(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2019/038639 Al 28 February 2019 (28.02.2019) W P O PCT

(51) International Patent Classification: C07C 237/20 (2006.01) A61P 25/16 (2006.01) (21) International Application Number: PCT/TB2018/056127 (22) International Filing Date: 15 August 2018 (15.08.2018) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/548,1 11 2 1 August 2017 (21.08.2017) US (71) Applicant: NEURODERM LTD [IL/IL]; c/o David Bon- fil, 3 Pekeris Street, 7670212 Rehovot (IL). (72) Inventor: YACOBY-ZEEVI, Oron; 204 Hanarkissim Street, 6094600 Moshav Bitsaron (IL).

(74) Agent: SHIMONI, Gila et al.; P.O.Box 2453, 7612401 Re¬ hovot (IL). (81) Designated States (unless otherwise indicated, for every = kind of national protection available) : AE, AG, AL, AM, = AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, ≡ CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, = DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, = HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, ≡ KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, ≡ MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, Ξ OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, = SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, = TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every — kind of regional protection available) : AR PO (BW, GH, = GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, = UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, = TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, = EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, ~ MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, = TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG).

Ξ Published: — with international search report (Art. 21(3)) — in black and white; the international application as filed — contained color or greyscale and is available for download from PATENTSCOPE

(54) Title: CRYSTALLINE LEVODOPA AMIDE FREE BASE AND METHODS OF MAKING AND USING SAME © (57) Abstract: A crystalline levodopa amide free base and a process of making it are provided. Particularly, a substantially pure crystalline levodopa amide free base is disclosed, suitable for the preparation of pharmaceutical compositions for treatment of diseases or disorders characterized by neurodegeneration and/or reduced levels of brain dopamine such as Parkinson's disease. CRYSTALLINE LEVODOPA AMIDE FREE BASE AND METHODS OF MAKING AND USING SAME FIELD OF THE INVENTION

[0001] The present invention relates, in part, to levodopa amide free base, particularly but not exclusively, pharmaceutically acceptable crystalline levodopa amide free base.

BACKGROUND [0002] Parkinson's disease is a degenerative condition characterized by reduced concentration of the neurotransmitter dopamine in the brain. Levodopa (L-dopa or LD), L- 3,4-dihydroxyphenylalanine, is an immediate metabolic precursor of dopamine that, unlike dopamine, is able to cross the blood brain barrier, and is most commonly used for restoring the dopamine concentration in the brain. For the past 40 years, levodopa has remained the most effective therapy for the treatment of Parkinson's disease.

[0003] However, conventional treatments for Parkinson's disease with LD have proven to be inadequate for many reasons of record in the medical literature. For example, systemic administration of levodopa, although producing clinically beneficial effects at first, is complicated by the need to increase the dosages over time, which may result in adverse side effects. The peripheral administration of LD is further complicated by the fact that levodopa has a short half-life in plasma that, even under best common current standard of care, results in pulsatile dopaminergic stimulation. Only about 1-3% of the levodopa administered actually enters the brain unaltered, the remainder being metabolized extracerebrally to dopamine, predominantly by decarboxylation. Long-term therapy is therefore complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for some patients.

[0004] The metabolic transformation of L-dopa to dopamine is catalyzed by the aromatic L- amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain, and brain capillaries. Due to the possibility of extracerebral metabolism of L-dopa, it is necessary to administer large doses of L-dopa leading to high extracerebral concentrations of dopamine that cause nausea in some patients. Therefore, L-dopa is usually administered concurrently with oral administration of a L-dopa decarboxylase inhibitor, such as carbidopa or benserazide, which reduces by 60-80% the L-dopa dose required for a clinical response and, respectively, some of the side effects related, e.g., to conversion of levodopa to dopamine outside the brain, although not sufficiently.

[0005] It is well accepted in the art that many of the problems recited above result from the unfavorable pharmacokinetic properties of LD and, more particularly, from its poor water solubility, bioavailability and fast degradation in vivo. Thus, there is still an urgent need for effective therapeutic formulations for treating neurological disorders such as Parkinson's disease.

[0006] Levodopa derivatives, for example levodopa amide derivatives and ester derivatives are known in the art as prodrugs of levodopa. Derivatization of LD, e.g., amidation or esterification is used as a means to improve water solubility and/or stability of the drug. For example, mixtures of various impure levodopa amide and derivatives thereof, and use thereof in formulations for treatment, e.g., of Parkinson's diseases, are disclosed, for example, in US 8,048,926 and WO 2017/090039.

[0007] Substantially pure crystalline forms of levodopa amide free base, 2-amino-3-(3,4- dihydroxyphenyl) propenamide, do not appear to have been achieved. Crystallization, or polymorphism (i.e., the ability of a substance to crystallize in more than one crystal lattice arrangement), can influence many aspects of solid state properties of a drug substance. A crystalline substance may differ considerably from an amorphous form, and different crystal modifications of a substance may differ considerably from one another in many respects including solubility, dissolution rate and/or bioavailability. Therefore, it can be advantageous to have a crystalline form of a therapeutic agent for certain formulations, e.g., formulations suitable for subcutaneous use.

SUMMARY

[0008] In one aspect, the present disclosure provides a crystalline free base of levodopa amide (L-dopamide), i.e. a compound represented by: [0009] In an embodiment, provided herein is a crystalline form of L-dopamide free base, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θat about 19.7 and about 21.0. Such crystalline form may further have characteristic peaks in degrees 2Θat about 18.1, and about 28.9.

[0010] For example, provided herein is a crystalline form of L-dopamide free base, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 164°C, and a peak at about 172.4°C. Such a crystalline form may have less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than 1%, between about 0.01% and 10%, or between about 0.01% and 1%, in content, of a crystalline hydrochloric acid salt of L-dopamide, and/or less than about 1%, or less than about 0.5% levodopa and/or levodopa salt. For example, provided herein is a crystalline L- dopamide wherein the crystalline form has less than about 0.3% levodopa and/or levodopa salt. Such impurities may be analyzed by, e.g., HPLC.

[0011] In some embodiments, the purity of the crystalline free base form is above 99% as determined by HPLC.

[0012] Also provided herein is a L-dopamide pharmaceutically acceptable salt formed from a process comprising reacting the disclosed free base crystalline form with an acid; thereby forming an acid salt of L-dopamide. The acids, which may form acid addition salts with LDA free base include, for example, hydrochloric acid, fumaric acid, lactic acid, phosphoric acid, sulfuric acid, and glucoheptanoic acid.

[0013] Contemplated herein is a pharmaceutical composition comprising the disclosed crystalline free base or salts formed therefrom, and a pharmaceutically acceptable excipient.

[0014] A drug substance is also contemplated herein, comprising e.g., at least a detectable amount of the crystalline LDA free base of the disclosure, and/or comprising substantially pure crystalline form of the L-levodopa amide of the disclosure. [0015] Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

BRIEF DESCRIPTION OF THE FIGURES

[0016] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0017] In the drawings: Fig. 1 depicts the XRPD peaks pattern of crystalline L-dopamide freebase, obtained using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software; Fig. 2 is the ^-NMR plot in intensity vs. ppm for crystalline L-dopamide freebase; Fig. 3 is a TG/DTA thermogram of crystalline L-dopamide free base analyzed in a temperature range from 25 °C to 300 °C at 10 °C per minute; and Fig. 4 is a DSC thermogram of crystalline L-dopamide free base analyzed in a temperature range from 30 °C to 300 °C at 10 °C per minute.

DETAILED DESCRIPTION

[0018] The present disclosure is directed, in part, to the discovery of a substantially pure crystalline form of L-dopamide free base. Such a form can be useful in making therapeutically acceptable salt forms of L-dopamide. [0019] For example, provided here is a pharmaceutically acceptable crystalline of the compound 2-amino-3-(3,4-dihydroxyphenyl) propanamide, represented by:

[0020] Herein the compound 2-amino-3-(3,4-dihydroxyphenyl) propanamide is interchangeably referred to as "levodopa amide", "L-dopamide", "L-dopamide free base", "LDA free base", or simply "LDA FB".

[0021] The term "crystalline" as used herein refers to a solid material relating to, resembling or composed of crystals. The term "crystal" as used herein refers to a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered, periodic microscopic structure, forming a crystal lattice that extends in all directions. The three- dimensional structure of crystals is defined by regular, repeating planes of atoms that form a crystal lattice, as opposed to an amorphous solid. A crystal structure may also be characterized by its unit cell, a basic repeating unit that defines the crystal structure, and contains the maximum symmetry that uniquely defines the crystal structure.

[0022] Crystallization is the process of forming a crystalline structure from a fluid or from materials dissolved in a fluid. The same group of atoms can often crystallize in many different ways. Polymorphism is the ability of a solid to exist in more than one crystal form. Depending on the conditions, a single fluid can solidify into many different possible forms termed "polymorphs" or "phases". It can form a single crystal, perhaps with various possible phases, stoichiometries, impurities, defects, and habits. Or, it can form a polycrystal, with various possibilities for the size, arrangement, orientation, and phase of its grains. The final form of the solid is determined by the conditions under which the fluid is being solidified, such as the chemistry of the fluid, the ambient pressure, the temperature, and the speed with which all these parameters are changing.

