]

[0029] "Treating" includes any effect, eg, alleviating, reducing, modulating, or eliminating, that results in the improvement of a condition, disease, disorder, or the like.

[0030] The term "disorder" refers to, and is used interchangeably with, the terms "disease," "condition," or "illness," unless otherwise indicated.

[0013]

[0031] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other unanticipated reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0014]

[0032] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein refers to any and all solvents, dispersion media, coating agents, isotonicity agents, absorption retardants, etc., that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that achieve complementary, additional or enhanced therapeutic functions.

[0015]

[0033] The term "pharmaceutical composition," as used herein, refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable excipients.

[0016]

[0034] "Individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans. The compounds of the present disclosure can be administered to mammals, such as humans, but also to other mammals, such as animals requiring veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the method of the present disclosure is preferably a mammal in which treatment of, for example, cancer or a blood disorder is desired. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0017]

[0035] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a subject compound that induces the biological or medical response of a tissue, system or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician or other clinician. The compounds of the present disclosure are administered in a therapeutically effective amount to treat disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or prophylactic effect.

[0018]

[0036] The term "pharmaceutical acceptable salts" as used herein refers to salts of basic groups that may be present in the compounds used in the compositions. Compounds that are basic in nature and are included in the compositions of the present invention are capable of forming a wide variety of salts with various inorganic and organic acids.

[0019]

[0037] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise stated.

[0038] As used herein, the terms "a" and "an" mean one or more, unless otherwise specified. For example, the term "an agent" includes both a single agent and a combination of two or more agents.

[0020]

[0039] When the term "about" is used before a quantitative value, the disclosure also includes the specific quantitative value itself unless otherwise specified. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or implied. The term "about" in the context of a peak at 2θ degrees means that there is an uncertainty of ±0.2 (expressed in 2θ) in the measurement of 2θ, or there is an uncertainty of ±0.1 (expressed in 2θ), or there is an uncertainty of ±0.05 (expressed in 2θ) in the measurement of 2θ. In general, DSC thermograms may have a variation in the range of ±3°C. Thus, the temperature value should be understood to include values ​​in the range of about ±3°C.

[0021]

[0040] Generally, unless otherwise indicated, crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine substantially free of any other crystalline forms are provided herein. As used herein, "substantially pure," "substantially free," or "substantially free of any other crystalline forms" means that the disclosed crystalline forms contain no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, or no more than about 1% of any other substances, such as other crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, as measured, for example, by XRPD, or contain less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of any other substances, such as other crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, as measured, for example, by XRPD. Thus, the disclosed crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, which are described herein as "substantially pure" or "substantially free of any other crystalline forms", are understood to contain greater than 80% (w / w), greater than 90% (w / w), greater than 95% (w / w), greater than 98% (w / w) or greater than 99% (w / w) of said crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. Thus, in some embodiments, the disclosed crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine may contain only 1%-20% (w / w), 5%-20% (w / w), or 5%-10% (w / w) of one or more other crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine.

[0022] Crystal morphology

[0041] This disclosure is directed, at least in part, to crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine.

[0023]

[0042] For example, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (referred to herein as "Form N"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.1 degrees 2θ.

[0024]

[0043] In one embodiment, crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.7 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.8 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 12.6 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 16.2 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 16.3 degrees 2θ; In another embodiment, crystalline Form N is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 12.6, 16.3, and 20.1 degrees 2θ, an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 17.3 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 20.1 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 25.7 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 29.8 degrees 2θ, an X-ray powder diffraction pattern having at least one characteristic peak at about 30.0 degrees 2θ, and / or an X-ray powder diffraction pattern having at least one characteristic peak at about 34.2 degrees 2θ. In another embodiment, crystalline Form N is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 12.6, 16.3, and 20.1 degrees 2θ. In a further embodiment, the crystalline form N is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.7, 8.7, 12.6, 16.3, 20.1, and 25.7 degrees 2θ. In yet another embodiment, the crystalline form N is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.7, 8.7, 8.8, 12.6, 16.2, 16.3, 17.3, 20.1, 25.7, 29.8, 30.0, and 34.2 degrees 2θ. For example, contemplated crystalline forms have the X-ray powder diffraction pattern shown in FIG. 1. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0025]

[0044] Contemplated crystalline Form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic broad endotherm with an onset at about 135° C. and a peak at about 159° C.; a characteristic endotherm with an onset at about 174° C. and a peak at about 176° C.; a characteristic exotherm with an onset at about 177° C.; and a peak at about 178° C.; and a characteristic endotherm with an onset at about 272° C. and a peak at about 278° C. For example, Form N can be characterized by a differential scanning calorimetry (DSC) profile exhibiting an exothermic event with an onset at about 177° C. and a melting endotherm with an onset at about 272° C. Form N can be characterized by, for example, the differential scanning calorimetry profile shown in FIG. 2.

[0026]

[0045] A contemplated crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 15% by weight between about 22° C. and about 196° C. For example, form N can be characterized by the TGA profile shown in FIG. 3. In some embodiments, crystalline form N can be characterized by a dynamic water vapor sorption (DVS) profile exhibiting a reversible total mass change of about 0.6% by weight between about 40% and about 80% relative humidity (RH) at 25° C. Crystalline form N is physically stable, for example, at 75% RH and 40° C. In some embodiments, crystalline form N can be characterized by a Karl Fischer (KF) analysis exhibiting 15.6% water by weight (about 3.7 equivalents on a molar basis).

[0027]

[0046] The contemplated crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine has an aqueous solubility of about 184.34 mg / ml at a pH of about 1.17, an aqueous solubility of about 9.46 mg / ml at a pH of about 2.60, an aqueous solubility of about 4.06 mg / ml at a pH of about 3.00, an aqueous solubility of about 2.86 mg / ml at a pH of about 3.27, an aqueous solubility of about 1.54 mg / ml at a pH of about 3.92, an aqueous solubility of about 1.64 mg / ml at a pH of about 3.83, an aqueous solubility of about 1.78 mg / ml at a pH of about 4.68, and an aqueous solubility of about 1.08 mg / ml at a pH of about 4.68. It can be characterized by an aqueous solubility of about 1.33 mg / ml, an aqueous solubility of about 1.29 mg / ml at a pH of about 5.00, an aqueous solubility of about 1.37 mg / ml at a pH of about 6.04, an aqueous solubility of about 0.51 mg / ml at a pH of about 6.78, an aqueous solubility of about 18.86 mg / ml at a pH of about 7.56, an aqueous solubility of about 111.38 mg / ml at a pH of about 8.69, an aqueous solubility of about 58.68 mg / ml at a pH of about 9.43, and / or an aqueous solubility of about 155.48 mg / ml at a pH of about 10.26.

[0028]

[0047] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (referred to herein as "Form A"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.0 degrees 2θ.

[0029]

[0048] In one embodiment, crystalline form A of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 4.7 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.5 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.3 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.0 degrees 2θ, and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.1 degrees 2θ. In another embodiment, crystalline form A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.7, 9.5, 18.3, 19.0, and 21.1 degrees 2θ. For example, contemplated crystalline forms have the X-ray powder diffraction pattern depicted in FIG. 4. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0030]

[0049] The contemplated crystalline form A of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 10.2% by weight between about 40° C. and about 200° C.

[0031]

[0050] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (referred to herein as "Form B"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.2 degrees 2θ.

[0032]

[0051] In one embodiment, crystalline form B of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.5 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 14.6 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 14.8 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 17.7 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 20.3 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 22.9 degrees 2θ; In another embodiment, crystalline form B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 14.5, 14.6, 14.8, 17.7, 20.3, 22.9, 23.2, 25.4, 27.3, 29.5, 30.2, and 31.3 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 4. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0033]

[0052] Contemplated crystalline Form B of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset at about 96° C. and a peak at about 119° C.; a characteristic endotherm with an onset at about 161° C. and a peak at about 176° C.; and a characteristic endotherm with an onset at about 275° C. and a peak at about 280° C. Form B can be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 5.

[0034]

[0053] Contemplated crystalline form B of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 15.6% by weight between about 40° C. and about 200° C. ( FIG. 5 ). In some embodiments, crystalline form B can be characterized by a Karl Fischer (KF) analysis exhibiting 17.2% water by weight (about 2.2 equivalents on a molar basis).

[0035]

[0054] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.0 degrees 2θ (herein referred to as “Form C”).

