MAKING AND USING SAME

FIELD OF THE INVENTION

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

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 or derivatives thereof, particularly 2- amino-3-(3,4-dihydroxyphenyl) propanamide, 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, or pharmaceutically acceptable salts thereof 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 pharmaceutically acceptable salt of levodopa amide (LDA) compound represented by:

wherein

Y is a solvent such as, but not limited to,

m is a fractional ur whole number between about 0. and about 3 inclusive; and X is a compound ox a counter ion that forms a salt, such as, but not limited to, HC1,

[0009] For example, the present disclosure provides a pharmaceutically acceptable salt and/or solvate (e.g., hydrate) of levodopa amide (L-dopamide) (e.g., as shown above), wherein the salt is selected, for example, from die group consisting of hydrochloric acid, fumaric acid, lactate, phosphate, and sulfate salt. For example, provided herein is a hydrate of a hydrochloric acid salt of L-dopamidc or an anhydrous hydrochloric acid salt of L- dopamide.

[(ΗΠ0] Also provided herein are crystalline forms of pharmaceutically acceptable salts and/or solvates (e.g., hydrates) of L-dopamide. For example, provided herein is a crystalline form of a hydrochloric acid salt of L-dopamide, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 10.0 about 23.8 and about 31.5 (herein designated "crystalline form B").

[0011 J In a further aspect, the present disclosure provides a crystalline form of an anhydrous hydrochloric acid salt of L-dopamide, wherein the crystalline farm is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 20.9, about 24.0, about 28.5 and about 30.5 (herein designated "crystalline form A").

100121 The present disclosure also provides a crystalline form of a fumaratc salt of L- dopamide, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 5.6, about 15.0, about 17.0 and about 24.8; and a crystalline form of a lactate salt of L-dopamide, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 8.2, about 11.0. about 18 -5, about 20.0 and about 29.0. [0013] Provided herein, in some embodiments, is a crystalline form of a phosphate salt of L-dopamide, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 11.0, about 18.6, at about 18.9 and about 2S.S. The present disclosure also provides, for example, a crystalline form of a sulfate salt of L-dopamide, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 16.5, about 23.5, about 2S.0, at about 29, and about 31.0.

[0014] All X-ray powder diffraction analyses were obtained using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube emitting Ka radiation, and a Pixcel detector system under the conditions specified in the Material and Methods section herein.

[0015] Contemplated herein is a pharmaceutical composition comprising a disclosed salt, solvate and/or crystalline form of the disclosure, and a pharmaceutically acceptable excipient.

[0016] A drug substance is also contemplated, comprising e.g., at least a detectable amount of the crystalline form of the salt of the disclosure, and/or comprising substantially pure crystalline form of a salt of the disclosure.

[0017] 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

[0018] 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.

[0019] In the drawings:

Fig. 1A is the X-ray powder diffraction (XRPD) peaks pattern of hydrated L- dopatnide HCI salt (Pattern B), obtained using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray cube and a Pixcel detector system. XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software;

Fig. IB is the Ή-NMR plot in intensity vs. ppm of hydrated L-dopamide HCI salt having XRPD peak pattern designated Pattern B;

Fig. 2A is the XRPD peaks pattern of anhydrous L-dopamide HCI salt (Pattern A), obtained using the diffractometer specified in Fig. 1A;

Fig. 2B is the Ή-NMR plot in intensity vs. ppm of anhydrous L·dopaπlide HCI salt; having XRPD peak pattern designated Pattern A;

Fig. 3A is the XRPD peaks pattern of L-dopamide sulfate salt, obtained using the diffractometer specified in Fig. I A;

Fig. 3B is the 'H-NMR plot in intensity vs. ppm of L-dopanndc sulfate salt;

Fig. 4A is the XRPD peaks pattern of L-dopamide lactate salt, obtained using the diffractometer specified in Fig. 1A;

Fig.4B is the Ή-NMR plot in intensity vs. ppm of L-dopamide lactate salt;

Fig. 5A is the XRPD peaks partem of L-dopamide phosphate salt, obtained using the diffractometer specified in Fig. 1A;

Fig. SB is the Ή-NMR plot in intensity vs. ppm of L-dopamide phosphate salt;

Fig. 6A is the XRPD peak pattern of L-dopamide fumarate salt, obtained using the diffractometer specified in Fig. 1A;

Fig. 6B is the 'H-NMR plot in intensity vs. ppm of L-dopamidc fumarate salt; and

Fig. 7 is the XRPD peak pattern of L-dopamide gluceptic acid, obtained using the diffractometer specified in Fig. 1A.