[0023] A crystalline substance may differ considerably from an amorphous form, and different crystal modifications of a substance, e.g. different polymorphs, may differ considerably from one another in many respects including solubility, dissolution rate and/or bioavailability. Different crystalline forms or different crystallinity may further arise due to refinement of milling of an already formed crystals. Generally, it is difficult to predict whether or not a given compound will form various crystalline forms. It is even more difficult to predict the physical properties of these crystalline forms. Clear identification of different crystalline forms or different crystallinity is critical when developing pharmaceuticals because crystal polymorph and crystallinity influence medicinal effects and formulation stability.

[0024] A crystalline substance may be detected and characterized, for example, by its X-ray diffraction pattern. When a focused X-ray beam interacts with a plane of atoms in a crystal, part of the beam is refracted and scattered and part is diffracted. The part of the X-ray that is not scattered passes through to the next layer (plane) of atoms, where again part of the X- ray is scattered and part passes through to the next layer. This causes an overall diffraction pattern, similar to how a grating diffracts a beam of light. In order for an X-ray to diffract, the sample must be crystalline and the spacing between atom layers must be close to the radiation wavelength. X-rays are diffracted by each crystal differently, depending on what atoms make up the crystal lattice and how these atoms are arranged.

[0025] A powder X-ray diffractometer consists of an X-ray source, usually an X-ray tube, a sample stage, a detector and a way to vary angle Θ. The X-ray is focused on the sample at some angle Θ, while the detector opposite the source reads the intensity of the X-ray it receives at angle 2Θaway from the source path. The incident angle is than increased over time while the detector angle always remains 2Θabove the source path. The diffraction peak position is recorded as the detector angle, 2Θ. For typical powder patterns, data is collected at degree 2Θranging from about 5° to about 70°, and these varying angles are preset in the X-ray diffraction scan.

[0026] An X-ray tube usually contains a metal target (e.g., Cu, Fe, Mo, Cr) which is bombarded by accelerated electrons that knock core electrons out of the metal. Electrons in the outer orbitals or higher levels of the metal drop down to fill the vacancies in the lower levels, emitting X-ray photons. For example, knocked K shell (n = 1) in a metal target, may be filled by electrons in higher L (n = 2) shell, giving rise to K emitted X-ray radiation, and/or K shell may be filled by electrons from M (n = 3) shell, thus producing Κ β X-ray radiation. A characteristic radiation is thus obtained, composed of discrete peaks. The energy (and wavelength) of the peaks depends solely on the metal used for the target. These X-rays are collimated and directed onto the sample, which is ground to a fine powder (typically to produce particle sizes of less than 10 microns). The diffracted X-ray signal is detected by the detector, processed and converted to a count rate. Changing the angle between the X-ray source, the sample, and the detector at a controlled rate between preset Θlimits generates an X-ray scan.

[0027] The diffraction peak pattern is a product of the unique crystal structure of a material. The position and intensity of peaks in a diffraction pattern are determined by the crystal structure and serve as the crystal's "fingerprints". The purity of a sample can be determined from its diffraction pattern, as well as the composition of any impurities present.

[0028] Described crystalline forms have X-ray powder diffraction (XRPD) pattern that may be obtained using Cu K radiation. Copper is the common target material for powder X-ray diffraction, with Cu K radiation = 1.5418A. The term "about" in this context of XRPD means that there is an uncertainty in the measurements of the 2Θof ± 0.5 (expressed in 2Θ) or that there is an uncertainty in the measurements of the 2Θof ±0.2 (expressed in 2Θ).

[0029] The crystalline form of L-dopamide free base is provided herein. The X-ray diffraction pattern of crystalline LDA free base was measured on X-ray diffractometer Panalytical Xpert Pro equipped with a Cu X-ray tube emitting K radiation, and a Pixcel detector system, under the conditions specified in the Material and Methods section herein.

[0030] The crystalline form of LDA FB provided herein is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 19.7 and about 21.0 and may have additional peaks in degrees 2Θ at for example, about 18.1, and about 28.9. Such a crystalline form may have a powder X-ray diffraction pattern substantially the same as depicted in Figure 1. The X-ray diffraction peak pattern presented in Figure 1 is termed herein "LDA FB Pattern A" or "Pattern A".

[0031] Crystal polymorphism and crystallinity are influenced by temperature change, thus thermal analysis techniques are indispensable in understanding the thermophysical properties of crystalline pharmaceuticals. Calorimetry is a technique for determining the quantity of heat that is either absorbed or released by a substance undergoing a physical or a chemical change, which alters the internal energy of the substance known as enthalpy, H. The enthalpy of a crystalline substance decreases or lowered in an exothermic process such as crystallization decomposition, whereas endothermic processes such as evaporation, dehydration and melting increase the enthalpy. Thermal analysis techniques are classified according to the property under study. For example, temperature changes of a process may be assessed by heating/cooling curves analysis; temperature differences of a process or reaction may be assessed by differential thermal analysis (DTA); the heat of a process may be assessed by calorimetry or differential scanning calorimetry (DSC); and mass changes may be assessed by thermogravimetry (TG) or thermogravimetric analysis (TGA).

[0032] Differential scanning calorimetry (DSC) is a thermal analysis technique that provides quantitative and qualitative data on endothermic (heat absorption) and exothermic (heat evolution) processes of a sample of known mass as it is heated or cooled. According to this technique, the difference in the amount of heat required to increase the temperature of a sample and a reference are measured as a function of temperature, while both the sample and reference are maintained at nearly the same temperature throughout the experiment. The basic principle underlying this technique is that when the sample undergoes a physical transformation such as phase transitions, more or less heat will need to flow to it than to the reference to maintain both at the same temperature. Whether less or more heat must flow to the sample depends on whether the process is exothermic or endothermic. By observing the difference in heat flow between the sample and reference, differential scanning calorimeters are able to measure the amount of heat absorbed or released during such transitions. The changes in heat flow (or heat flux) allow the detection of transitions such as melts, phase changes, evaporation, dehydration and crystallization. In crystals, phase changes or polymorphs can be observed as well as the degree of purity.

[0033] The result of a DSC experiment is a curve of heat flux versus temperature or versus time, herein referred to as a "DSC thermogram". This curve can be used to calculate the enthalpy of a transition, ∆Η, by integrating the peak corresponding to a given transition. Often, a DSC thermogram of a contemplated crystalline may serve as an identifier or fingerprint of the crystalline. [0034] In an embodiment, the provided crystalline form of L-dopamide free base form has a DSC thermogram with an endotherm having an onset at about 164 °C, and a peak at about 172.4 °C, as shown in Figure 4.

[0035] A "substantially pure crystalline", as referred to herein, is a crystalline comprising, besides molecules of the principle material or active pharmaceutical ingredient (API), further trace amounts of molecules or atoms of various origins or types collectively termed herein "impurities". Such impurities include, for example, residual solvent molecules, degradation products, residual amounts of crystallization reagents, starting materials, optical isomers, salt forms of the API, metal atoms, and polymorphs. Voids in the crystalline arrangement are also referred to herein as impurities. Impurities can be incorporated into crystals in a number of ways. For example, surface impurities are left when residual mother liquor on the surface of the crystals evaporates, leaving behind any dissolved impurities. Inclusions of mother liquor may be formed in crystals, especially at high growth rates. Occlusions are voids formed between individual crystals, usually in agglomerates.

[0036] A "trace amount", as referred to herein, is a very small, a tiny or even scarcely detectable amount. Impurities, including trace amounts of purities, are usually detected using means known in the art, such as, but not limited to, chromatography techniques such as high- pressure liquid chromatography (HPLC) or gas chromatography (GC). Purity of a product may be further assessed using means such as nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, mass spectroscopy (MS) and the like.

[0037] In some embodiments, purity of a disclosed LDA free base was determined using the HPLC system Agilent 1200 Series, under the conditions specified in the Materials and Methods section herein. A contemplated substantially pure crystalline will typically contain trace amounts of impurities as defined herein in a total amount which is less than 5.0% of total composition of the crystalline. For example, the amount of impurities may be less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.3%, less than 2.0%, less than 1.8%, less than 1.5%, less than 1.2%, less than 1.0%, less than 0.8%, less than 0.5%, less than 0.3%, less than 0.2%, less than 0.15%, less than 0.1%, less than 0.05%. [0038] For example, a contemplated substantially pure crystalline LDA FB may comprise between 0% to about 0.03%, between 0.00% to about 0.01%, between about 0.01% to about 5.0%, between about 0.01% to about 1.0%, between about 0.05% to about 1.0%, between about 0.1% to about 1.0%, between about 0.03% to about 0.08%, between about 1.2% to about 2.0%, between about 2.0% to about 5.0%, or between about 3.5% to about 5.0%, of impurities. In some embodiments, a substantially pure crystalline is essentially devoid or free of any impurities.

[0039] In some embodiments, a disclosed substantially pure crystalline LDA free base may have some levodopa and/or levodopa salt impurities. For example, such a crystalline may have less than about 1.0%, less than about 0.5%, less than about 0.03% or less than about 0.01% levodopa and/or levodopa salt, wherein such levels can be characterized by HPLC.

[0040] In some exemplary embodiments, a substantially pure crystalline LDA free base has about 0.3% levodopa and/or levodopa salt as measured by, e.g., HPLC.