[0036]

[0055] In one embodiment, crystalline form C of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.4 degrees 2θ; In another embodiment, crystalline form C is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.7, 9.0, 13.3, 13.5, 15.2, 15.4, 19.7, 20.5, 22.1, 25.7, 27.9, and 28.1 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 4. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0037]

[0056] Contemplated crystalline form C of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset at about 145° C. and a peak at about 158° C.; a characteristic exotherm with an onset at about 175° C. and a peak at about 178° C.; and a characteristic endotherm with an onset at about 269° C. and a peak at about 275° C. (FIG. 6). Crystalline form C of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 1.75% by weight between about 30° C. and about 190° C. For example, crystalline form C can be characterized by the TGA profile presented in FIG. 6.

[0038]

[0057] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 degrees 2θ (herein referred to as “Form D”).

[0039]

[0058] In one embodiment, crystalline form D of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.2 degrees 2θ; In another embodiment, crystalline form D is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 11.7, 17.0, 17.8, 18.6, 18.9, 19.2, 20.9, 23.6, 26.1, 26.7, 27.3, and / or 28.5 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 7. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0040]

[0059] Contemplated crystalline Form D of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic broad endotherm with an onset at about 79° C. and a peak at about 97° C.; a characteristic endotherm with an onset at about 147° C. and a peak at about 152° C.; a characteristic endotherm with an onset at about 175° C. and a peak at about 176° C.; a characteristic exotherm with an onset at about 178° C. and a peak at about 179° C.; a characteristic exotherm with an onset at about 183° C. and a peak at about 191° C.; and a characteristic endotherm with an onset at about 263° C. and a peak at about 270° C. Form D can be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 8. A contemplated crystalline form D of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 38% by weight between about 30° C. and about 211° C. For example, crystalline form D has the TGA profile shown in FIG.

[0041]

[0060] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.8 degrees 2θ (herein referred to as “Form E”).

[0042]

[0061] In one embodiment, crystalline form E of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.3 degrees 2θ. In another embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 10.8, 12.5, 14.8, 15.2, 17.9, 20.3, 20.9, 23.3, 23.5, 24.4, 25.8, and 26.3 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 7. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0043]

[0062] A contemplated crystalline form E of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 11.5% by weight between about 40° C. and about 200° C. In some embodiments, crystalline form E can be characterized by a dynamic water vapor sorption (DVS) profile exhibiting a total reversible mass change of about 8% by weight between about 0 and about 90% relative humidity (RH) at 25° C.

[0044]

[0063] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.8 degrees 2θ (herein referred to as “Form G”).

[0045]

[0064] In one embodiment, crystalline form G of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.6 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.8 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 13.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.3 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 19.4 degrees 2θ; In another embodiment, crystalline form G is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.6, 8.8, 13.5, 15.3, 15.5, 19.4, 21.0, 21.8, 22.3, 25.4, 27.8, and 29.9 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 7. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0046]

[0065] Contemplated crystalline Form G of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset at about 126° C. and a peak at about 130° C.; a characteristic endotherm with an onset at about 159° C. and a peak at about 169° C.; a characteristic exotherm with an onset at about 171° C. and a peak at about 176° C.; and a characteristic endotherm with an onset at about 264° C. and a peak at about 271° C. Form G can be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 9.

[0047]

[0066] A contemplated crystalline form G of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 15% by weight between about 42° C. and about 208° C. (FIG. 9). In some embodiments, crystalline form G can be characterized by a dynamic water vapor sorption (DVS) profile exhibiting a reversible total mass change of about 2.6% by weight between about 40% and about 80% relative humidity (RH) at 25° C. In some embodiments, crystalline form G can be characterized by a Karl Fischer (KF) analysis exhibiting 12.3% water by weight (about 2.3 equivalents on a molar basis).

[0048]

[0067] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ (herein referred to as “Form H”).

[0049]

[0068] In one embodiment, crystalline form H of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.0 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 11.4 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 12.3 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 14.2 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 14.6 degrees 2θ; In another embodiment, crystalline form H is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.0, 8.7, 11.4, 12.3, 14.2, 14.6, 15.5, 16.1, 18.7, 21.1, 21.4, and 22.9 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 10. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0050]

[0069] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ (herein referred to as “Form I”).

[0051]

[0070] In one embodiment, crystalline Form I of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.4 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 7.5 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 8.8 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 13.9 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 14.2 degrees 2θ. In another embodiment, the crystalline Form I is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.4, 7.5, 8.7, 8.8, 13.9, 14.2, 15.5, 21.1, 21.6, 21.9, 22.7, and 26.2 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 10. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0052]

[0071] The contemplated crystalline Form I of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 11% by weight between about 30° C. and about 212° C.

[0053]

[0072] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.8 degrees 2θ (herein referred to as “Form J”).

[0054]

[0073] In one embodiment, crystalline form J of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 4.4 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.8 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 13.9 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 18.9 degrees 2θ; In another embodiment, crystalline form J is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 4.4, 7.5, 8.8, 13.9, 15.5, 18.9, 21.4, 21.6, 21.8, 22.7, 26.2, and 29.5 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 10. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0055]

[0074] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.4 degrees 2θ (herein referred to as “Form K”).

[0056]

[0075] In one embodiment, the crystalline form K of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 11.0 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 13.4 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.4 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 18.8 degrees 2θ; In another embodiment, the crystalline form K is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.5, 8.5, 11.0, 13.4, 15.4, 18.8, 20.8, 21.0, 22.1, 25.1, 25.8, and 27.7 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 11. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0057]

[0076] The contemplated crystalline form K of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 17% by weight between about 22° C. and about 203° C. ( FIG. 12 ).

[0058]

[0077] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (referred to herein as "Form L"), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ.

[0059]

[0078] In one embodiment, crystalline form L of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.6 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.0 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 11.1 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 13.4 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.5 degrees 2θ; In another embodiment, crystalline form L is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.6, 8.0, 8.7, 11.1, 13.4, 15.5, 19.2, 20.9, 21.5, 22.2, 25.3, and 27.8 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 11. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0060]

[0079] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ (herein referred to as “Form M”).

[0061]

[0080] In one embodiment, crystalline form M of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.6 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.8 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 11.1 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 13.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.5 degrees 2θ; In another embodiment, crystalline form M is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.6, 8.7, 8.8, 11.1, 13.5, 15.5, 20.9, 21.5, 21.8, 22.3, 25.3, and 27.8 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 11. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0062]

[0081] Contemplated crystalline form M of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 17% by weight between about 22° C. and about 199° C. For example, crystalline form M can have the TGA profile shown in FIG. 13. In some embodiments, crystalline form M can be characterized by a Karl Fischer (KF) analysis exhibiting 17.8% water by weight (about 4.3 equivalents on a molar basis).

[0063]

[0082] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ (herein referred to as “Form O”).

[0064]

[0083] In one embodiment, crystalline form O of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 11.1 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 13.6 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.4 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.5 degrees 2θ; In another embodiment, crystalline form O is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.5, 8.7, 11.1, 13.6, 15.4, 15.5, 18.9, 21.0, 21.4, 21.6, 22.3, and / or 25.5 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 14. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0065]

[0084] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ (herein referred to as “Form P”).

[0066]

[0085] In one embodiment, crystalline form P of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an X-ray powder diffraction pattern with a characteristic peak at about 7.4 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 11.4 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 14.0 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 15.5 degrees 2θ; characterized by an X-ray powder diffraction pattern with a characteristic peak at about 18.7 degrees 2θ; In another embodiment, crystalline form P is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.4, 8.7, 11.4, 14.0, 15.5, 18.7, 20.2, 21.4, 21.5, 22.8, 26.2, and 28.2 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 15. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0067]

[0086] In another embodiment, disclosed herein is a crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ (herein referred to as “Form Q”).

[0068]

[0087] In one embodiment, crystalline form Q is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.8 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.7 degrees 2θ. In another embodiment, crystalline form Q is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at degrees 2θ of about 8.7, 13.5, 15.4, 19.2, 20.9, 21.6, 22.2, 25.4, 27.8, and 29.7. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 15. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0069]

[0088] In another embodiment, a substantially amorphous form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is disclosed herein. For example, a contemplated amorphous form has the powder X-ray diffraction pattern shown in FIG.

[0070]

[0089] Embodiments of the present disclosure are directed to highly pure forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. According to some embodiments, the ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine has a purity of greater than about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, about 99.6%, about 99.75% or about 99.9%. In some embodiments, the ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine has a purity of greater than about 99%. In some embodiments, the ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine has a purity of greater than about 99.5%. In some embodiments, the ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine has a purity of greater than about 99.6%. In some embodiments, the ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine has a purity of greater than about 99.9%. According to some embodiments, the highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is polymorph N.