DETAILED DESCRIPTION

[0020] The present disclosure, in an aspect thereof, is directed to salts of levodopa amide derivatives and solvates thereof, which may serve as prodrug of levodopa, especially new crystalline forms thereof. For example, pharmaceutically acceptable salts of crystalline levodopa amide derivatives such as hydrochloric acid, fumarate, lactate, phosphate, and sulfate salts, or solvates thereof, for example, hydrates, are described herein. For example, a hydrate of a hydrochloric acid salt of a levodopa amide derivative and an anhydrous hydrochloric acid salt of levodopa amide derivative are contemplated herein.

[0021] Embodiments of the present disclosure concern salts of the levodopa amide compound propanamide, herein interchangeably referred to as "L-dopamide" or "LDA". The terms "L-dopamide salt" and "LDA salt" are interchangeably used herein to denote a salt of 2-amino-3-(3,4-dihydroxyphenyl) propanamide.

[0022] For example, provided here is a discovery of new crystalline forms of a pharmaceutically acceptable salt of the LDA compound or a solvated form thereof, represented by:

wherein

Y is a solvent;

m is a fractional or whole number between about 0 and about 3 inclusive; and X is a compound or a counter ion that forms a salt with LDA, for example, an L- dopamide acid addition salt. X is further referred to herein as "salt former" or "acid salt former".

[0023] The term" solvate" as used herein, refers to an aggregate or a complex that consists of a solute ion or molecule associated with one or more solvent molecules. When the solvent molecules are water, the solvate is also referred to herein as "hydrate".

[0024] A "non-solvate" or "non-solvated compound" is a solute ion or molecule substantially free of solvent molecules. For example, a solute substantially free of water molecule is referred to as "anhydrate". [0025] The indicator "m" represents the amount of solvent relative to LDA in the solvate, for example, the number of moles of solvent associated with 1 mole of LDA, or number of solvent molecules associated with one LDA molecule, or weight percent of the solvent remains in a LDA solvate.

[0026] In the context of embodiments described herein, a non-solvate is characterized with the indicator m being in the range of from 0.0 to about 0.1, or from 0.00 to about 0.01.

[0027] In some embodiments, Y is selected from, for example, H2O, CH3CH2OH, CH3OH, isopropanol, acetonitrile, tetrahydrofuran (THF), and mixtures thereof, for example, THF/water (50:50 %v/v), THF/water (98:2 %v/v), or MeOH/THF/water.

[0028] The salt former X may be, for example, HQ, acetic acid, ascorbic acid, L-aspartic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, p- toluenesulfonic acid, hippuric acid, formic 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, oxalic acid, phosphoric acid propionic (propanoic) acid, succinic (butanedioic) acid, sulfuric acid acid and xinafoic (l-hydroxy-2- naphthoic) acid. The salt former X may also be a base such as, but not limited to, L-arginine and L-histidine.

[0029] In some exemplary embodiments, X is an acidic salt former, for example, selected from the group consisting of

(lactic acid), (maleic acid) and

acid).

[0030] Solvates (e.g., hydrates) and non-solvates (e.g., anhydrates) crystalline forms of LDA are contemplated herein. For example, in some embodiments, m is 0, in other embodiments m is about 1, in still other embodiments m is from about 1.2 to about 1.5, and in yet other embodiments m is about 1.6. For example, X may be HC1 and m is 0, or X may be HC1 and Y may be H2O and m is, for example, about 1.6. [0031] In some embodiments, X is selected from the group consisting of H3PO4, CH3CH(OH)CC>OH and H(¼CCH=CHC02H. In some embodiments, X is selected from the group consisting of H3PO4, CI¾CH(OH)CC)OH and H(¼CCH=CHC02H, and m is 0.

[0032] In some embodiments, X is H02CCH=CHC02H and Y is CH3CH2OH. In some embodiments, X is H(¼CCH=CHC0 ₂ H and Y is CH ₃ CH ₂ OH, and m is from about 1.2 to about l.S. Alternatively, for example, X is H2SO4 and m is about 1.