[0041] A contemplated crystalline L-dopamide FB may be reacted with an acid or a base to form a pharmaceutically acceptable salt. L-dopamine pharmaceutically acceptable salts are also provided herein. An acid or base that forms a salt with LDA free base is termed herein "salt former". The salt former may be, for example, HC1, acetic acid, ascorbic acid, L- aspartic acid, benzenesulfonic acid, benzoic acid, citric acid, fumaric acid, galactaric acid, gluceptic (glucoheptanoic), acid D-gluconic acid, D-glucuronic acid, L-glutamic acid, glutaric (pentanedioic) acid, glycolic (hydroxyacetic) acid, isethionic (2-hydroxy- ethanesulfonic) acid, L-lactic acid, lactobionic acid, L-maleic (but-2-enedioic) acid, L-malic acid, methanesulfonic acid, phosphoric acid (H3PO4), propionic (propanoic) acid, succinic (butanedioic) acid, sulfuric acid (H2SO4), L-tartaric acid and xinafoic (l-hydroxy-2- naphthoic) acid. The salt former may also be a base such as, but not limited to, L-arginine and L-histidine. Solvates (e.g., hydrates) and non-solvates (e.g., anhydrates) crystalline forms of LDA free base or a salt thereof are also contemplated herein.

[0042] The term "pharmaceutically acceptable salt", as used herein, refers to any salt of an acidic or a basic group as described herein, which do not produce an adverse, allergic or other untoward reaction and is compatible with pharmaceutical administration. A LDA salt may be, for example, a substantially pure salt containing trace amounts (e.g., 0 to about 3%) of LDA FB.

[0043] In some embodiments, a disclosed crystalline LDA free base has less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than 1%, between about 0.01% and 10%, or between about 0.01% and 1%, in content, of crystalline salt of LDA, such as, but not limited to, crystalline LDA HC1 salt, crystalline LDA sulfate salt, crystalline LDA phosphate salt, crystalline LDA lactate salt, crystalline LDA maleate salt, crystalline LDA fumarate salt, and crystalline LDA gluceptic acid salt.

Drug substances

[0044] In a further aspect, the disclosure provides a drug substance comprising at least a detectable amount (e.g., an amount detectable within the limits of detection of a technique known to those of skill in the art, e.g., HPLC), of a contemplated L-dopamide free base of the disclosure, for example, in its crystalline form.

[0045] The term "drug substance", as referred to herein, is any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product, and that, when used in the production of a drug, becomes an active ingredient of the drug product, (namely, the API). Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body. The drug substance, depending on its purity, is mostly composed of the API or the 'naked' drug without excipients.

[0046] In some embodiments, a drug substance comprises substantially pure crystalline form of LDA FB of the disclosure, for example crystalline having X-ray powder diffraction peak pattern A substantially as shown in Figure 1.

Pharmaceutical composition and Formulations

[0047] In still a further aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable LDA free base as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the composition is a formulation for pharmaceutical administration and comprises a pharmaceutically acceptable carrier.

[0048] The term "pharmaceutical composition", as used herein, refers to a formulation designed for medicinal utilization such as, but not limited to, therapeutic or diagnostic utilization. "Formulation" as used herein refers to any mixture of different components or ingredients prepared in a certain way, i.e., according to a particular formula. For example, a formulation may include one or more drug substances or active ingredients (APIs) combined or formulated together with, for example, one or more carriers, excipients, stabilizers and the like. The formulation may comprise solid and/or non-solid, e.g., liquid, gel, semi-solid (e.g. gel, wax) or gas components. Usually, in a formulation for pharmaceutical administration the APIs are combined or formulated together with one or more pharmaceutically and physiologically acceptable carriers, which can be administered to a subject (e.g., human or non-human subject) in a specific form, such as, but not limited to, tablets, linctus, ointment, infusion or injection. A pharmaceutical composition is sometimes also referred to herein as "medicinal formulation".

[0049] Some embodiments described herein pertain to liquid pharmaceutical compositions, for example aqueous formulations.

[0050] In some embodiments, a contemplated pharmaceutical composition, e.g., formulation, is a suspension.

[0051] The terms "active agent", "active ingredient" and "active pharmaceutical ingredient (API)" as used herein are interchangeable, all of which refer to a compound, which is accountable for a desired biological or chemical effect. In the context of embodiments described in the present disclosure, the active agent may be substantially pure crystalline form of LDA FB of the disclosure, for example, crystalline having X-ray powder diffraction peak pattern A substantially as shown in Figure 1.

[0052] As used herein, the terms "pharmaceutically acceptable", "pharmacologically acceptable" and "physiologically acceptable" are interchangeable and mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. These terms include formulations, molecular entities, and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by, e.g., the U.S. Food and Drug Administration (FDA) agency, and the European Medicines Agency (EMA).

[0053] Contemplated pharmaceutical compositions may include from 1% to about 25%, or more of a disclosed LDA FB. For example, a disclosed formulation may comprise, pure or substantially pure crystalline pharmaceutically acceptable LDA FB in amounts ranging from about 5% to about 20%, from about 1% to about 5%, from about 3% to about 8%, from about 5% to about 10%, from about 5% to about 15%, from about 8% to about 15%, from about 5% to about 20%, from about 10% to about 15%, from about 10% to about 20%, from about 12% to about 18%, from about 15% to about 20%, from about 5% to about 25%, from about 17% to about 23%, or from about 20% to about 25%, and any ranges, subranges and individual values therebetween.

[0054] In some embodiments, a contemplated formulation comprises from about 5% to about 20%, from about 10% to about 25%, about 5%, about 10%, about 15% or about 25% by weight of a disclosed substantially pure crystalline form of LDA FB of the disclosure, for example, crystalline having X-ray powder diffraction peak pattern A substantially as shown in Figure 1.

[0055] A contemplated pharmaceutical composition may, optionally, further comprise one or more physiologically acceptable excipients and/or a physiologically acceptable carrier.

[0056] Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition (formulation) to further facilitate process and administration of the active ingredients. "Pharmaceutically acceptable excipients", as used herein, encompass preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. Pharmaceutically acceptable excipients, as used herein, also encompass pharmaceutically acceptable carriers, namely, approved carriers or diluents that do not cause significant irritation to an organism and do not abrogate the biological activity and properties of a possible active agent. Physiologically suitable carriers in liquid medicinal formulations may be, for example, solvents or dispersion media. The use of such media and agents in combination with pharmaceutically active agents is well known in the art.

[0057] Excipients suitable for formulations described herein may comprise, for example, an enhancer (e.g., pyrrolidones, polyols, terpenes and the like) and/or a gelation agent (e.g., cellulose polymers, carbomer polymers and derivatives thereof), and/or a thickening agent (e.g., polysaccharides (agarose), polyacrylic polymers).

[0058] Contemplated formulations described herein are useful in the treatment of diseases or disorders characterized by neurodegeneration and/or reduced levels of brain dopamine, for example, Parkinson's disease.

[0059] In some embodiments, a disclosed pharmaceutical composition may further comprise one or more active agents, herein termed "secondary active agents" which may be added to the formulation so as to support, enhance, intensify, promote or strengthen the biological activity of the main or prime active agent(s). Additionally or alternatively, the secondary active compounds may provide supplemental or additional therapeutic functions. Non- limiting examples of a secondary active agent that may be useful in treating diseases or disorders characterized by neurodegeneration and/or reduced levels of brain dopamine include a decarboxylase inhibitor such as carbidopa, a carbidopa prodrug and/or a pharmaceutically acceptable salt thereof, e.g., the arginine-, histidine-, or lysine-salt of carbidopa; benserazide, a prodrug thereof or a pharmaceutically acceptable salt thereof; a catechol-O-methyl transferase (COMT) inhibitor; or a monoamine oxidase (MAO) (either MAO-A or MAO-B) inhibitor. Particular COMT inhibitors include, without limiting, entacapone, tolcapone and opicapone; and particular MAO inhibitors can be selected from, e.g., moclobemide, rasagiline, selegiline, or safinamide. Further secondary active agents may be exemplified by adamantans (e.g., amantadine), nicotinic receptor agonists (e.g., nicotine, galantamine), dopamine receptor agonists (e.g., apomorphine, rotigotine).

[0060] When a contemplated medicinal formulation comprises a crystalline pharmaceutically acceptable LDA free base of the disclosure and, e.g., a decarboxylase inhibitor (for example, carbidopa or a prodrug thereof), these main and secondary active ingredients, respectively, can be combined and formulated in the same formulation, namely, as a single unit dosage from or, alternatively, can be formulated in separate formulations, namely a plurality of dosage unit forms, for example, two or more dosage unit forms, each comprising one or more of a first active agent, and/or a second active agent.

[0061] A disclosed pharmaceutical composition may often comprise one or more antioxidants, namely, substances which slow down the damage that can be caused to other substances by the effects of oxygen (i.e., oxidation). Non-limiting examples of antioxidants include ascorbic acid (vitamin C) or a salt thereof (e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate); cysteine or a cysteine derivative such as L-cysteine, N-acetyl cysteine (NAC), glutathione, a thiol precursor such as L-2-oxo-4-thiazolidine carboxylic acid (OTC), or a salt thereof; lipoic acid; uric acid; carotenes; a-tocopherol (vitamin E); and ubiquinol (coenzyme Q).