[0071]

[0090] According to some embodiments, the highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an HPLC chromatogram having a peak at about 22.65 RT. In some embodiments, the HPLC chromatogram has peaks at about 16.86, 18.45, 21.79, 22.65, 23.90, 25.99, 26.62, 30.39, 30.83, 31.90, 32.20, 32.76, 33.43, 34.95, 37.01 and 39.92 RT. In some other embodiments, the highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an HPLC chromatogram having a peak at about 22.56 RT. According to some embodiments, the HPLC chromatogram has peaks at about 5.81, 20.81, 21.71, 22.56, 33.38 and 36.88 RT. In some embodiments, the HPLC chromatogram has peaks at about 5.80, 20.82, 21.72, 22.56, 33.39 and 36.89 RT. According to some embodiments, the highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an HPLC chromatogram having a peak at about 22.55 RT. In some embodiments, the HPLC chromatogram has peaks at about 5.80, 20.81, 21.70, 22.55, 33.37 and 36.87 RT. According to some embodiments, the highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is characterized by an HPLC chromatogram having a peak at about 22.54 RT. In some embodiments, the HPLC chromatogram has peaks at about 5.80, 20.80, 21.70, 22.54, 33.38 and 36.88 RT.

[0072]

[0091] According to some embodiments, the color of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, e.g., polymorph N prepared according to any of the methods detailed herein, when dissolved in TRIS buffer, is defined as Y5, Y6, Y7, B5, B6, B7, BY5, BY6 or BY7. It is noted that the color scales referred to herein are color reference solutions Y1-Y7, which are related to Ph.Eur. Y1-Y7 Certipur®, BY1-BY7, which are related to Ph.Eur. BY1-BY7 Certipur®, and B1-B7, which are related to Ph.Eur. B1-B7 Certipur®.

[0073]

[0092] According to some embodiments, the crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine disclosed herein are purified from a previously prepared batch of crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine.

[0074]

[0093] ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine may be purified to remove color caused by impurities. According to some embodiments, activated carbon may be used to purify ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. According to some embodiments, the activated carbon is selected from newcarb, pencarb, Alquandracarb, Eno PC Carb, HW Carb, Tri Carb, C-CA activated carbon, C-HA activated carbon, C-VA activated carbon, C-VW activated carbon, norite carbon, penta carb, or any combination thereof. According to some embodiments, a single dose of activated carbon may be used, and in this context, a single dose is considered a step in the purification process, where activated carbon is added to a container to purify the material observed therein. According to some embodiments, two, three, four, five or more portions of activated carbon may be used. In some embodiments, at least two portions of activated carbon are used in the method. According to some embodiments, each portion of activated carbon comprises one type of activated carbon. According to some embodiments, each portion of activated carbon comprises two, three, four, five or more types of activated carbon. According to some embodiments, when more than one portion of activated carbon is used, the type of activated carbon used in each portion may be different from each other. According to some embodiments, when more than one portion of activated carbon is used, the type of activated carbon used in each portion may be the same.

[0075]

[0094] In some embodiments, the amount of activated carbon added in each portion is about 5% w / w to about 50% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 5% w / w to about 10% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 10% w / w to about 50% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 10% w / w to about 15% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 15% w / w to about 20% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 20% w / w to about 25% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 25% w / w to about 30% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 30% w / w to about 35% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 35% w / w to about 40% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 40% w / w to about 45% w / w of the weight of the crystalline compound being purified. In some embodiments, the amount of activated carbon added in each portion is about 45% w / w to about 50% w / w of the weight of the crystalline compound being purified. According to some embodiments, the amount of activated carbon added in each portion is about 10% w / w, 15% w / w, 20% w / w, 25% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, or 50% w / w, based on the weight of the crystalline compound being purified. According to some embodiments, the amount of activated carbon added in each portion is about 15% w / w, 20% w / w, 25% w / w, or 30% w / w, based on the weight of the crystalline compound being purified.According to some embodiments, the amount of activated carbon added in each portion is about 15% w / w relative to the weight of the crystalline compound being purified.

[0076]

[0095] According to some other embodiments, an acidic agent may be used to purify ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. Exemplary acidic agents include, but are not limited to, HF, such as HBr in acetic acid, trifluoroacetic acid, and thioanisole, and BBr3, BCl3, or BF3 ether complexes, or combinations thereof. According to some embodiments, a single portion of acidic agent may be used, and in this context, a single portion is considered a step in the purification process, where the acidic agent is added to a vessel to purify the material found therein. According to some embodiments, two, three, four, five, or more portions of acidic agent may be used. According to some embodiments, each portion of acidic agent includes one type of acidic agent. According to some embodiments, each portion of acidic agent includes two, three, four, five, or more types of acidic agents. According to some embodiments, when more than one portion of acidic agent is used, the types of acidic agents used in each portion may be different from each other. According to some embodiments, when more than one portion of acidic agent is used, the type of acidic agent used in each portion may be the same.

[0077]

[0096] According to some embodiments, ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is first prepared and then purified, including color purification. According to other embodiments, ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is

[0078] [ka]

[0079] and the material is purified during the preparation process. For example, when a purification process is carried out during the preparation of crystalline form N,

[0080] [ka]

[0081] Form.

[0097] According to some embodiments, the ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is purified in alcohol. According to some embodiments, the alcohol is methanol, ethanol, propanol, iso-propanol, butanol, iso-butanol or any other suitable alcohol. According to some embodiments, the alcohol is methanol.

[0082]

[0098] In further embodiments, disclosed herein are pharmaceutical compositions comprising the disclosed crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine and pharma- ceutically acceptable excipients. For example, disclosed herein are pharmaceutical compositions comprising crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine and pharma- ceutically acceptable excipients. In another embodiment, disclosed herein are pharmaceutical compositions formed from the disclosed crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. For example, disclosed herein are pharmaceutical compositions formed from crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine.

[0083]

[0099] In yet another embodiment, disclosed herein is a pharmaceutical composition comprising the disclosed amorphous form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine and a pharma- ceutically acceptable excipient.

[0084]

[0100] In an embodiment, disclosed herein is a drug substance comprising at least a detectable amount of the disclosed crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. In another embodiment, disclosed herein is a drug substance comprising a substantially pure crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. For example, disclosed herein is a drug substance comprising a substantially pure crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine.

[0085] composition

[0101] Another aspect of the present disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein, formulated together with pharmaceutically acceptable excipients.In particular, the present disclosure provides pharmaceutical compositions comprising the crystalline compounds disclosed herein, formulated together with one or more pharmaceutically acceptable excipients.These formulations include those suitable for oral, topical (e.g., transdermal), buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), rectal, vaginal or aerosol administration, although in any given case, the most suitable form of administration depends on the extent and severity of the condition to be treated and the nature of the specific compound used.For example, the disclosed compositions may be formulated as a unit dose and / or formulated for oral, subcutaneous or intravenous administration.

[0086]

[0102] The exemplary pharmaceutical compositions of the present disclosure may be used in the form of pharmaceutical compositions, for example, in solid, semi-solid or liquid form, which contain one or more compounds of the present disclosure as active ingredients in a mixture with organic or inorganic excipients, or excipients suitable for external, enteral or parenteral use.The active ingredients may be mixed with, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other forms suitable for use, with normal non-toxic pharmaceutically acceptable excipients.The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0087]

[0103] When preparing solid compositions such as tablets, the main active ingredient can be mixed with pharmaceutical excipients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum, and other pharmaceutical diluents, such as water, to form a solid preformulation composition that contains a homogeneous mixture of the compound of the present disclosure or its non-toxic pharmaceutically acceptable salt.When these preformulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly distributed throughout the composition, so that the composition can be easily divided into equally effective unit dosage forms, such as tablets, pills and capsules.

[0088]

[0104] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions may contain one or more pharma- ceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) agar, calcium carbonate, or the like; The composition may be mixed with any of the following: (1) disintegrating agents such as wheat, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, (2) dissolution retarders such as paraffin, (3) absorption promoters such as quaternary ammonium compounds, (4) wetting agents such as acetyl alcohol and glycerol monostearate, (5) absorbents such as kaolin and bentonite clay, (6) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof, and (7) coloring agents. In the case of capsules, tablets and pills, the composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0089]

[0105] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets may be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings, well known in the pharmaceutical formulation art.