[0033] The LDA salts contemplated herein may be pharmaceutically acceptable salts as defined herein, for example, hydrated or anhydrous pharmaceutically acceptable hydrochloric acid, fumaric acid, lactic acid, phosphoric acid, and sulfuric acid LDA salt. In exemplary embodiments, a hydrochloric acid salt of L-dopamide or an anhydrous hydrochloric acid salt of L-dopamide is contemplated.

[0034] The LDA salt and solvates thereof described herein may be crystalline or noncrystalline.

[0035] 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. The unit cells are stacked in three-dimensional space to form the crystal.

[0036] 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. The different polymorphs are usually referred to as different phases. Depending on the conditions, a single fluid can solidify into many different possible forms. 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.

[0037] A crystalline substance may differ considerably from an amorphous form, and different crystal modifications of a substance, i.e., different polymorphs may differ considerably from one another in many respects including solubility, dissolution rate and/or bioavailability. 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.

[0038] 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.

[0039] 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 2Θ away from the source path. The incident angle is than increased over time while the detector angle always remains 2Θ above the source path. The diffraction peak position is recorded as the detector angle, 2Θ. For typical powder patterns, data is collected at degree 2Θ ranging from about 5° to about 70°, and these varying angles are preset in the X-ray diffraction scan.

[0040] 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 Ka emitted X-ray radiation, and/or K shell may be filled by electrons from M (n = 3) shell, thus producing Kp 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 Θ limits generates an X-ray scan.

[0041] 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.

[0042] Described crystalline forms have X-ray powder diffraction (XRPD) pattern that may be obtained using Cu Ka radiation. Copper is the common target material for powder X-ray diffraction, with The term "about" in this context of XRPD means that there is an uncertainty in the measurements of the 2Θ of ± 0.S (expressed in 2Θ) or that there is an uncertainty in the measurements of the 2Θ of ±0.2 (expressed in 2Θ).

[0043] Embodiments described herein provide a crystalline form of a pharmaceutically acceptable salt solvate of LDA, for example, a crystalline form of a hydrate of hydrochloric acid salt of LDA (hydrated LDA HC1 salt). In exemplary embodiments, the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 10.0, about 23.8 and about 31.S. In particular embodiments, the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 1 A and/or the of Figure IB.

[0044] The X-ray diffraction peak pattern presented in Figure 2A is termed herein "Pattern A". A crystalline characterized by or exhibiting peak Pattern A is designated herein "crystalline form A". [0045] Tn further exemplary embodiments, a crystalline form of anhydrous hydrochloric acid salt of IDA is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 20.9. about 24.0. about 28.S and about 30.5. Tn exemplary embodiments, the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 2A and/or the Ή-NMR of Figure 2B.

[0046] The X-ray diffraction peak pattern presented in Figure 1A is termed herein "Pattern B". A crystalline characterized by or exhibiting peak Pattern B is designated herein "crystalline form B".

[0047] Tn some embodiments, a crystalline form of a fumaric acid salt of LDA is provided, wherein the crystalline form of the fumarate salt of LDA is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 5.6, about 15.0, about 17.0' and about 24.8. Tn exemplary embodiments, the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 6A and/or the Ή-NMR of Figure 6B.

100481 In some embodiments, a crystalline form of a lactate salt of LDA is provided, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 8.2 about 11.0, about 18.5, about 20.0 and about 29.0. In exemplary embodiments, the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 4A and/or the Ή-ΝΜΚ of Figure 4B.

[0049] In some embodiments, a crystalline form of a phosphate salt of LDA is provided, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2Θ at about 11.0, about 18.6, at about 18.9 and about 25.5. In exemplary embodiments, the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 5A and/or the ¹ H-NMR of Figure 5B.

[0050] Tn some embodiments, a crystalline form of a sulfate salt of LDA is provided, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 16.5, about 23.5, about 25.0, at about 29, and about 31.0. In exemplary embodiments, the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 3 A and/or the ' H-NMR of Figure 3B. [0051 ] In some embodiments, a disclosed 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 about 1%, between about 0.01% and 10%, or between about 0.01% and 1%, in content, of crystalline free base form of L-dopamide (herein designated "LDA FB").

[0052] Embodiments described herein concern LDA salt such as LDA HQ salt, optionally in their pure crystalline form. In some embodiments the LDA salts are substantially pure products, for example, substantially pure crystalline products.