[0062] Further antioxidants are exemplified by phenolic antioxidants such as di-teri-butyl methyl phenols, teri-butyl-methoxyphenols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tert- butylhydroquinone (TBHQ)), propyl gallate, flavonoid compounds, cinnamic acid derivatives, coumarins, and sulfite salts such as sodium hydrogen sulfite or sodium bisulfite (e.g. sodium metabisulfite).

[0063] For example, a disclosed formulation can include one, two, or more antioxidants selected from ascorbic acid or a salt thereof, for example, sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate, particularly sodium ascorbate, and cysteine or a cysteine derivative, for example, L-cysteine, NAC, glutathione, or a salt thereof.

[0064] The amount of one or more antioxidants in a contemplated formulation may be in the range of from about 0.01% to about 1% by weight. For example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1.0%, by weight antioxidant. [0065] Contemplated formulations may include at least one of a basic amino acid or an amino sugar. The basic amino acid and/or the amino sugar may be added to a disclosed formulation so as to help is solubilizing the decarboxylase inhibitor. The basic amino acid may be, for example, arginine, histidine, or lysine. The amino sugar may be, for example, meglumine, D-glucosamine, sialic acid, N-acetylglucosamine, galactosamine or a combination thereof.

[0066] Contemplated formulations may contain a surfactant. Non-limiting examples of surfactants include polysorbate 20, 40, 60 and/or 80, (Tween®-20, Tween®-40, Tween®- 60 and Tween®-80, respectively), Span 20, Span 40, Span 60, Span 80, Span 85, polyoxyl 35 castor oil (Cremophor EL), polyoxyethylene-660-hydroxystearate (macrogol 660), triton or Poloxamer 188 (Pluronic® F-68).

[0067] For example, polysorbate 80 (Tween® 80) may be present in varying amounts, ranging, for example, from about 0.01% to about 5.0%, from about 0.1% to about 0.5%, or about 0.3% by weight of polysorbate 80 or another surfactant.

[0068] A contemplated pharmaceutical composition, e.g., medicinal formulation may comprise a buffer. Examples of buffers that may be used in accordance with described embodiments include, without limiting, citrate buffer, acetate buffer, sodium acetate buffer, tartrate buffer, phosphate buffer, borate buffer, carbonate buffer succinic acid buffer, Tris buffer, glycine buffer, hydrochloric acid buffer, potassium hydrogen phthalate buffer, sodium buffer, sodium citrate tartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, or a mixture thereof.

[0069] Also contemplated herein is a stable lyophilized powder comprising LDA free base of the disclosure. Such a lyophilized powder can be reconstituted into a liquid formulation by addition of water with or without antioxidants, surfactants and other excipients.

[0070] A disclosed pharmaceutical composition may be formulated as a liquid, gel, cream, solid, film, emulsion, suspension, solution, lyophylisate or aerosol. For example, a contemplated pharmaceutical composition may be formulated as a liquid. When the pharmaceutical composition comprises a plurality of dosage unit forms, for example two dosage unit forms, these dosage unit forms can be formulated in different forms. For example, a first unit dosage form comprising, e.g. one or more pharmaceutical acceptable LDA FB may be formulated as a liquid formulation, and the second unit dosage form comprising, e.g., a decarboxylase inhibitor such as carbidopa, can be formulated as a solid formulation.

[0071] Disclosed pharmaceutical compositions may be formulated for any suitable route of administration, e.g., for subcutaneous, transdermal, intradermal, transmucosal, intravenous, intraarterial, intramuscular, intraperitoneal, intratracheal, intrathecal, intraduodenal, intrapleural, intranasal, sublingual, buccal, intestinal, intraduodenally, rectal, intraocular, or oral administration. The compositions may also be formulated for inhalation, or for direct absorption through mucous membrane tissues.

[0072] In embodiments described herein, the pharmaceutical compositions disclosed are aqueous formulations particularly useful for subcutaneous administration e.g., via an infusion pump.

[0073] In some embodiments, a contemplated formulation is designed for oral or buccal administration, and may be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Such compositions may further comprise one or more excipients selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

[0074] In some embodiments, a contemplated formulation is designed for administration by inhalation and delivery, e.g., as an aerosol spray. A contemplated formulation may be designed for rectal administration as suppositories or retention enemas. Contemplated pharmaceutical compositions may also be formulated for local administration, such as a depot preparation. Such long acting formulations may be administered by implantation, e.g., subcutaneously or intramuscularly, or by intramuscular injection. In some embodiments, contemplated formulations are designed for topical administration in the form of, for example limiting, lotions, suspensions, ointments gels, creams, drops, liquids, sprays emulsions and powders. [0075] In some embodiments, a contemplated formulation is designed for administration via a dermal patch suitable for transdermal or subcutaneous administration of an active agent.

[0076] In some embodiments, a contemplated formulation is designed for parenteral administration, e.g., by bolus injection or continuous infusion. Injectable formulations may be suspensions, solutions, e.g., aqueous solutions, or emulsions in oily or aqueous vehicles, and may contain excipients such as suspending, stabilizing, dispersing agents, substances which increase the viscosity of a suspension, and/or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient(s) may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

[0077] In some embodiments, a pharmaceutical composition as disclosed herein is designed for a slow release of the pharmaceutically acceptable LDA free base and, therefore, includes particles including the API and a slow release carrier (typically, a polymeric carrier). Slow release biodegradable carriers are well known in the art.

[0078] All compositions for any form of administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0079] A contemplated composition or formulation comprising a disclosed API may be stable for at least 24 hours. For example, for at least 30 hours, at least 48 hours, at least 50 hours, at least 60 hours, at least 72 hours, at least 80 hours, at least 96 hours, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 moth, at least 2 month, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 1 year, at least 2 years and even more, at room temperature or at -20 °C to -80 °C.

[0080] According to the present disclosure, the pharmaceutical compositions can be administered over a defined time period, e.g., days, weeks, months, or years.

[008 1] A contemplated pharmaceutical composition may have a "physiologically acceptable pH", namely, a pH that facilitates administration of the formulation or composition to a patient without significant adverse effects, e.g., a pH of about 4 to about 9.8 (for example, about 4 ± 0.3 to about 9.5 ± 0.3). [0082] "Ambient temperature" as understood by a person of skill in the art refers to a temperature of from about 10°C to about 30°C. In exemplary embodiments, ambient temperature can be 25°C.

Methods of treatment

[0083] In an aspect of the disclosure, provided herein is a method of treatment of a subject inflicted with a neurological disease or disorder, the method comprising administrating to the subject an effective amount of a formulation described and/or a drug substance herein, thereby threating the subject.

[0084] The neurological disease or disorder treatable by a contemplated method may be a neurological disorder such as a disorder associated with reduced dopamine or loss of dopaminergic neurons, or a movement disorder. Such diseases and disorders include, for example, restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's like syndrome, progressive supranuclear palsy (PSP), Amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome (also known as multiple system atrophy (MSA)), dystonia, Alzheimer's disease, Lewy body dementia (LBD), akinesia, bradykinesia, and hypokinesia; conditions resulting from brain injury including carbon monoxide or manganese intoxication; and conditions associated with a neurological a disorder including alcoholism, opiate addiction, and erectile dysfunction.

[0085] In an exemplary embodiment, the neurological disease is Parkinson's disease.

[0086] Treating a disease, as referred to herein, means ameliorating, inhibiting the progression of, delaying worsening of, and even completely preventing the development of a disease, for example inhibiting the development of neurological manifestations in a person who has neurological disease or disorder. Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or a pathological condition after it has begun to develop. In particular examples, however, treatment is similar to prevention, except that instead of complete inhibition, the development, progression or relapse of the disease is inhibited or slowed.

[0087] An effective amount or a therapeutically effective amount of a compound, i.e., an API, and/or a formulation comprising it is a quantity of API and/or formulation sufficient to achieve a desired effect in a subject being treated. An effective amount of a compound or of a formulation comprising it can be administered in a single dose, or in several doses, for example daily, during a course of treatment. However, the effective amount of the API will be dependent on the API applied, the subject being treated, the severity and type of the affliction, and the manner of administration of the compound.

[0088] In some embodiments, the method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable LDA FB or described herein.

[0089] For example, the composition administered to a subject in need thereof may comprise form about 5% to about 25% of a pure pharmaceutically acceptable LDA of a disclosed such as a substantially pure crystalline form of LDA FB of the disclosure, for example, crystalline having X-ray powder diffraction peak pattern A substantially as shown in Figure 1.

[0090] "Administration" as referred to herein is introduction of the API or a pharmaceutical composition or formulation comprising it as defined herein into a subject by a chosen route. Administration of the active compound or pharmaceutical composition can be by any route known to one of skill in the art, and as appropriate for the particular condition and location under treatment. Administration can be local or systemic. Examples of local administration include, but are not limited to, topical administration, subcutaneous administration, intramuscular administration, intrathecal administration, intrapericardial administration, intra-ocular administration, topical ophthalmic administration, or administration to the nasal mucosa or lungs by inhalational administration. In addition, local administration includes routes of administration typically used for systemic administration, for example by directing intravascular administration to the arterial supply for a particular organ. Thus, in particular embodiments, local administration includes intra-arterial administration, subcutaneous administration, intraduodenally administration, and intravenous administration when such administration is targeted to the vasculature supplying a particular organ. Local administration also includes the incorporation of the API and/or formulation comprising it into implantable devices or constructs, such as vascular stents or other reservoirs, which release the API over extended time intervals for sustained treatment effects. [0091] Systemic administration includes any route of administration designed to distribute the API or a pharmaceutical composition or formulation comprising it widely throughout the body via the circulatory system. Thus, systemic administration includes, but is not limited to, intra-arterial and intravenous administration, topical administration, subcutaneous administration, intraduodenally administration, intramuscular administration, or administration by inhalation, when such administration is directed at absorption and distribution throughout the body by the circulatory system.