[0090]

[0106] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or their mixtures, and powders.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups and elixirs.In addition to the subject composition, liquid dosage forms may contain other solvents, solubilizers and emulsifiers commonly used in the art, such as water or ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrin and their mixtures.

[0091]

[0107] Suspensions may contain, in addition to the subject compositions, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0092]

[0108] Formulations for rectal or vaginal administration may be provided as suppositories, which can be prepared by mixing the subject compositions with one or more suitable non-irritating excipients or excipients including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and thus will melt in the body cavity and release the active agent.

[0093]

[0109] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient may be mixed under sterile conditions with a pharma- ceutically acceptable excipient, and with any preservatives, buffers or propellants which may be required.

[0094]

[0110] The ointments, pastes, creams and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0095]

[0111] Powders and sprays may contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0096]

[0112] Alternatively, the compositions and compounds of the present disclosure may be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal formulation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension can be used. Sonic nebulizers can be used because they minimize the exposure of the agent to shear that can cause the degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject composition with conventional pharma- ceutically acceptable excipients and stabilizers. Excipients and stabilizers vary according to the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween, Pluronic or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0097]

[0113] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise the subject composition in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use, and may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending agents, or thickening agents.

[0098]

[0114] Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and their suitable mixtures, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.For example, the crystalline forms provided herein can be milled to obtain a specific particle size, and in at least some embodiments, such crystalline forms can be substantially stable when milled.

[0099]

[0115] The amount of the crystalline compound described herein in the formulation may vary depending on factors such as individual disease state, age, sex and body weight.Dosage regimen can be adjusted to achieve optimal therapeutic response.For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.For ease of administration and uniformity of dosage, it is particularly advantageous to formulate parenteral compositions in dosage unit form.Dosage unit form, as used herein, refers to a physically discrete unit suitable as a unitary dosage for the mammalian subject to be treated, each unit containing a predetermined amount of active crystalline compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0100]

[0116] The specifications for the dosage unit forms of the present disclosure are dictated by and directly dependent upon (a) the inherent characteristics of the crystalline compound selected and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the technology of compounding such active crystalline compounds for the treatment of a susceptibility in an individual.

[0101]

[0117] The disclosed compositions can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high drug concentration. The carrier can be, for example, a solvent or dispersion medium, including water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by using a coating agent such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using surfactants. In many cases, it is suitable to include an isotonic agent in the composition, for example, sugar, polyalcohol such as mannitol, sorbitol, or sodium chloride. Prolonged absorption of the injectable composition can be achieved by including an agent that delays absorption in the composition, for example, monostearate salts and gelatin.

[0102]

[0118] The disclosed crystalline compound can be administered in a time-release formulation, for example, in a composition that includes slow-release polymer.The crystalline compound can be prepared with a carrier that protects the compound from rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic acid copolymers, polyglycolic acid copolymers (PLG), and the like.Many methods for preparing such formulations are generally known to those skilled in the art.

[0103]

[0119] According to an alternative embodiment of the present disclosure, the disclosed crystalline compounds can be formulated with one or more additional compounds that enhance the solubility of the compound. method

[0120] In some embodiments, the disclosure provides a method of treating a neurodegenerative condition and / or a condition characterized by reduced dopamine levels in the brain in a patient in need of such treatment, comprising administering to the patient an effective amount of a disclosed crystalline compound, e.g., a disclosed crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine. In other embodiments, the disclosure provides a method of treating a neurodegenerative condition and / or a condition characterized by reduced dopamine levels in the brain in a patient in need of such treatment, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a disclosed crystalline compound, e.g., a disclosed crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine and a pharma- ceutically acceptable excipient.

[0104]

[0121] For example, the disclosed crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine are useful for preventing or treating Parkinson's disease, secondary parkinsonism, Huntington's disease, parkinsonian syndrome, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome, dystonia, Alzheimer's disease, dementia with Lewy bodies (LBD), akinesia, bradykinesia and hypokinesia. In addition, the disclosed crystalline forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine are useful for preventing or treating diseases or symptoms caused by brain damage, including carbon monoxide poisoning or manganese poisoning, or diseases or symptoms associated with nervous system diseases or disorders, including alcoholism, drug addiction or erectile dysfunction.

[0105]

[0122] In some embodiments, the neurodegenerative condition and / or the condition characterized by decreased dopamine levels in the brain is Parkinson's disease.For example, disclosed herein is a method for treating Parkinson's disease in a patient in need of Parkinson's disease treatment, comprising administering to the patient an effective amount of the disclosed crystalline compound, for example, the disclosed crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine.In other embodiments, the present disclosure provides a method for treating Parkinson's disease in a patient in need of Parkinson's disease treatment, comprising administering to the patient an effective amount of the pharmaceutical composition comprising the disclosed crystalline compound, for example, the disclosed crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine and a pharma- ceutical acceptable excipient.

[0106]

[0123] In particular, in certain embodiments, the present disclosure provides a method of treating the above medical indications, comprising administering an effective amount of a crystalline compound disclosed herein to a patient in need of treatment of the above medical indications. In certain other embodiments, the present disclosure provides a method of treating the above medical conditions in a patient in need of treatment, comprising orally, subcutaneously or intravenously administering to the patient a composition comprising the disclosed crystalline form.

[0107]

[0124] The crystalline compounds disclosed herein can be used as medicines or pharma- ceutical acceptable compositions, for example, in the form of pharmaceutical preparations for oral, enteral, parenteral or topical administration, and the contemplated methods disclosed herein can include administering the disclosed crystalline compounds or compositions comprising or formed from such disclosed crystalline compounds orally, enterally, parenterally or topically.For example, the disclosed crystalline forms, when administered by a certain route (e.g., oral) or in a certain formulation, can allow for control of one or more pharmacokinetic properties (e.g., longer or shorter release profile) compared to different routes (e.g., subcutaneous) or other formulations, such as formulations with amorphous morphology.In one embodiment, the disclosed crystalline forms can provide substantial reproducibility between formulations. EXAMPLES

[0108]

[0125] The compounds described herein can be prepared in a number of ways, based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the disclosure.

[0109] device

[0126] X-ray powder diffraction (XRPD) analysis was performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. Samples were analyzed at ambient temperature in transmission mode and held between low density PVC films. The Almac default XRPD program was used (range 4-40° (2θ), step size 0.01313°, count time 92 s, run time approx. 20 min, count time 46 s, run time approx. 10 min, count time 23 s, run time approx. 5 min). Samples were rotated at 60 rpm during data collection. XRPD patterns were classified and manipulated using HighScore Plus v4.9 software.

[0110]

[0127] Differential scanning calorimetry (DSC) analyses were performed on a Perkin Elmer Jade Differential Scanning Calorimeter or a Perkin Elmer DSC8500 Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminum pans (i.e., sealed but not airtight). Each sample was heated under nitrogen at a rate of 10°C / min up to 300°C. Indium metal was used as the calibration standard.

[0111]

[0128] Thermogravimetric analysis was performed on a Mettler Toledo TGA / DSC1 STARe. Calibration standards were indium and tin. Samples were placed in aluminum sample pans, inserted into the TG furnace and accurately weighed. Under nitrogen flow at a rate of 10°C / min, the heat flow signal was allowed to stabilize at 30°C for 1 min before heating to 300°C.

[0112]

[0129] Thermogravimetric analysis was also performed on a TA Instruments Discovery TGA550 instrument. A standard aluminum pan and lid were placed into a 100 μL platinum pan and tared. Approximately 5-10 mg of material was carefully placed into the aluminum pan and the lid was crimped in place. The sample was heated to 300 °C at 10 °C / min under a nitrogen environment.

[0113]

[0130] Dynamic water vapor sorption (DVS) was performed using a Hiden Analytical Instruments IGAsorp water vapor sorption balance. Approximately 30 mg of sample was placed in a wire-mesh water vapor sorption balance pan and loaded onto the IGAsorp water vapor sorption balance and held at 25°C ± 0.1°C. The sample was subjected to a step profile from 40 to 90% RH in 10% increments, followed by desorption from 90 to 0% RH, and a second sorption cycle from 0 to 40% RH. Equilibrium criteria were set for 99.0% step completion within a minimum of 60 minutes and a maximum of 5 hours for each increment. Weight change was monitored during the sorption cycle to allow for a determination of the hygroscopicity of the sample. Data collection intervals were in seconds.