[0053] A "pure product", as referred to herein, is a chemical entity or species produced or formed, e.g., in a chemical process or reaction, comprising, besides molecules of the principle compound, further 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, metal atoms, and polymorphs. Voids in a crystalline product are also referred to herein as impurities. Impurities can be incorporated into solid products, for example, crystals, in a number of ways. For example, surface impurities are left when residual mother liquor on the surface of the solid product evaporates, leaving behind any dissolved impurities. Inclusions of mother liquor may be formed in crystals, especially at high growth rates.

[0054] A pure product in the context of some embodiments described herein is, for example, a pharmaceutically acceptable LDA salt, also referred to herein as "active pharmaceutical ingredient" or "ΑΡΓ', produced or made by a disclosed process, for example, a crystallization process, which contains, besides the principle API molecules, small amounts of impurities as defined herein, particularly, but not exclusively, remains of L-dopamide free base, L-dopa and/or L-dopa salt, reaction solvent, anion and/or cations e.g., of salts or buffers used in the crystallization process. Herein, a "small amount" of impurities is defined as a total amount of impurities which is less than 10% of total product, namely of total content or total composition of the product.

[0055] Thus, a pure product according to embodiments described herein, is a pharmaceutically acceptable LDA salt product and/or a solvate thereof, for example, crystalline LDA HC1 salt, containing less than 10% of impurities as defined herein. For example, the amount of impurities in a product obtained from a contemplated purification process and/or production process may be less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% of total product.

[0056] For example, a pure pharmaceutically acceptable pharmaceutically acceptable LDA salt or a solvate thereof may comprise residual amounts of LDA free base, L-dopa (LD) and/or a L-dopa salt (LD salt) in total amounts of from about 1% to about 10%, for example, from about 1% to about 2%, from about 2% to about 4%, from about 3% to about 5%, from about 5% to about 10%, or from about 8% to about 10%, of total product, and any ranges, subranges or individual values therebetween.

[0057] In exemplary embodiments, a pure pharmaceutically acceptable LDA salt, for example, a hydrated LDA HC1 salt or an anhydrous LDA HQ salt, may contain less than less than 10%, less than 8%, less than 5%, or less than 3%, of LDA free base, LD and/or a LD salt.

[0058] A "substantially pure product", as referred to herein, is a chemical product as defined herein comprising, besides molecules of API, trace amounts of impurities as defined herein. A "trace amount", as referred to herein, is a very small, a tiny or even scarcely detectable amount. Impurities, including trace amounts of impurities, are usually detected and optionally cleared 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.

[0059] In some embodiments, purity of a disclosed LDA salt 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 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%, of the crystalline.

[0060] For example, a contemplated substantially pure crystalline pharmaceutically acceptable LDA salt 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.

[0061] In some embodiments, a disclosed substantially pure crystalline LDA salt may have some LD and/or LD 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% LD and/or LD salt, wherein such levels can be characterized by HPLC.

[0062] In some exemplary embodiments, a substantially pure crystalline LDA salt has about 0.3% LD and/or LD salt by HPLC (namely assessed or detennined by HPLC).

[0063] In some embodiments, a disclosed substantially pure crystalline LDA salt may have some L-dopamide 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% crystalline free base form of L-dopamide by HPLC.

[0064] In some exemplary embodiments, a substantially pure crystalline LDA salt has from about 0.3% to about 2.5% crystalline free base form of L-dopamide.

[0065] Crystals of L-dopamide salts and/or hydrates may be obtained using any one or more crystallization techniques known in the art. Non-limiting examples of commonly used techniques include solvent evaporation, slow cooling of the solution, solvent/non-solvent diffusion, vapour diffusion or vapour stress, sublimation, sonication, slurry formation, and the melt-cool technique. The choice of technique may be dictated, for example, by the amount of sample, stability of the crystalline product and reagents availability. Some of the crystallization techniques are further described and exemplified in Example 1 herein. [0066] In some embodiments, a contemplated crystalline LDA salt is obtained by the solvent evaporation technique, which is the simplest technique for air stable samples. A near saturated solution is prepared in a suitable solvent. The sample can then be left in a sample vial or a crystallization dish that has a perforated cap/cover, wherein the size of the perforations depends to some extent on the volatility of the sample. When the solvent is completely evaporated, the crystals may be collected.

[0067] In some embodiments, a contemplated crystalline LDA salt is obtained by the slow cooling technique. This technique is suitable for less soluble solute-solvent systems where the boiling point of the solvent is in the range of 30 - 90 °C. A saturated solution is prepared where the solvent is heated to just below the boiling point for, e.g., an hour, and then allowed to cool, for example to room temperature. Solids formed after few days may then be collected.