[0092] In accordance with a contemplated method, a disclosed pharmaceutical composition may be administered to a patient in need thereof via one or more routes such as, but not limited to, parenteral routes selected from subcutaneous, transdermal, intradermal, intratracheal, intraocular, intramuscular, intraarterial, intraduodenally or intravenous.

[0093] In some embodiments, the pharmaceutical compositions are administered continuously, for example by a designated pump. Alternatively, or additionally, formulations may be administered non-continuously, e.g., as bolus, injection, a pill taken orally or eye drops.

[0094] In some embodiments, a disclosed method features subcutaneous and substantially continuous administration of a disclosed pharmaceutical.

[0095] By "substantially continuous" administration is meant that a dose of the formulation being administered is not administered as a bolus, e.g., a pill taken orally or a bolus injection, but rather that a single dose of the composition is being administered to a patient or individual over a particular predetermined period of time. For example, substantially continuous administration can involve administration of a dosage, e.g., a single dosage, at over a period of at least 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 18 hours, 2 1 hours, 24 hours, 12 to 16 hours, 16 to 18 hours, 18 to 20 hours, or 20 to 24 hours.

[0096] For example, a disclosed pharmaceutical composition may be administered, e.g., substantially continuously, at a rate of from 0.01 ml/hour/site to 0.6 ml/hour/site, e.g., from 0.08 ml/hour/site to 0.24 ml/hour/site. Such rates may be constant throughout the day and night or varied according to patient's need, e.g., may reflect a patient resting or sleeping schedule and waking or higher activity level schedule.

[0097] For example, a contemplated method may comprise subcutaneous or intraduodenal administration of a disclosed pharmaceutical composition at a rate of, for example, 0.32 ml/hour/site or 1.0 ml/hour, respectively, in the morning (e.g., for 2-4 hours before waking), 0.24 ml/hour/site during the daytime or activity time (e.g., for 10 to 14 hours), and/or 0.08 ml/hour/site or 0.0 to 0.5 ml/hour, respectively, at rest or at night.

[0098] Substantially continuous administration can be achieved using a means such as transdermal patch or a pump device that continuously administers the formulation to a patient over time. For example, a pump for subcutaneous infusion or a transdermal patch may be operated at an average rate of from about 10 µΙ ηο Γ to about 1000 µ ο , 300 ± 100 ο , or 200 ± 40 ουτ continuously for 24 hours; 440 ± 200 µΙΤηοι Γ or 200 ±

50 µ ο continuously for 16 hours (during waking hours) and from 0 to about 80 µ ο or 0 to 200 µ Ι ο for 8 hours (at night).

[0099] Substantially continuously administering a disclosed composition to a patient can be doubled or tripled by using more than one pump, patch, or infusion site. In exemplary embodiments, substantially continuously administering using, e.g., a liquid composition, can be at an average rate of 0.2-2 µ ο , or 1 ± 0.5 µ ο continuously for 24 hours; 1 ± 0.5 µΙ ηο continuously for 16 hours (during waking hours) and from 0 to about 0.5 µ ο for 8 hours (at night), via a pump, transdermal patch, or a combination of delivery devices that are suitable for, e.g., subcutaneous, intravenous, intrathecal, and/or intraduodenal administration.

[0100] In some embodiments, administration includes acute and immediate administration such as inhalation or injection.

[0101] In some embodiments, the formulation administered according to a contemplated method may comprise one or more pharmaceutically acceptable LDA FB or a salt thereof of the disclosure as a first active agent, and at least one decarboxylase inhibitor as a second active agent, for example carbidopa, a carbidopa prodrug and/or a pharmaceutically acceptable salt thereof. Such a formulation may further comprise one or more of a basic amino acid, an amino sugar, a catechol-O-methyl transferase (COMT) inhibitor, or a monoamine oxidase (MAO) inhibitor, as defined herein.

[0102] In some embodiments, the method comprises co-administering to a patient in need thereof of at least two separate formulations, i.e., at least two dosage unit forms, a first formulation (or unit form) comprising one or more pure pharmaceutically acceptable LDA free base or a salts thereof of the present disclosure, and a second formulation comprising a decarboxylase inhibitor e.g., carbidopa, a prodrug thereof and/or a pharmaceutically acceptable salt thereof, and, optionally, one or more of a basic amino acid, an amino sugar, a COMT inhibitor, or a MAO inhibitor. In accordance with these embodiments, the at least two dosage unit forms may be administered simultaneously, or sequentially at a predetermined time interval.

[0103] Two or more dosage unit forms may be administered to a subject by the same route of administration or, alternatively, by different routes of administration. For example, a first dosage form (e.g., pharmaceutically acceptable LDA FB described herein) may be administered subcutaneously, and a second unit dosage form (e.g., a carbidopa formulation) may be administered orally or intravenously, either simultaneously or at different times.

[0104] In some embodiments, a particular dosage form may be administered by two or more different routes, for example, both subcutaneously and orally either simultaneously of subsequently.

[0105] Two or more dosage unit forms may be administered to a subject at the same rate, or at different rates.

Kits [0106] In an aspect of the present disclosure, there is provided a kit comprising a LDA free base and/or a salt thereof of the present disclosure, or a formulation comprising it as defined in any of the embodiments described herein and, optionally, instructions and means for administration of the active agents and/or the formulation to a subject in need thereof.

[0107] In some embodiments, the kit comprises a first pharmaceutical composition comprising pharmaceutically acceptable LDA free base described herein; (ii) a second pharmaceutical composition comprising one or more decarboxylase inhibitors or salts thereof; (iii) optionally, one or more of a basic amino acid, an amino sugar, a catechol-O- methyl transferase (COMT) inhibitor, or a monoamine oxidase (MAO) inhibitor; and (iv) optionally, instructions for co-administration of the pharmaceutical compositions.

[0108] A contemplated kit is useful for treatment of a disease or disorder characterized by neurodegeneration and/or reduced levels of brain dopamine as described herein, for example Parkinson's disease.

[0109] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[01 10] As used herein the term "about" refers to ± 10 .

[0111] The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

[01 12] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0113] Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. [0114] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Materials and Methods

X-ray powder diffraction (XRPD)

[0115] XRPD analyses were performed using a Panalytical X'pert Pro diffractometer equipped with a Cu X-ray tube (Cu anode, wavelength 0.154 nm, max. 2.2 kW, 60 kV, long fine focus ceramic tube, type PW3373/00) and a Pixcel detector system. The isothermal samples were analysed in transmission mode and held between low density polyethylene films. The Almac default XRPD program was used (range 3 - 40 °2Θ, step size 0.013°, counting time of 46 sec or 99 sec, depending on run time of -11 min or -22 min). XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software.

Differential scanning calorimetry (DSC) [0116] Differential scanning calorimetry (DSC) is a thermal analysis technique in which the difference in the amount of heat required to increase the temperature of a sample and a reference is measured as a function of temperature. While the sample and the reference were heated (or cooled) individually (by two separate heaters), "zero equilibrium" principle was realized, namely, a temperature difference between the sample and the reference of ∆Τ 0 was permanently provided. The heaters automatically adapted to the temperature changes between the tested sample and the reference by supplying additional power. The difference between the heat flow (or power applied) to the test sample and the reference was measured as a function of temperature and/or time. The temperature program for the DSC analysis was designed such that the temperature increased linearly as a function of time. The reference sample used had a well-defined heat capacity over the range of temperatures scanned, it was inert to the sample in the temperature range used, it did not exhibit any physical transitions in the temperature range used, and its melting point was sufficiently high.

[0117] In the DSC thermograms obtained for L-dopamide FB, endotherms appear as upward peaks whereas exotherms are registered as downward peaks. Y axis may be a plot of difference in heat output of the two heaters, indicated as heat flow, outputted in units of heat q supplied per unit time, t (q/t = heat flow), e.g., mW or J/sec.

[0118] The difference in heat output of the two heaters against temperature is the heat absorbed by the test sample. Thus, alternatively, Y axis may be a plot of heat capacity, Cp, of the test sample. The heat capacity of the sample is the amount of heat it takes to get a certain temperature increase in the sample (Cp = heat flow/heating rate; and heating rate = AT/t).

[0119] DSC analyses were carried out on a PerkinElmer® Jade Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminium pans. An empty pan identical to the one with sample was used as the reference. Each sample was heated under nitrogen at a rate of 10 °C/minute to a maximum of 300 °C. Temperatures were reported at the transition onset to the nearest 0.01 degree. Enthalpy of a transition, ∆Η, was calculated from on the area under the curve (A) in a DSC thermogram of a tested crystalline using the formula ∆Η = KA, where K is the calorimetric constant, which depend on the instrument. Indium metal was used as the calibration standard.