[0114]

[0131] Volumetric Karl Fischer (KF) analysis was performed using a Mettler Toledo V30 KF titrator. A weighed amount of solid sample was added directly to the KF cell. The solution was stirred and the water content of the sample was then determined by automatic titration against a standard KF reagent titrant. This procedure was performed in duplicate and the average water content was reported.

[0115]

[0132] The color determinations mentioned in Examples 18a, 18b, 18c and 19 were carried out using Certipur® color reference solutions (series BY→BY1-BY7; series Y→Y1-Y7). Color reagent test (CRT) samples (per 20 mL) were prepared by mixing 20 mg of potassium sulfite and 3.2 grams of Tris base in 16 grams of water until completely dissolved (pH=10.5±0.3). For the color reaction, 375 mg of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was added to 5 mL of CRT solution, stirred until dissolved, and filtered through a PES 0.22 μm syringe filter. The color of the reacted solution was determined within about 1 hour of the color reaction. The reference and reaction solutions were placed in diffuse daylight or in a light box and observed vertically against a white background. The solutions were assigned to standards Y3 through Y7 or BY6 through BY7.

[0116] Screening Methods Procedure A: Slurry experiments

[0133] Sufficient ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (amorphous) was added to a given solvent until the solid remained undissolved at the desired temperature (5, 20 or 50° C.). The vial was sealed and the slurry was maintained at the selected temperature and agitated by magnetic stirring for 7 days. The solid was isolated by filtration / centrifugation and air-dried for 1-2 hours before being analyzed by XRPD.

[0117] Step B: Temperature Cycling

[0134] Approximately 50 volumes of the indicated solvent were added to ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form G) and thus did not completely dissolve. The sample was stirred at 600 rpm and heated from 20° C. at 0.5° C. / min to within 3° C. of the boiling point of the solvent (or 100° C., whichever was lower), then cooled at 0.2° C. / min to 20° C., and the cycle was repeated for an additional hour. The sample was held at ambient temperature for several hours, allowed to settle, and the recovered solid was analyzed by XRPD.

[0118] Step C: Steam stress

[0135] Approximately 25 mg of amorphous ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was added to a vial and placed unsealed within a larger sealed container containing the indicated solvent. After approximately 7 days, the sample was removed and analyzed by XRPD.

[0119] Step D: Planetary mill grinding

[0136] Approximately 20 mg of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form G) was added to a vial containing steel milling balls and solvent (10 μL). The vial was sealed and the contents were milled using a planetary mill at a rotation speed of 400 rpm for 30 minutes with a 30 minute break between milling cycles (24 cycles). The resulting milled material was analyzed using XRPD. EXAMPLES

[0120]

[0137] A material of crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine according to procedure A at 20° C. using acetone / water (18:82% v / v) as the solvent. The XRPD pattern of crystalline form N is shown in FIG. 1. Characteristic peaks include one or more of the peaks shown in Table 1.

[0121] [Table 1-1]

[0122] [Table 1-2]

[0123]

[0138] Figure 2 illustrates the differential scanning calorimetry (DSC) profile of crystalline form N. As shown in Figure 2, crystalline form N exhibits a characteristic broad endotherm with an onset at about 135°C and a peak at about 159°C; a characteristic endotherm with an onset at about 174°C and a peak at about 176°C; a characteristic exotherm with an onset at about 177°C and a peak at about 178°C; and a characteristic endotherm with an onset at about 272°C and a peak at about 278°C.

[0124]

[0139] Crystalline form N of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 15% by weight between about 22 °C and about 196 °C (Figure 3). Crystalline form N exhibited a dynamic water vapor sorption (DVS) profile showing a reversible total mass change of about 0.6% by weight between about 40% and about 80% relative humidity (RH) at 25 °C. Karl Fischer (KF) analysis showed 15.6% by weight water (about 3.7 equivalents on a molar ratio basis).

[0125]

[0140] Single crystals of Form N were grown by vapor diffusion using water:DMSO (9:5 v / v) as the solvent and trifluoroethanol as the antisolvent and analyzed by single crystal X-ray analysis. The crystals were observed to be dihydrates, with unit cell parameters indicating a monoclinic crystal system with a C2 space group, and other crystallographic details are shown in Table 1A below. The X-ray crystal structure is shown in Figure 19, with hydrogen atoms omitted for clarity.

[0126] [Table 1-3] EXAMPLES

[0127]

[0141] The XRPD pattern of crystalline form A of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is shown in Figure 4. Characteristic peaks include one or more of the peaks shown in Table 2.

[0128] [Table 2]

[0129]

[0142] Crystalline form A of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine exhibited a thermogravimetric analysis (TGA) profile that exhibited a mass loss of about 10.2 wt % between about 40° C. and about 200° C. EXAMPLES

[0130]

[0143] Crystalline form B material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared by recrystallization of form G from water. Form B was also prepared following procedure A at 5° C. using dioxane / water (82:18% v / v) as the solvent. The XRPD pattern of crystalline form B is shown in FIG. 4. Characteristic peaks include one or more of the peaks shown in Table 3.

[0131] [Table 3-1]

[0132] [Table 3-2]

[0133]

[0144] Figure 5 illustrates the differential scanning calorimetry (DSC) profile of crystalline form B. As shown in Figure 5, crystalline form B exhibits a characteristic endotherm with an onset at about 96°C and a peak at about 119°C; a characteristic endotherm with an onset at about 161°C and a peak at about 176°C; and a characteristic endotherm with an onset at about 275°C and a peak at about 280°C. Crystalline form B exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 15.6 wt% between about 40°C and about 200°C. Karl Fischer (KF) analysis showed 17.2 wt% water (about 2.2 equivalents on a molar ratio basis). EXAMPLES

[0134]

[0145] Crystalline form C material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared according to procedure A at 5° C. and 50° C. using ethanol / water (96:4% v / v) as the solvent. Crystalline form C was also prepared according to procedure C using ethanol / water (96:4% v / v) as the solvent. The XRPD pattern of crystalline form C is shown in FIG. 4. Characteristic peaks include one or more of the peaks shown in Table 4.

[0135] [Table 4]

[0136]

[0146] Figure 6 illustrates the differential scanning calorimetry (DSC) profile of crystalline form C. As shown in Figure 6, crystalline form C exhibits a characteristic endotherm with an onset at about 145°C and a peak at about 158°C; a characteristic exotherm with an onset at about 175°C and a peak at about 178°C; and a characteristic endotherm with an onset at about 269°C and a peak at about 275°C. Crystalline form C exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 1.75 wt% between about 30°C and about 190°C. Crystalline form C converted to form G upon storage at ambient conditions. EXAMPLES

[0137]

[0147] Crystalline form D material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared at 5° C. according to procedure A or procedure C, respectively, using water as the solvent. The XRPD pattern of crystalline form D is shown in FIG. 7. Characteristic peaks include one or more of the peaks shown in Table 5.

[0138] [Table 5-1]

[0139] [Table 5-2]

[0140]

[0148] FIG. 8 illustrates the differential scanning calorimetry (DSC) profile of crystalline form D. As shown in FIG. 8, crystalline form D exhibits a characteristic broad endotherm with an onset at about 79° C. and a peak at about 97° C.; a characteristic endotherm with an onset at about 147° C. and a peak at about 152° C.; a characteristic endotherm with an onset at about 175° C. and a peak at about 176° C.; a characteristic exotherm with an onset at about 178° C. and a peak at about 179° C.; a characteristic exotherm with an onset at about 183° C. and a peak at about 191° C.; and a characteristic endotherm with an onset at about 263° C. and a peak at about 270° C. Crystalline form D exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 38% by weight between about 30° C. and about 211° C. (FIG. 8). Crystalline form D converted to form N upon storage at ambient conditions. EXAMPLES

[0141]

[0149] Crystalline form E material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared in a TG / DTA instrument by heating a sample of form B (approximately 5 mg) to just above the desolvation temperature and then held at that temperature until the weight loss stabilized (15-20 minutes). The sample was then cooled to ambient temperature and immediately analyzed by XRPD. The XRPD pattern of crystalline form E is shown in FIG. 7. Characteristic peaks include one or more of the peaks shown in Table 6.

[0142] [Table 6]

[0143]

[0150] Crystalline form E exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 11.5 wt% between about 40° C. and about 200° C. Crystalline form E exhibited a dynamic water vapor sorption (DVS) profile showing a reversible total mass change of about 8 wt% between about 0 and about 90% relative humidity (RH) at 25° C. Crystalline form E converted to form B upon storage at ambient conditions. EXAMPLES

[0144]

[0151] The XRPD pattern of crystalline form G of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is shown in Figure 7. Characteristic peaks include one or more of the peaks shown in Table 7.