[0068] Alternative methods of cooling are flash cooling which involves (partial) evaporation of the solvent or direct cooling via insertion of a cold gas or coolant.

[0069] In some embodiments, a contemplated crystalline LDA salt is obtained by melt crystallization technique, also referred to herein as "melt-cool" technique. This technique can be regarded as a special form of cooling crystallization process, the main difference being the absence of solvents, which implies that most melt crystallization processes are operated close to the melting point of the pure product. The feed (initial product) for a melt crystallization process is an impure melt. Cooling this melt below the equilibrium temperature will typically result in the formation of a solid phase that is purer than the feed, while the impurities prefer to stay in the impure mother liquor.

[0070] In some embodiments, a contemplated crystalline LDA salt is obtained by the solvent diffusion technique, particularly suitable for microgram quantities of sample that are air and/or solvent sensitive. A solution is placed in a sample tube, then a second less dense solvent is carefully dripped down the side of the tube using either a pipette or a syringe to form a discreet layer. Crystals form at the boundary where the solvents slowly diffuse.

[0071] In some embodiments, a contemplated crystalline LDA salt is obtained by sonication. Sonication also known as sonocrystallization is the application of ultrasound insonation to initiate and enhance the crystallization process. The main attributes of the sonocrystallization process are fast nucleation rate, promoting nucleation at low supersaturation levels, and yielding fine crystals with a narrow crystal size distribution.

[0072] The term "pharmaceutically acceptable salt", as used herein, refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure, which do not produce an adverse, allergic or other untoward reaction and is compatible with pharmaceutical administration. As is known to those of skill in the art, "salts" of the compounds of the present disclosure may be derived from inorganic or organic acids and bases.

[0073] The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, bitartrate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, flucoheptanoate, gentisinate, gluconate, glucaronate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, isonicotinate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, picrate, pivalate, propionate, saccharate, salicylate, succinate, sulfate, tannate, tartrate, thiocyanate, tosylate, undecanoate, and the like. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group such as in L-dopa. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

Drug substances

[0074] 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 salt of the disclosure or a solvate thereof, for example, in its crystalline form. [0075] 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.

[0076] In some embodiments, a drug substance comprises substantially pure crystalline form of an LDA salt of the disclosure, for example crystalline form A and/or crystalline form B as defined herein.

Pharmaceutical composition and Formulations

[0077] In still a further aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable LDA salt and a pharmaceutically acceptable excipient. In some embodiments, the composition is a formulation for pharmaceutical administration and comprises a pharmaceutically acceptable carrier.

[0078] 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". [0079] Some embodiments described herein pertain to liquid pharmaceutical compositions, for example aqueous formulations.

[0080] In some embodiments, a contemplated pharmaceutical composition, e.g., formulation, is a suspension.

[0081] 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 one or more of a LDA salt as defined herein, for example, at least one of the pure crystalline pharmaceutically acceptable LDA salt.

[0082] 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).

[0083] Contemplated pharmaceutical compositions may include from 1% to about 25%, or more of a disclosed LDA salt. For example, a disclosed formulation may comprise, pure or substantially pure crystalline pharmaceutically acceptable LDA salt 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. [0084] 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 pharmaceutically acceptable LD A HC1 salt in their crystalline form.

[0085] A contemplated pharmaceutical composition may, optionally, further comprise one or more physiologically acceptable excipients and/or a physiologically acceptable carrier.

[0086] 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.

[0087] 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).

[0088] 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.

[0089] 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).

[0090] When a contemplated medicinal formulation comprises a pure pharmaceutically acceptable LDA salt 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.

[0091] 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).

[0092] Further antioxidants are exemplified by phenolic antioxidants such as di-tert-butyl methyl phenols, terr-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).

[0093] 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.

[0094] 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.

[0095] 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, galactos amine or a combination thereof.

[0096] 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).

[0097] 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. [0098] 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.

[0099] Also contemplated herein is a stable lyophilized powder comprising a LDA salt described herein. Such a lyophilized powder can be reconstituted into a liquid formulation by addition of water with or without antioxidants, surfactants and other excipients.

[0100] 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 salt 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.

[0101] 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.