Hyper differential scanning calorimetry (HDSC) [0120] Hyper differential scanning calorimetry (HDSC) is a variant of DSC useful for detection and quantifying low levels (e.g., less than 1.5%) of amorphous content in samples that are mostly crystalline, or for indicating an overall amorphous form of a crystal. Unlike

DSC, HDSC technique can accurately measure the glass transition temperature, Tg, of non crystalline solids. The glass transition is a property of only amorphous solids or the amorphous portion of a semi-crystalline solid, and glass transition temperature relates to the temperature at which the transition in the amorphous between the glassy and rubbery state occurs. A given crystal sample does not have a unique value of Tg because the glass phase is not at equilibrium. The measured value of Tg depends, inter alia, on a crystal's thermal history and age, the water content in the crystal and on the rate of heating or cooling. Tg is roughly (0.67) Tm, the melting temperature of the crystalline material in degrees K. HDSC uses scan rates (heating rates) that are much faster than conventional DSC (e.g., 100-500 °C/minute in heating as well as in cooling over a broad temperature range). The rapid scan- rate can substantially enhance the sensitivity (by at least a factor of ten over most conventional DSC analyses), allowing small transitions such as the glass transition to be detected more readily and accurately. Increased sensitivity of HDSC further enables the use of very low sample mass (ca. 1mg) without any loss in detection of Tg. For HDSC analysis, a crystalline sample was heated to melt, rapidly cooled and the resulting solid was rapidly heated again. The sample's heat capacity Cp during the second melting process was outputted as a function of temperature, and Tg of the amorphous was measured. A glass transition doesn't occur suddenly but takes place over a temperature range, and the transition from a disordered solid to a liquid appears as a step (endothermic direction) in the HDSC curve. The middle of the incline in the endotherm was taken to be the measured Tg (also termed herein "Tg midpoint" or "half height Cp").

[0121] A PerkinElmer® diamond Differential Scanning Calorimeter was used for HDSC measurements. The DSC was calibrated for temperature and heat flow with reference materials having transitions in the range of interest. Depending on the required cooling rates, different cooling devices such as Intracooler or CryoFill (a liquid nitrogen device) were used.

Thermogravimetric/Differential thermal analysis (TG/DTA) [0122] Mass changes in a material as a function of temperature (or time) under a controlled atmosphere is known as thermogravimetric (TG) analysis, and its principal uses include measurement of a material's thermal stability and composition. The changes that usually occur upon heating a sloid sample include melting, phase transition, sublimation, and decomposition. Differential thermal analysis (DTA) is a thermal analysis method, in which the temperature of a sample is compared with that of an inert reference material during a programmed change of temperature. The temperature difference between the crystalline sample and the reference material (∆Τ) remains the same until a thermal event occurs, such as melting, decomposition or change in the crystal structure. If an endothermic event takes place within the sample, the temperature of the sample will lag behind that of the reference and a minimum will be observed on a curve of ∆Τ versus T (temp), whereas if an exothermal event takes place, the temperature of the sample will exceed that of the reference and a maximum will be observed on the curve. The area under the endotherm or exotherm is related to the enthalpy of the thermal event, ∆Η. It is advantageous to use both DTA and TG, because DTA events can then be classified into those which do or do not involve mass change. [0123] Thermal analysis using a combined TG/TDA analysis was applied to contemplated crystalline L-dopamide free base samples in order to assess crystallinity, purity and changes in properties of the sample related to an imposed change in the temperature. Thermogravimetric analyses were carried out on a Mettler Toledo TGA/DSC1 STARe. The calibration standards were indium and tin. Samples were placed in an aluminium sample pan, inserted into the TG furnace and accurately weighed. The heat flow signal was stabilised for one minute at 25 °C, prior to heating to 300 °C in a stream of nitrogen at a rate of 10 °C/minute.

High Pressure Liquid Chromatography (HPLC)

[0124] The HPLC method used to determine LDA free base purity is outlined in Table 1. The retention time of L-dopamide was typically 6.3+0.1 min. Samples were dissolved in Diluent A.

Table 1: HPLC methodfor equilibrium solubility analysis of L-dopamide

1H Nuclear magnetic resonance spectroscopy (NMR)

[0125] NMR analysis was carried out on a Bruker 400 MHz or 500 MHz instrument in DMSO. Spectral peaks are listed on the spectrum plots. Dynamic vapor sorption (DVS)

[0126] Dynamic vapor sorption (DVS) is a gravimetric technique that measures how quickly and how much of a solvent, for example water, is absorbed by a sample, for example, powdered crystalline material, by varying the vapor concentration, e.g., relative humidity (RH) surrounding the sample, and measuring the change in mass which this produces. The DVS instrument used measures uptake and loss of moisture by flowing a carrier gas at a specified relative humidity (or partial pressure) over the sample (weigh between 1 mg and 4 g) suspending from the weighing mechanism of an ultra-sensitive recording microbalance, which is capable of measuring changes in sample mass lower than 1 part in 10 million.

[0127] The water sorption isotherms obtained from DVS measurements of crystalline L- dopamide free base show the equilibrium amount of vapor sorbed by the sample as a function of steady state relative humidity at a constant temperature. For water sorption isotherms, the sample was exposed to a series of step changes in RH, for example, a cycle of 40 - 90 - 0 - 40 % RH change, and the mass change was monitored as a function of time. The sample mass allowed to reach gravimetric equilibrium at each step change in RH before progressing to the next humidity level. Then, the equilibrium mass values at each RH step were used to generate the isotherm. The hygroscopicity of the sample was determined according the European Pharmacopoeia Classification, setting the degree of hygroscopicity of a substance as ranging from non-hygroscopic to very hygroscopic based on the weight increases measured at 40-80% RH (25 °C). According to this classification: weight gain <0.2 %, non-hygroscopic; weight gain >0.2 % and <2 %, slightly hygroscopic; weight gain >2 % and <15%, hygroscopic; weight gain >15%, very hygroscopic; and deliquescent - sufficient water was absorbed to form a liquid.

Optical microscopy

[0128] Microscopy analyses were carried out using an Olympus BX51 stereomicroscope with crossed-polarised light and a 1st order red compensator plate. Photomicrographic images were captured using a ColorView IIIu digital camera and SynchronizIR basic V5.0 imaging software with objective lens magnification of xlO EXAMPLE 1

Synthesis of L-dopamide free base

[0129] L-dopamide free base was synthesized starting from levodopa according to the procedure depicted in Scheme 1, as follows.

1. 25% aqueous NH3, -8° C to -12° C, 16-24 h

2 . Azeoptrope NH3 from 2-propanol

hydrochloride salt 11

1. Dissolve in H20 Re-precipitate as before, collect solid

crude L-Dopamide, collect solid L-Dopamide, free base hydrochloride salt 13

L-Dopamide, hydrochloride salt L-Dopamide, free base 14 15 Scheme 1

1. Synthesis ofL-dopa methyl ester hydrochloride salt (compound 11)

[0130] Methanol (135.0 kg) was cooled to a temperature of from about -5 °C to about 10 °C under nitrogen. Thionyl chloride (22.6 kg, 190.0 mol, 1.5 eq.) was added while keeping the temperature below -5 to 0 °C. Levodopa (L-Dopa; compound 10) (25.0 kg, 126.8 mol) was added while maintaining the temperature within the range of from about -5 °C to about 10 °C. Then the temperature was adjusted to 20 - 25°C, and the mixture was stirred at this temperature for 12-24 hours until at least 95% conversion of 10 to compound 11 was achieved (as assessed by HPLC). The mixture was concentrated by distillation under reduced pressure to a volume of ca. 40 L. Acetonitrile (MeCN) (165.0 kg) was added to the distillation residue, and the resulting solution was concentrated to approx. 210 L by distillation at reduced pressure in order to remove any residual methanol. The hydrochloride salt of L-dopa methyl ester 11 (3,4-dihydroxy-L-phenylalamine methyl ester hydrochloride) precipitated during this process. The temperature of the suspension was adjusted to 40 - 45 °C and then cooled to 20 - 25 °C over 10 hours, and the suspension was stirred at 20 - 25 °C for 2 - 24 hours. The solid was collected by filtration, and the filter cake was washed with acetonitrile. The wet solid was dried in vacuum at 20 -25 °C for at least 10 hours to afford 29.8 kg of 11 (95%) as an off-white solid.