[0145] [Table 7-1]

[0146] [Table 7-2]

[0147]

[0152] Figure 9 illustrates the differential scanning calorimetry (DSC) profile of crystalline form G. As shown in Figure 9, crystalline form G exhibits a characteristic endotherm with an onset at about 126°C and a peak at about 130°C; a characteristic endotherm with an onset at about 159°C and a peak at about 169°C; a characteristic exotherm with an onset at about 171°C and a peak at about 176°C; and a characteristic endotherm with an onset at about 264°C and a peak at about 271°C.

[0148]

[0153] Crystalline form G exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 15 wt% between about 42 °C and about 208 °C (Figure 14). Crystalline form G exhibited a dynamic water vapor sorption (DVS) profile showing a reversible total mass change of about 2.6 wt% between about 40 and about 80% relative humidity (RH) at 25 °C. Karl Fischer (KF) analysis showed 12.3 wt% water (about 2.3 equivalents on a molar ratio basis).

[0149]

[0154] By polarized optical microscopy, crystalline form G exhibited a crystalline particle size of <100 μm with significant agglomeration / aggregation, whereas fine crystalline particles (<20 μm) were observed in the case of form N. Crystalline form N material was less hygroscopic (0.6% w / w increase between 40 and 80% RH) than form G material (2.6% w / w between 40 and 80% RH), and DVS analysis showed that pattern N material was a more stable hydrate, losing significantly less water at low RH. EXAMPLES

[0150]

[0155] Crystalline form H material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared in a TG / DTA instrument by heating a sample of form G (approximately 5 mg) to just above the desolvation temperature and then held at that temperature until the weight loss stabilized (15-20 minutes). The sample was then cooled to ambient temperature and immediately analyzed by XRPD. The XRPD pattern of crystalline form H is shown in FIG. 10. Characteristic peaks include one or more of the peaks shown in Table 8.

[0151] [Table 8] EXAMPLES

[0152]

[0156] The XRPD pattern of crystalline form I of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is shown in Figure 10. Characteristic peaks include one or more of the peaks shown in Table 9. Crystalline form I exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 11 wt% between about 30°C and about 212°C.

[0153] [Table 9-1]

[0154] [Table 9-2] EXAMPLES

[0155]

[0157] Crystalline form J material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared. The XRPD pattern of crystalline form J is shown in FIG. 10. Characteristic peaks include one or more of the peaks shown in Table 10.

[0156] [Table 10-1]

[0157] [Table 10-2] EXAMPLES

[0158]

[0158] Crystalline form K material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared following procedure B using methyl isobutyl ketone as the solvent. The XRPD pattern of crystalline form K is shown in Figure 11. Characteristic peaks include one or more of the peaks shown in Table 11. Crystalline form K exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 17% by weight between about 22°C and about 203°C (Figure 12).

[0159] [Table 11] EXAMPLES

[0160] Crystalline form L material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared according to procedure B using trifluorethanol as the solvent. Crystalline form L material was also prepared according to procedure D using acetone or heptane as the solvent. The XRPD pattern of crystalline form L is shown in FIG. 11. Characteristic peaks include one or more of the peaks shown in Table 12.

[0161] [Table 12] EXAMPLES

[0162]

[0160] Procedure D was followed for the preparation of crystalline form M material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine using tetrahydrofuran as the solvent. The XRPD pattern of crystalline form M is shown in Figure 11. Characteristic peaks include one or more of the peaks shown in Table 13. Crystalline form M exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 17% by weight between about 22°C and about 203°C (Figure 13).

[0163] [Table 13] EXAMPLES

[0164]

[0161] The XRPD pattern of crystalline form O of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is shown in Figure 14. Characteristic peaks include one or more of the peaks shown in Table 14.

[0165] [Table 14] EXAMPLES

[0166]

[0162] The XRPD pattern of crystalline form P of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is shown in Figure 15. Characteristic peaks include one or more of the peaks shown in Table 15.

[0167] [Table 15-1]

[0168] [Table 15-2] EXAMPLES

[0169]

[0163] The XRPD pattern of crystalline form Q of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine is shown in Figure 15. Characteristic peaks include one or more of the peaks shown in Table 16.

[0170] [Table 16] EXAMPLES

[0171] Amorphous material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine was prepared as follows: A sample of crystalline form N material of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (400 mg) was dissolved in methanol (20 mL) and heated using sonic irradiation, and the solution was filtered through a 0.2 μm PTFE filter. The filtrate was rotary evaporated under vacuum at 60° C. and 150 RPM for 15 minutes to remove the methanol solvent. A colorless film was observed. The flask was removed from the water bath and dried under vacuum at room temperature overnight. During this time the appearance of the film changed and consisted of an off-white solid. XRPD analysis showed the material to be amorphous, as shown in FIG. 16.

[0172] The amorphous form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 13.7% by weight between about 42° C. and about 208° C. (FIG. 17). Karl Fischer (KF) analysis showed 0.96% by weight water (about 0.2 equivalents on a molar basis).

[0173]

[0166] Figure 18 illustrates the differential scanning calorimetry (DSC) profile of the amorphous form. As shown in Figure 18, after drying the amorphous material under vacuum for a second night, the amorphous form exhibited a characteristic broad endotherm with an onset at about 57°C and a peak at about 86°C; a characteristic exotherm with an onset at about 140°C, a characteristic exotherm with an onset at about 177°C; and a characteristic endotherm with an onset at about 270°C and a peak at about 275°C.

[0174]

[0167] The amorphous form exhibited a dynamic water vapor sorption (DVS) profile showing a reversible total mass change of about 4.19 wt% between about 40 and about 80% relative humidity (RH) at 25°C, indicating that the amorphous form is hygroscopic. Analysis by XRPD after DVS cycling showed that the amorphous form converted to Pattern N material during the DVS analysis. EXAMPLES

[0175] Example 18a: Purification of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine - 30% activated charcoal 20 grams of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (polymorph N having a color of BY3) was dissolved in 600 ml of methanol. 6 grams of activated charcoal in dry form was added to the vessel and the contents were mixed. After about 45 minutes, the activated charcoal was filtered off. An additional amount of 6 grams of activated charcoal was added to the vessel and the contents were mixed. After about 45 minutes, the activated charcoal was filtered off. The solution was distilled to remove most of the methanol, leaving about 100 ml of methanol in the vessel, and then charged with 40 ml of water and 200 ml of iso-propyl alcohol (IPA). The contents of the vessel were stirred for about 2 hours and then filtered to obtain a wet solid. An additional 100 ml of water and the contents of the vessel were stirred for approximately 2 hours, after which the contents were filtered and the solid was collected and dried, which provided ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (polymorph N) in highly pure form.

[0176]

[0169] A highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine prepared according to the method as detailed above had a purity of 99.632% as measured by HPLC (1.0 RRT). Details of the HPLC results are presented in Table 17 below. LD-Tyr in the following table corresponds to ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine.

[0177] [Table 17]

[0178]

[0170] HPLC was obtained using mobile phase A which was 0.1% TFA in water and mobile phase B which was 0.1% TFA in MeOH:ACN (8:2) with an injection volume of 20.00 μL, a run time of 65.0 min, a dilution of 0.1% OPA in water, column: Atlantis T3 150*4.6 mm 3μ, a flow rate of 1.0 mL / min, and a sample concentration of 1.0 mg / mL.

[0179]

[0171] The color of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine in highly pure form, prepared according to the method as detailed above, was BY6. The yield was 65%.

[0180] Example 18b: Purification of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine - 15% activated charcoal, 20 gram sample 20 grams of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (polymorph N having a color of BY3) was dissolved in 600 ml of methanol. 3 grams of activated charcoal in dry form was added to the vessel and the contents were mixed. After about 45 minutes, the activated charcoal was filtered off. An additional amount of 3 grams of activated charcoal was added to the vessel and the contents were mixed. After about 45 minutes, the activated charcoal was filtered off. The solution was distilled to remove most of the methanol, leaving about 100 ml of methanol in the vessel, and then charged with 40 ml of water and 200 ml of iso-propyl alcohol (IPA). The contents of the vessel were stirred for about 2 hours and then filtered to obtain a wet solid. An additional 100 ml of water and the contents of the vessel were stirred for approximately 2 hours, after which the contents were filtered and the solid was collected and dried, which provided ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (polymorph N) in highly pure form.