[0102] In embodiments described herein, the pharmaceutical compositions disclosed are aqueous formulations particularly useful for subcutaneous administration e.g., via an infusion pump. [0103] 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.

[0104] 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.

[010S] In some embodiments, a contemplated formulation is designed for administration via a dermal patch suitable for transdermal or subcutaneous administration of an active agent.

[0106] 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.

[0107] In some embodiments, a pharmaceutical composition as disclosed herein is designed for a slow release of the pharmaceutically acceptable LDA salt, 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. [0108] All compositions for any form of administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0109] 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 SO 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.

[0110] According to the present disclosure, the pharmaceutical compositions can be administered over a defined time period, e.g., days, weeks, months, or years.

[0111] 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).

[0112] "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 2S°C.

Methods of treatment

[0113] 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 herein, thereby threating the subject.

[0114] 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.

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

[0116] 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.

[0117] 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.

[0118] 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 salt or described herein.

[0119] 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 salt.

[0120] ''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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] In some embodiments, a disclosed method features subcutaneous and substantially continuous administration of a disclosed pharmaceutical. [0125] 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, IS hours, 18 hours, 21 hours, 24 hours, 12 to 16 hours, 16 to 18 hours, 18 to 20 hours, or 20 to 24 hours.

[0126] 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.

[0127] 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.S ml/hour, respectively, at rest or at night.

[0128] 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 uL/hour to about 1000 μΧ/hour, 300 ± 100 μL/hour, or 200 ± 40 uL/hour continuously for 24 hours; 440 ± 200 μ-Jhour or 200 ± 50 μL/hour continuously for 16 hours (during waking hours) and from 0 to about 80 μΧ/hour or 0 to 200 uL/hour for 8 hours (at night).

[0129] 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 pL/hour, or 1 ± 0.S pL/hour continuously for 24 hours; 1 ± 0.S μΙΤηοιιτ continuously for 16 hours (during waking hours) and from 0 to about 0.S μ-Jhour 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.

[0130] In some embodiments, administration includes acute and immediate administration such as inhalation or injection.

[0131] In some embodiments, the formulation administered according to a contemplated method may comprise one or more pharmaceutically acceptable LDA salt or LDA free base obtained by a process described herein 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.

[0132] 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 salts or LDA free base obtained by the processes described herein, 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.

[0133] 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., pure pharmaceutically acceptable LDA salts 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.

[0134] 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. [013S] Two or more dosage unit forms may be administered to a subject at the same rate, or at different rates.

Kits

[0136] In an aspect of the present disclosure, there is provided a kit comprising a LDA salt, 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.

[0137] In some embodiments, the kit comprises a first pharmaceutical composition comprising one or more pure pharmaceutically acceptable LDA salts 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.

[0138] 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.

[0139] 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.

[0140] As used herein the term "about" refers to ± 10 %.

[0141] The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to". [0142] 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.

[0143] 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.

[0144] 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

[014S] 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 disclosed inventions.

Materials and Methods

L-dopamide acid addition salts formation

(i) Preparation of L-dopamide free base stock solutions

[0146] L-dopamide free base (1962 mg) was added to a 25 mL volumetric flask and a THF/water (50:50 %v/v) mixture was added. The mixture was sonicated for 10 minutes before being made to volume. The suspension was stirred at -45 °C for 10 minutes before being sonicated again for a further 5 minutes, at which point dissolution was observed to afford a 0.4 M solution. (ii) Salt formation

[0147] An acid or base used for LDA salt formation is referred to herein as "salt former".

[0148] Experiments were carried out at a scale of -20 mg and mostly with 1 : 1 stoichiometry for LDA:salt former, except for some few occasions wherein experiments were set up with 2: 1 or 1 :2 stoichiometry. Experiments were carried out by adding solutions of LDA free base (FB) in the chosen solvent or neat free base to either solutions of the salt former or neat salt former.

[0149] The aqueous or methanol (MeOH) acid solutions of salts formers were prepared as described in Table 1.

Table 1. Acids stock solutions

Therefore 2.5 mL and 1.5 mL of these solutions were added to experiments. (Hi) Solubility estimation

[0150] Aliquots of the test solvent (water, typically ,10 uL) were added to an accurately weighed sample of L-dopamide or a salt thereof (-10 mg) at ambient temperature. Complete dissolution of the test material was determined by visual and infrared (IR) inspection. Dissolution and precipitation events were recorded as the point of complete transmission of IR and the onset of turbidity by IR, respectively. The solubility was estimated from these experiments based on the total solvent used to provide complete dissolution. The solubility values for LDA and salts thereof were expressed as a range and rounded to the nearest whole number.