2. Production of crude L-dopamide hydrochloride salt (compound 13)

[0131] Ammonia solution (25%) (81.0 kg) was cooled to a temperature of from about -8 °C to about -12 °C under nitrogen, and compound 11 (15.0 kg, 60.6 mol) was added. The reaction mixture was stirred at -8 °C to -12 °C for 16-24 hours until minimum 99.0% conversion of 11 to compound 12 (crude L-dopamide free base) was achieved (assessed by HPLC). The excess of ammonium hydroxide was removed by azeotropic distillation with 2-propanol (164.0 kg) under reduced pressure. Purified water (40.0 kg) was added to the distillation residue, and the pH of the resulting mixture was adjusted to pH 2.5 - 2.7 at 20 - 25 °C with addition of hydrochloric acid (37%) (-2.125 kg). Activated carbon pH 4 - 7 (1.410 kg) was added and the mixture was stirred for 30 - 60 minutes at 20 - 25 °C. Celite (0.705 kg) was added and the mixture was then filtered on a pad of celite (1.50 kg). The filter cake was washed with purified water (12.4 kg). 2-Propanol (143.5 kg) was added to the filtrate and the pH was adjusted to pH 2.5 - 2.7 at 20 - 25 °C with addition of hydrochloric acid (37%) (-0.250 kg). Azeotropic distillation with 2-propanol was performed under reduced pressure until a water content of 7.0-8.5% w/w (Karl Fischer (KF) titration) was achieved for the solution of HC1 salt of L-dopamide (compound 13) in 2-propanol. The temperature of the mixture was then adjusted to 40 - 45 °C, and seeding was performed if needed. For precipitation from aqueous solution an organic solvent is required, and tert- Butyl methyl ether (TBME) was chosen as the best candidate. ieri-Butyl methyl ether (TBME, 18.7 kg) was added. The mixture was then cooled to 20 - 25 °C and stirred at this temperature for 1 - 2 hours. teri-Butyl methyl ether (6.60 kg) was added over at least 1 hour and the mixture was stirred at 20 - 25 °C for 2 - 20 hours. The suspension was then cooled to 0 - 5 °C and stirred at this temperature for 2 - 6 hours. The solid was collected by filtration in two portions, and the filter cake was washed with cold (0 - 5 °C) 2-propanol (38.5 kg). The solid was dried in vacuum at 38 - 43 °C for at least 16 hours to afford 12.0 kg of crude L-2-amino-3-(3,4-dihydroxyphenyl) propanamide hydrochloride (13) (85%) as a white to off-white solid.

3. Production of purified L-dopamide hydrochloride salt (compound 14)

[0132] Crude compound 13 (2.70 kg, 11.6 mol) was dissolved in purified water (5.85 kg). The mixture was treated with activated carbon at pH 4 - 7 (0.270 kg) for 30 - 60 minutes at 15 -25 °C. Celite (0. 135 kg) was added and the mixture was filtered on a pad of celite (0.200 kg). The filter cake was washed with purified water (2.08 kg), and the filtrate was then subjected to polish filtration. 2-Propanol (27.6 kg) was added to the filtered solution and the pH was adjusted to 2.5 -2 .7 at 20 - 25 °C with addition of hydrochloric acid (37%) (-0.025 kg). Azeotropic distillation with 2-propanol was performed under reduced pressure until a content of 7.0 - 8.5% w/w (KF titration) was achieved for the solution of 13 in 2-propanol. The temperature of the mixture was adjusted to 40 - 45 °C and seeding was performed if needed. teri-Butyl methyl ether (7.2 kg) was added and the mixture was stirred at 20 - 25 °C for 2 - 20 hours. The suspension was then cooled to 0 - 5 °C and stirred at this temperature for 2 - 6 hours. The solid was collected by centrifugation, and the filter cake was washed with a cold (0 - 5 °C) mixture of 2-propanol (3.2 kg) and teri-butyl methyl ether (3.0 kg). If the content of L-dopa in a sample was < 0.50%, the solid was dried in vacuum at 38-43 °C for at least 38 hours, to afford 2.0 kg of compound 14 (74%) as a white to off-white solid.

4. Production of L-dopamidefree base (compound 15)

[0133] Compound 14 (9.30 kg, 40.0 mol) was dissolved in purified water (27.9 kg). The mixture was treated with activated carbon at pH 4 - 7 (0.930 kg) for 30 - 60 minutes at 15 - 25 °C. Celite (0.465 kg) was added and the mixture was filtered on a pad of celite (1.50 kg). The filter cake was washed with purified water (10.9 kg), and the filtrate was then subjected to polish filtration. The pH was adjusted to pH 7.4 - 7.6 at 20 - 25 °C with addition of sodium hydroxide (NaOH, 27%) (-2.32 kg) and seeding was performed. The pH was adjusted to 8.1 - 8.3 at 20 - 25 °C with addition of sodium hydroxide (27%) (-2.46 kg), and the resulting suspension was stirred at 20 - 25 °C for 2 - 3 hours. The solid was collected by centrifugation, and the filter cake was washed with purified water (29.0 kg), ethanol (18.9 kg) and teri-butyl methyl ether (13.2 kg). Content of L-dopa in a sample of the wet filter cake was determined by HPLC analysis. If the content of L-dopa was < 0.50%, the solid was dried in vacuum at 38 - 43 °C for at least 12 hours, to afford 5.3 kg of L-dopamide free base (compound 15) as an off-white to brownish solid.

[0134] Synthesis of 14 was also conducted on a scale of 10.7 mol of 11 following a procedure similar to that described above, and 14 was produced in 67.9% (overall yield from 11). Synthesis of 15 was also conducted on a scale of 10.2 mol of 11 following a procedure similar to that described above, and 15 was produced in 59.8% (overall yield from 11).

[0135] The overall process for producing crystalline LDA free base was a rather lengthy process, especially the amindation step, which comprised nearly 46 stages and lasted 60 hours, mainly due to the need to distil the LDA HC1 salt and recrystallize it so as to obtain purification. In addition, the color of the final product being brownish resulted in brownish formulation.

EXAMPLE 2

Physical and chemical analysis of crystalline L-dopamide free base

[0136] Crystalline L-dopamide free base (LDA FB) was subjected to X-ray powdered diffraction analysis, Thermogravimetric/Differential Thermal Analysis (TG/DTA) and DSC analysis.

(i) X-ray powdered diffraction analysis

[0137] The XRPD pattern obtained for LDA FB is indicative of a crystalline material. This unique X-ray diffraction peak pattern, herein referred to as "Pattern A", is shown in Figure 1. The XRPD peaks are listed in Table 2. The XRPD peaks pattern of the crystalline LDA free base of the present disclosure is characterized, for example, by at least peaks No. 8 and No. 10. Additional peaks which characterize the crystalline LDA FB of the disclosure include, for example, peaks Nos. 5, 27, 29 and 34. Table 2. XRPD peaks of L-dopamidefree base

Peak No. Pos. Area Backgr. d-spacing [A] Height Rel. Int. [°2Θ.] [cts*°2Th.] [cts] [cts] [%] 1 9.8019 34.94 670.94 9.02385 692.22 24.79 2 10.6807 8.57 646.22 8.28322 169.72 6.08 3 13.4973 62.58 560.76 6.56037 991.88 35.52 4 17.3487 8.99 488.74 5.11169 118.74 4.25 5 18.0669 176.35 479.22 4.91007 2329.25 83.41 6 18.8399 59.07 466.48 4.71033 936.21 33.52 7 19.4367 54.96 454.81 4.56702 725.93 25.99 8 19.6935 246.68 449.25 4.50804 2792.69 100.00 9 20.1717 41.70 437.98 4.40225 660.91 23.67 10 21.0048 214.83 415.54 4.22948 2128.1 76.20 11 21.468 9.36 401.90 4.13927 185.35 6.64 12 22.231 77.32 381.39 3.99889 1225.55 43.88 13 23.0276 33.98 366.77 3.86234 448.85 16.07 14 23.8506 5.92 355.53 3.73089 78.24 2.80 15 24.2537 23.60 349.44 3.66979 467.65 16.75 16 24.447 95.87 346.32 3.6382 1152.33 41.26 17 24.5154 38.84 345.18 3.63722 622.48 22.29 18 25.311 47.99 330.45 3.51593 769.10 27.54 19 25.8074 15.11 319.92 3.44941 242.13 8.67 20 25.9868 27.89 315.91 3.42601 335.27 12.01 21 26.1884 109.52 311.30 3.40008 1316.3 47.13 22 26.257 47.21 309.71 3.39979 756.61 27.09 23 27.1213 38.64 289.78 3.28521 309.6 11.09 24 27.49 20.24 281.23 3.24199 121.61 4.35 25 28.2016 111.35 263.71 3.16177 1338.34 47.92

26 28.2835 39.59 261.59 3.16064 634.4 22.72 27 28.8797 134.37 245.68 3.08906 1615.04 57.83 28 28.96 49.87 243.48 3.08833 799.13 28.62 29 29.1135 15.56 239.26 3.06478 249.42 8.93 30 29.709 21.20 224.57 3.00469 203.81 7.30 31 30.0456 35.62 217.49 2.9718 342.49 12.26 32 31.7421 27.23 194.26 2.81672 327.3 11.72

33 31.9756 17.19 196.2 2.79669 137.72 4.93 34 32.2967 134.78 198.06 2.76961 1295.95 46.41 35 32.392 41.59 198.4 2.76854 666.53 23.87 36 32.615 14.17 198.74 2.74331 85.15 3.05 37 33.0669 61.28 197.28 2.70684 736.56 26.37 38 33.1576 24.96 196.61 2.70635 400 14.32

39 33.5306 36.61 192.7 2.67046 440.08 15.76 40 33.7877 17.34 188.92 2.65072 208.41 7.46 41 34.2332 44.42 180.67 2.61724 427.08 15.29 42 35.1277 10.10 164.22 2.55262 40.47 1.45 43 35.7598 18.50 161.34 2.50893 111.15 3.98 44 36.277 8.13 158.63 2.47434 65.12 2.33 45 37.21 34.82 152.72 2.41441 334.81 11.99 46 38.0279 9.17 148.35 2.36434 146.88 5.26 47 38.5764 14.00 149.55 2.33198 168.22 6.02 48 39.0434 21.35 150.52 2.30515 64.14 2.30

(ii) Thermal analysis

[0138] Thermogravimetry/Differential Thermal Analysis (TG/DTA) was performed, as described in Materials and Methods, to determine the thermal profile and associated % weight changes of L-dopamide FB. The results are shown in Figure 3. No weight loss was observed between 25 °C and -170 °C suggesting that L-dopamide free base is an anhydrous material. The weight loss at temperatures higher than 170 °C corresponds to the initiation of decomposition of the material. [0139] Differential scanning calorimetry (DSC) analyses were carried out as described in Materials and Methods. The DSC thermogram obtained for L-dopamide FB upon heating at a 10 °C/min rate is shown in Figure 4. A melting endotherm was seen at onset 164 °C.