[0181]

[0173] A highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine prepared according to the method detailed above had a purity of 99.517% as measured by HPLC (1.0 RRT). The details of the HPLC results are presented in Table 18 below.

[0182]

[0174] HPLC was obtained using mobile phase A which was 0.1% TFA in water and mobile phase B which was 0.1% TFA in MeOH:ACN (8:2) with an injection volume of 20.00 μL, a run time of 65.0 min, a dilution of 0.1% OPA in water, column: Atlantis T3 150*4.6 mm 3μ, a flow rate of 1.0 mL / min, and a sample concentration of 1.0 mg / mL.

[0183] [Table 18]

[0184] A highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, prepared according to the method detailed above, was colored BY6. The yield was 82.5%. Comparing this yield to the yield obtained in Example 18a, shows that the use of 15% activated carbon is preferred over 30% activated carbon.

[0185] Example 18c: Purification of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine - 15% activated charcoal, 100 gram sample 100 grams of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (polymorph N having a color of BY3) was dissolved in 600 ml of methanol. 15 grams of activated charcoal in dry form was added to the vessel and the contents were mixed. After about 45 minutes, the activated charcoal was filtered off. An additional amount of 15 grams of activated charcoal was added to the vessel and the contents were mixed. After about 45 minutes, the activated charcoal was filtered off. The solution was distilled to remove most of the methanol, leaving about 100 ml of methanol in the vessel, and then charged with 40 ml of water and 200 ml of iso-propyl alcohol (IPA). The contents of the vessel were stirred for about 2 hours and then filtered to obtain a wet solid. An additional 100 ml of water and the contents of the vessel were stirred for approximately 2 hours, after which the contents were filtered and the solids collected and dried, which provided ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (polymorph N) in highly pure form. This test was performed twice on two separate 100 gram samples.

[0186]

[0177] The highly pure forms of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine prepared according to the method detailed above had purity levels of 99.56% and 99.688% as measured by HPLC (1.0 RRT). Details of the HPLC results are presented in Tables 19-1, 19-2, 20-1 and 20-2 below.

[0187]

[0178] HPLC was obtained using mobile phase A which was 0.1% TFA in water and mobile phase B which was 0.1% TFA in MeOH:ACN (8:2) with an injection volume of 20.00 μL, a run time of 65.0 min, a dilution of 0.1% OPA in water, column: Atlantis T3 150*4.6 mm 3μ, a flow rate of 1.0 mL / min, and a sample concentration of 1.0 mg / mL.

[0188] [Table 19-1]

[0189] [Table 19-2]

[0190] [Table 20-1]

[0191] [Table 20-2]

[0192]

[0179] The color of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine in highly pure form prepared from both batches according to the method detailed above was BY6. The yields were 77% and 78%, respectively, for each batch. Comparison of these yields with those obtained in Examples 18a and 18b shows that (a) the use of 15% activated carbon is preferable to 30% activated carbon, and (b) the yields are more or less maintained even when the larger batches are purified. EXAMPLES

[0193] Example 19: Preparation of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine in highly pure form 10 grams of ZL-Dopa-Tyr-OBzl (the structure of which is shown below)

[0194] [ka]

[0195] was mixed in a vessel with 200 ml of methanol and 1 gram of palladium on carbon (Pd / C). The contents were stirred for about 1 hour, after which the contents were filtered, thereby removing the Pd / C. 2 grams of activated carbon was added to the vessel, and the contents were stirred for about 30 minutes, followed by filtration, thereby removing the activated carbon. 1 gram of palladium scavenger was added to the vessel, and the contents were stirred for about 1 hour, followed by filtration, thereby removing the palladium scavenger. An additional amount of 2 grams of activated carbon was added to the vessel, and the contents were stirred for about 30 minutes, followed by filtration, thereby removing the activated carbon. The remaining liquid in the vessel was distilled to remove most of the methanol, leaving about 50 ml of methanol in the vessel. The vessel was then charged with 20 ml of water and 100 ml of iso-propyl alcohol (IPA). The solution was stirred for about 2 hours, after which the solution was filtered and the solids were collected.

[0196] The resulting solid was dissolved in 50 ml of water, stirred for about 2 hours, filtered and dried, thereby obtaining highly pure polymorphic N form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine.

[0197]

[0182] A highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine prepared according to the method detailed above had a purity of 99.191% as measured by HPLC (1.0 RRT). The details of the HPLC results are presented in Table 21 below.

[0198] [Table 21-1]

[0199] [Table 21-2]

[0200]

[0183] HPLC was obtained using mobile phase A which was 0.1% TFA in water and mobile phase B which was 0.1% TFA in MeOH:ACN (8:2) with an injection volume of 20.00 μL, a run time of 65.0 min, a dilution of 0.1% OPA in water, column: Atlantis T3 150*4.6 mm 3μ, a flow rate of 1.0 mL / min, and a sample concentration of 1.0 mg / mL.

[0201]

[0184] A highly pure form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine, prepared according to the method as detailed above, had the color B6.

[0202] Incorporation by Reference

[0185] All publications and patents referred to in this specification, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In the case of conflict, the present application, including any definitions herein, will control.

[0203] Equivalent

[0186] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not limiting. Numerous variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the present disclosure should be determined by reference to the claims, along with their full scope of equivalents, and this specification, along with such variations.

[0204]

[0187] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless specifically indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form N), characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.1 degrees 2θ.

2. 2. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 12.6, 16.3 and 20.1 degrees 2-theta.

3. 3. The crystalline form of claim 1 or 2, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.7, 8.7, 12.6, 16.3, 20.1 and 25.7 degrees 2-theta.

4. 4. The crystalline form of any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.7, 8.7, 8.8, 12.6, 16.2, 16.3, 17.3, 20.1, 25.7, 29.8, 30.0 and 34.

2.

5. The crystalline form of any one of claims 1 to 4, wherein the powder X-ray diffraction pattern is obtained using Cu Kα radiation.

6. 6. The crystalline form of any one of claims 1 to 5, characterized in that its Differential Scanning Calorimetry (DSC) profile has a characteristic endotherm with an onset at about 135°C and a peak at about 159°C; a characteristic endotherm with an onset at about 174°C and a peak at about 176°C; a characteristic exotherm with an onset at about 177°C; and a peak at about 178°C; and a characteristic endotherm with an onset at about 272°C and a peak at about 278°C; and its Thermogravimetric Analysis (TGA) profile exhibits a mass loss of about 15% by weight between about 22°C and about 196°C.

7. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form A), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 4.7, 9.5, 18.3, 19.0 and 21.1, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

8. 9. The crystalline form of claim 8, characterized in that the thermogravimetric analysis (TGA) profile exhibits a mass loss of about 10.2 wt. % between about 40° C. and about 200° C.

9. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form B), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 14.5, 14.6, 14.8, 17.7, 20.3, 22.9, 23.2, 25.4, 27.3, 29.5, 30.2 and 31.3, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

10. 10. The crystalline form of claim 9, characterized in that its differential scanning calorimetry profile has a characteristic endotherm with an onset at about 96° C. and a peak at about 119° C.; a characteristic endotherm with an onset at about 161° C. and a peak at about 176° C.; and a characteristic endotherm with an onset at about 275° C. and a peak at about 280° C.; and its thermogravimetric analysis (TGA) profile exhibits a mass loss of about 15.6% by weight between about 40° C. and about 200° C.

11. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form C), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.7, 9.0, 13.3, 13.5, 15.2, 15.4, 19.7, 20.5, 22.1, 25.7, 27.9, and 28.1, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

12. 12. The crystalline form of claim 11, characterized in that its differential scanning calorimetry profile has a characteristic endotherm with an onset at about 145° C. and a peak at about 158° C.; a characteristic exotherm with an onset at about 175° C. and a peak at about 178° C.; and a characteristic endotherm with an onset at about 269° C. and a peak at about 275° C.; and its thermogravimetric analysis (TGA) profile exhibits a mass loss of about 1.75 wt % between about 30° C. and about 190° C.

13. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form D), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 11.7, 17.0, 17.8, 18.6, 18.9, 19.2, 20.9, 23.6, 26.1, 26.7, 27.3, and 28.5, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

14. 14. The crystalline form of claim 13, characterized in that its differential scanning calorimetry profile has a characteristic endotherm with an onset at about 79°C and a peak at about 97°C; a characteristic endotherm with an onset at about 147°C and a peak at about 152°C; a characteristic endotherm with an onset at about 175°C and a peak at about 176°C; a characteristic exotherm with an onset at about 178°C; and a peak at about 179°C; a characteristic exotherm with an onset at about 183°C and a peak at about 191°C; and a characteristic endotherm with an onset at about 263°C and a peak at about 270°C; and its thermogravimetric analysis (TGA) profile exhibits a mass loss of about 38% by weight between about 30°C and about 211°C.

15. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form E), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 10.8, 12.5, 14.8, 15.2, 17.9, 20.3, 20.9, 23.3, 23.5, 24.4, 25.8, and 26.3, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

16. 16. The crystalline form of claim 15, characterized in that its thermogravimetric analysis (TGA) profile exhibits a mass loss of about 11.5% by weight between about 40°C and about 200°C.

17. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form G), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.6, 8.8, 13.5, 15.3, 15.5, 19.4, 21.0, 21.8, 22.3, 25.4, 27.8, and 29.9, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

18. 18. The crystalline form of claim 17, characterized in that its differential scanning calorimetry profile has a characteristic endotherm with an onset at about 126°C and a peak at about 130°C; a characteristic endotherm with an onset at about 159°C and a peak at about 169°C; a characteristic exotherm with an onset at about 171°C and a peak at about 176°C; and a characteristic endotherm with an onset at about 264°C and a peak at about 271°C.

19. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form H), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 8.0, 8.7, 11.4, 12.3, 14.2, 14.6, 15.5, 16.1, 18.7, 21.1, 21.4, and 22.9, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

20. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form I), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.4, 7.5, 8.7, 8.8, 13.9, 14.2, 15.5, 21.1, 21.6, 21.9, 22.7, and 26.2, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

21. 21. The crystalline form of claim 20, characterized in that the thermogravimetric analysis (TGA) profile exhibits a mass loss of about 11% by weight between about 30°C and about 212°C.

22. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form J), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 4.4, 7.5, 8.8, 13.9, 15.5, 18.9, 21.4, 21.6, 21.8, 22.7, 26.2, and 29.5, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

23. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form K), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.5, 8.5, 11.0, 13.4, 15.4, 18.8, 20.8, 21.0, 22.1, 25.1, 25.8, and 27.7, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

24. 24. The crystalline form of claim 23, characterized in that the thermogravimetric analysis (TGA) profile exhibits a mass loss of about 17% by weight between about 22°C and about 203°C.

25. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form L), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.6, 8.0, 8.7, 11.1, 13.4, 15.5, 19.2, 20.9, 21.5, 22.2, 25.3, and 27.8, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

26. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form M), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.6, 8.7, 8.8, 11.1, 13.5, 15.5, 20.9, 21.5, 21.8, 22.3, 25.3, and 27.8, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

27. 27. The crystalline form of claim 26, characterized in that the thermogravimetric analysis (TGA) profile exhibits a mass loss of about 17% by weight between about 22°C and about 199°C.

28. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form O), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.5, 8.7, 11.1, 13.6, 15.4, 15.5, 18.9, 21.0, 21.4, 21.6, 22.3, and 25.5, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

29. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form P), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 7.4, 8.7, 11.4, 14.0, 15.5, 18.7, 20.2, 21.4, 21.5, 22.8, 26.2, and 28.2, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

30. 1. A crystalline form of ((S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl)-L-tyrosine (Form Q), characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees 2-theta of about 8.7, 13.5, 15.4, 19.2, 20.9, 21.6, 22.2, 25.4, 27.8, and 29.7, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

31. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 30 and a pharma- ceutically acceptable excipient.

32. A pharmaceutical composition comprising the crystalline form N according to any one of claims 1 to 6 and a pharma- ceutically acceptable excipient.

33. A pharmaceutical composition formed from the crystalline form of any one of claims 1 to 30.

34. A pharmaceutical composition formed from crystalline form N of any one of claims 1 to 6.

35. 31. A drug substance comprising at least a detectable amount of the crystalline form of any one of claims 1 to 30.

36. 31. A drug substance comprising the substantially pure crystalline form of any one of claims 1 to 30.

37. A drug substance comprising the substantially pure crystalline form N of any one of claims 1 to 6.

38. 31. The crystalline form of any one of claims 1 to 30, having a purity greater than about 99%.

39. 31. The crystalline form of any one of claims 1 to 30, having a purity greater than about 99.5%.

40. 31. The crystalline form of any one of claims 1 to 30, having a purity greater than about 99.6%.

41. 31. The crystalline form of any one of claims 1 to 30, having a purity greater than about 99.9%.

42. 39. The crystalline form of claim 38, characterized in that the HPLC chromatogram has a peak at about 22.65 RT.

43. 39. The crystalline form of claim 38, characterized in that the HPLC chromatogram has peaks at about 16.86, 18.45, 21.79, 22.65, 23.90, 25.99, 26.62, 30.39, 30.83, 31.90, 32.20, 32.76, 33.43, 34.95, 37.01 and 39.92 RT.

44. 40. The crystalline form of claim 39, characterized in that the HPLC chromatogram has a peak at about 22.56 RT.

45. 40. The crystalline form of claim 39, characterized in that the HPLC chromatogram has peaks at about 5.81, 20.81, 21.71, 22.56, 33.38 and 36.88 RT.

46. 40. The crystalline form of claim 39, characterized in that the HPLC chromatogram has a peak at about 22.56 RT.

47. 40. The crystalline form of claim 39, characterized in that the HPLC chromatogram has peaks at about 5.80, 20.82, 21.72, 22.56, 33.39 and 36.89 RT.

48. 41. The crystalline form of claim 40, characterized in that the HPLC chromatogram has a peak at about 22.55 RT.

49. 41. The crystalline form of claim 40, characterized in that the HPLC chromatogram has peaks at about 5.80, 20.81, 21.70, 22.55, 33.37 and 36.87 RT.

50. 41. The crystalline form of claim 40, characterized in that the HPLC chromatogram has a peak at about 22.54 RT.

51. 41. The crystalline form of claim 40, characterized in that the HPLC chromatogram has peaks at about 5.80, 20.80, 21.70, 22.54, 33.38 and 36.88 RT.

52. 52. The crystalline form of any one of claims 38 to 51, which is crystalline form N.

53. 10. The crystalline form of any one of the preceding claims, wherein upon dissolution in TRIS buffer, the colour of the crystalline form is defined as Y5, Y6, Y7, B5, B6, B7, BY5, BY6 or BY7 according to colour reference solutions Y1-Y7, which are related to Ph. Eur. Y1-Y7 Certipur®, BY1-BY7, which are related to Ph. Eur. BY1-BY7 Certipur®, and B1-B7, which are related to Ph. Eur. B1-B7 Certipur®.

54. 52. The crystalline form of any one of claims 38 to 51, purified from an already prepared batch of crystalline form N.

55. The refining process is 【Chemistry 1】 The crystalline form according to any one of claims 38 to 51, which is carried out during the preparation of crystalline form N from

56. 13. A method for purifying the crystalline form of any one of the preceding claims, comprising the use of activated carbon.

57. 57. The method of claim 56, wherein the activated carbon is selected from Newcarb, Pencarb, Alcandracarb, Eno PC Carb, HW Carb, Tri Carb, C-CA activated carbon, C-HA activated carbon, C-VA activated carbon, C-VW activated carbon, Norite carbon, Pentacarb, or any combination thereof.

58. 58. The method of claim 56 or 57, wherein at least two portions of activated carbon are used in the method.

59. 59. The method of any one of claims 56 to 58, wherein the amount of activated carbon is between about 10% w / w and about 50% w / w compared to the weight of the crystalline form being purified.

60. 60. The method of claim 59, wherein the amount of activated carbon is about 15% w / w compared to the weight of the crystalline form being purified.

61. 61. The method of any one of claims 56 to 60, further comprising the use of an acidic agent.

62. 62. The method of claim 61, wherein the acidic agent is selected from HF, HBr, trifluoroacetic acid and thioanisole, and BBr3, BCl3 or BF3 ether complexes or combinations thereof.

63. 63. The method of claim 62, wherein the HBr is present in acetic acid.

64. 64. The method of any one of claims 56 to 63, wherein the crystalline form is purified in alcohol.

65. 65. The method of claim 64, wherein the alcohol is methanol, ethanol, propanol, iso-propanol, butanol, iso-butanol or any other suitable alcohol.

66. 66. The method of claim 64 or 65, wherein the alcohol is methanol.

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