[0151] 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: heat from 20 °C to within 3 °C of solvent boiling point (or 100°C, whichever was lower) at 0.S °C/minute; cooling to 20 °C at 0.2 °C/minute; stirring at speed 400 rpm.

Crystallization (solid L-dopamide salt formation) methods

(i) Slow evaporation

[01S2] A solution of the salt former (-1 M, -100-10μ2L, 1 mol. eq.) or neat salt former (1 mol. eq.) and LDA in THF/water (50:50 %v/v, 0.4 M, 253 μL·, 1 mol. eq.) were added to a clean HPLC vial and mixed on a vortex stirrer. Where neat acid was used and the acid did not dissolve in THF/water (50:50 %v/v), known volumes of water were added to aid dissolution. The solutions were evaporated, and any solids present were isolated and analyzed by X-ray powder diffraction (XRPD). Oils or waxes which were generated were used for further experiments.

[0153] Samples which remained as solutions were evaporated to approximately half volume and allowed to stir for 3 days at ambient temperature. Any solids were collected by centrifugation, solvent decanted and the solids were dried with thin strips of filter paper prior to analysis by XRPD.

(iii) Slurry experiments

[0154] A solution of the salt former (-1 M, -100-102 μL, 1 mol. eq.) or neat salt former (1 mol. eq.) and LDA in THF/water (50:50 %v/v, 0.4 M, 253 μL·, 1 mol. eq.) were added to a clean HFLC vial and evaporated to dryness. Methanol (2 volumes) was added to the solids and the mixtures were slurred for 5 days at 40 °C. Any solids present were collected by centrifugation, solvent was decanted and the solids were dried with thin strips of filter paper prior to analysis by XRPD.

[0155] Where no solids precipitated, methyl terf-butyl ether (MTBE) (4 volumes) was added and the mixture was stirred for 90 minutes at 40 °C (-400 rpm) before the heat was switched off. Any solids present were collected by centrifugation, solvent decanted and the solids were dried as described above prior to analysis by XRPD. Oils or waxes which were isolated were used for further experiments.

[0156] When a stoichiometry of 2:1 LDA:salt former or 1:2 LDA:salt former was set up, a solution of the salt former (-1 M, -51-204 μL, 0.5-2 mol. eq.) or neat salt former (0.5-2 mol. eq.) was added to a clean HPLC vial and evaporated (where required) to dryness (under vacuum). L-dopamide (-20 mg, 1 mol. eq.) was added to each vial with ethanol (5 volumes) and slurred at -60 °C for 4 days, before being cooled to ambient temperature. Any solids present were isolated and analyzed by XRPD as described above.

(iv) Sonication

[01S7] Solutions or pastes of L-dopamide and salt former were subjected to a pulsed program of sonication at 70% power for 3-4 minutes before being cooled and stored at -5 °C for 1-2 weeks. Any solids present were dried with thin strips of filter paper prior to analysis by XRPD. Oils or waxes which were isolated were used for further experiments.

Humidity Stress

[01S8] There are in general two ways in which salts, once crystallized, can take up water again: by bringing it in contact with liquid water (dissolution) or with water vapor (deliquescence). Because of the hygroscopic properties of salts, deliquescence will occur when the relative humidity (RH) is higher than the equilibrium RH (RHeq) of the salt. For example, RHeq of NaCl is 75% at 21 °C. Known amounts of L-dopamide salts were weighed into a clean HPLC vial of known weight and sealed in a container of saturated NaCl to produce a 75% RH environment. Each container was placed inside an oven at 40°C for a period of 1 week. Any remaining solids were analyzed by XRPD and HPLC at -1 mg/mL.

Analysis techniques

(i) X-ray Powder Diffraction (XRPD)

[0159] X-ray powder diffraction analyses were performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system The isothermal samples were analyzed 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). X-ray powder diffraction patterns were sorted and manipulated using HighScore Plus 2.2c software. (Hi) Thermogravimetric Analysis (TGA)

[0160] Thermogravimetric analyses were carried out on a Mettler Toledo TGA/DSC1 STARe. The calibration standards were indium and tin. Samples were placed in an aluminum sample pan, inserted into the TG furnace and accurately weighed. The heat flow signal was stabilized for one minute at 25 °C, prior to heating to 300 °C in a stream of nitrogen at a rate of 10°C/minute.