[0140] Hyper DSC (HDSC) was performed in order to generate amorphous material from fast cooling of molten L-dopamide and determine the temperature of glass transition (Tg) during the re-heat cycle. Glass transition is characterized by change in heat capacity (Cp). A transition from the disordered solid to a liquid appeared as a step (endothermic direction) in the thermogram taken from the second heating of a heat-cool-heat cycle, demonstrating the presence of a Tg, observed at -131.5 °C (half height Cp value).

(Hi) NMR

[0141] The NMR analysis was conducted using d6-DMSO as the solvent. The ¾ NMR spectrum presented in Figure 2 was concordant with the molecular structure of L-dopamide FB. No other solvent was detected in the spectrum, in compliance with the TG data.

(iv) Dynamic vapour sorption (DVS)

[0142] The hygroscopicity and the sorption properties of L-dopamide were determined using dynamic vapour sorption (DVS) as described in Materials and Methods. The sample was cycled from 40-90-0-40 % RH at ambient temperature. The isotherm showed the material exhibited slow uptake of moisture, with a negligible increase in weight from 40 % RH to 80 % RH of 0.04 %, indicating that the sample was non-hygroscopic, based on the European Pharmacopoeia classification, which sets that weight increase <0.2 % from 40% RH to 80% RH at 25 °C accounts for a non-hygroscopic material.

Optical microscopy

[0143] A photomicrograph of L-dopamide free base showed the material had a needle like morphology with length scale of 5-80 µ .

[0144] In summary, XRPD analysis indicated that L-dopamide free base was a highly crystalline material, and the TG/DTA data showed negligible weight loss from 25-170 °C indicating the material was anhydrous. L-dopamide FB remained thermally stable up to 170 °C. Heat rate studies by DSC and hyper DSC indicated a melting point at onset -164 °C and a glass transition occurring at -131 °C (half height Cp value).

[0145] Dynamic vapor sorption (DVS) revealed that L-dopamide was a non-hygroscopic material with weight change of - 0.04 % (w/w dry basis) occurring between 40-80 % RH. XRPD analysis of post-DVS samples revealed no change in physical form.

EXAMPLE 3

Solubility of crystalline L-dopamide free base

[0146] The solubility of crystalline L-dopamide FB was assessed in 12 solvent systems using the aliquot addition method, described below. The solvents tested were: acetonitrile, acetone, ethanol, ethyl acetate, isopropanol (IPA), methanol, methyl teri-butyl ether, tetrahydrofuran (THF), toluene, water, IPA:water (90:10 v/v) and THF:water (82:18 % v/v, Aw~0.99.

[0147] Aliquots of about 10 of a test solvent, were added to an accurately weighed sample of L-dopamide (-10 mg) at ambient temperature until complete dissolution was determined by visual inspection. The solubility was estimated based on the total volume of solvent used to obtain complete dissolution. If dissolution did not occur after the last aliquot of solvent was added (typically -40 volumes of solvent), the sample was subjected to two cycles of the following temperature cycling regime, while stirring at 400 rpm: heating from 20 °C to within 3 °C of solvent boiling point (or 100 °C, whichever was lower) at 0.5 °C/minute; and cooling to 20 °C at 0.2 °C/minute.

[0148] From the infrared (IR) transmission data of the sample vials, dissolution and precipitation events were recorded as the point of complete transmission of IR and the onset of turbidity by IR, respectively. Samples were held at ambient temperature for 18 hours to maximize the chance of precipitation.

[0149] L-dopamide free base was soluble at ambient temperature in water at -26 mg/mL and THF/H2O at -29 mg/mL at -26 - 29 °C. At elevated temperatures L-dopamide free base was soluble in IPA and IPA/H2O. L-dopamide FB was practically insoluble in most organic solvents. INCORPORATION BY REFERENCE

[0150] The entire contents of all patents, published patent applications, websites, and other references cited herein are hereby expressly incorporated herein in their entireties by reference. CLAIMS

1. A crystalline form of L-dopamide free base, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θat about 19.7 and about 21.0.

2. The crystalline form of claim 1, further having characteristic peaks in degrees 2Θ at about 18.1, and about 28.9.

3. The crystalline form of claim 1 or 2, having a powder X-ray diffraction pattern substantially the same as depicted in Figure 1.

4. The crystalline form of any one of claims 1-3, wherein the powder X-ray diffraction pattern was obtained using X-ray diffractometer Panalytical Xpert Pro equipped with a Cu X-ray tube emitting K« radiation.

5. The crystalline form of any one of claims 1 to 4, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 164 °C, and a peak at about 172.4 °C.

6. The crystalline form of any one of claims 1 to 5, wherein the crystalline form has less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than 1%, between about 0.01% and about 10%, or between about 0.01% and about 1%, in content, of a crystalline hydrochloric acid salt of L-dopamide.

7. The crystalline form of any one of claims 1 to 6, wherein the crystalline form has less than about 1%, or less than about 0.5% levodopa and/or levodopa salt.

8. The crystalline form of any one of claims 1 to 7, wherein the crystalline form has less than about 0.3% levodopa and/or levodopa salt.

9. The crystalline form of any one of claims 1 to 8, wherein the purity of the crystalline form is above 99% as determined by HPLC. 10. A drug substance comprising at least a detectable amount of the crystalline form of any one of claims 1 to 9.

11. A pharmaceutical composition comprising the crystalline form or the drug substance of any one of claims 1 to 10, and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition of claim 11, wherein the composition is a formulation for pharmaceutical administration.

13. A pharmaceutically acceptable acid addition salt of L-dopamide free base formed from a process comprising reacting the crystalline form of any one of claims 1 to 9 with an acid; thereby forming an acid salt of L-dopamide.

14. The pharmaceutically acceptable salt of claim 13, wherein the acid is selected from the group consisting of hydrochloric acid, fumaric acid, lactic acid, phosphoric acid, sulfuric, glucoheptanoic acid, acetic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, citric acid, fumaric acid, galactaric acid, gluceptic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, glutaric acid, glycolic acid, isethionic acid, L-lactic acid, lactobionic acid, maleic acid, L-malic acid, methanesulfonic acid, propionic acid, succinic acid, L-tartaric acid, xinafoic acid, L-arginine, and L-histidine.

International application No PCT/IB2018/056127

A. CLASSIFICATION O F SUBJECT MATTER INV. C07C237/20 A61P25/16 ADD.

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols C07C C07B A61P

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , CHEM ABS Data

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

DAPHNE ATLAS ET AL: "-D0PA Conversion t o 1-14 Dopami ne and Generates a Sustained Level of Dopami ne at Dopami nergi c Neurons" , CNS NEUROSCI ENCE & THERAPEUTICS, vol . 22, no. 6 , 1 June 2016 (2016-06-01) , pages 461-467 , XP055352795, GB ISSN : 1755-5930, D0I : 10. 1111/cns . 12518 " L-DopAmi de, [(S) -2-Amino-3- (3,4-Di hydroxyphenyl ) Propanami de] " page 462 , col umn 1

US 8 048 926 B2 (YISSUM RES DEV CO [ I L] ) 1-14 1 November 2011 (2011-11-01) c i ted i n the appl i cati on "Synthesi s of L-Dopami de (LDA) " col umns 17-18

/ -

X Further documents are listed in the continuation of Box C. See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation or other " document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

20 November 2018 26/11/2018

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Guazzel l i Gi udi tta International application No PCT/IB2018/056127

C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

ZHOU T ET AL: "Design, synthesi s and 1-14 b i ologi cal eval uation of -dopa amide derivatives a s potenti al prodrugs for the treatment of Parki nson ' s di sease" , EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCI ENTI FIQUE ELSEVI ER, PARIS, FR, vol . 45, no. 9 , 1 September 2010 (2010-09-01) , pages 4035-4042 , XP027458833, ISSN : 0223-5234, D0I : 10. 1016/J . EJMECH .2010.05 .062 [retri eved on 2010-06-02] page 4040, paragraph 4 . 1 . 10; compound 10b

HI LFI KER R (EDITOR) ED - HI LFI KER R: 1-14 " Polymorphi sm i n the Pharmaceuti cal Industry" , 1 January 2006 (2006-01-01) , 20060101 , PAGE(S) 1 - 19, XP002528052, ISBN : 978-3-527-31146-0 page 1, paragraph 1 . 1 International application No Information on patent family members PCT/IB2018/056127

Patent document Publication Patent family Publication cited in search report date member(s) date

US 8048926 B2 01-11-2011 1596808 A2 23-11-2005 2006025385 Al 02-02-2006 2004069146 A2 19-08-2004