(iv) ¹ H Nuclear Magnetic Resonance spectroscopy (NMR)

[0161] NMR analysis was carried out on a Broker 400 MHz or 500 MHz instrument in DMSO.

(v) Optical microscopy

[0162] Microscopy analyses were carried out using an Olympus BX51 stereomicroscope with crossed-polarized 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.

(vi) High Pressure Liquid Chromatography (HPLC)

[0163] The HPLC method used to determine equilibrium solubility of L-dopamide salts at T=0 and T=l week (40°C/75% RH) is outlined in Table 2. The retention time of L-dopamide was typically 6.3±0.1 min. Samples were dissolved in Diluent A.

Table 2. HPLC method for equilibrium solubility analysis of L-dopamide

EXAMPLE 1

Crystalline solid L-dopamide salts screening

[0164] Screening of formation of L-dopamide salts was performed with 27 acids: 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 (1- hydroxy-2-naphthoic) acid; and 2 bases: L-arginine and L-histidine, in three different solvent systems (MeOH:THF:water; THF:water (98:2 %v/v); and ethanol).

[0165] The starting material L-dopamide free base (FB) was a crystalline anhydrate containing residual EtOH (-0.1 mol. eq.). When powdered FB was subjected to X-ray diffraction tests, it exhibited a unique XRPD peaks pattern, herein designated "Pattern A". Briefly, L-dopamide FB was prepared as described in Scheme 1, as follows:

[0166] Levodopa was contacted with a chlorinating mixture comprising n-propanol and thionyl chloride at a temperature of from about -S °C to about 0 °C so as to form L-dopa propyl ester. Crude L-dopa propyl eater was precipitated form a basic solution (pH 8), then dissolved in a mixture of ethyl acetate and BTH and precipitated from this mixture. Amidation of the purified L-dopa propyl ester to obtain L-dopamide free base was conducted in 28% aqueous ammonia, and precipitation of crude L-dopamide was effected from ethanol solution containing an antioxidant (e.g., 0.05%w/vBHT). The crude L-dopamde free base was purified by re-cyrstallization from ethanol solution containing an antioxidant (0.01 % L-ascorbyl palmitate) as a pale yellow solid.

[0167] L-dopamide salts were prepared as described in Materials and Methods. Most experiments were set up as 1:1 LDA:salt former molar ratio. Evaporation, slow cooling, sonication, slurry experiments, and vapour stress were the methods employed for solid salt formation. These methods are described in Material and Methods above.

[0168] The LDA salts were assessed using a number of properties; crystallinity, crystal habit, ease of manufacture, hygroscopicity, aqueous solubility, chemical stability, solvent content and polymorphic complexity. Some of the salt formers yielded oils, gels or solids composed of mixtures of FB and salt former.

[0169] All solids salts obtained were analyzed by XRPD and the resulting peak patterns were compared to those exhibited by the starting material FB. Novel XRPD patterns were assigned an alphabetical descriptor in order of discovery (Salt former Pattern A, Salt former Pattern B, etc.). Further analysis (e.g., NMR or thermogravimetric analyses (TGA)) was conducted on solids with novel XRPD patterns to allow tentative assignment of the novel pattern as a polymorph, solvate, hydrate, degradant or mixture thereof.

[0170] Five exemplary crystalline LDA salts presenting unique XRPD peaks patterns are described herein in details: 2 unique crystals of HQ salts exhibiting two distinct XRPD peak pattern, and a solvated fumarate salt, lactate salt, phosphoric acid salt, and a solvated sulfuric acid salt, all showing one XRPD peak pattern, as summarized in

[0171] Table 3. Table 3. Exemplary crystalline salts ofL-dopamide

(i) L-dopamide HCl salt

[0172] Unique (novel) crystalline solids exhibiting XRPD peaks pattern, herein designated "Salt Pattern B", were isolated from experiments with HQ (for example, using the slow evaporation, slurrying in water and sonication techniques). The XRPD peaks of pattern of Salt Pattern B of L-dopamide HQ salt is shown in Fig. 1A, and the 'H-NMR plot of this crystalline salt is shown in Fig. IB.

[0173] The hydrochloric salt of LDA presenting XRPD Salt Pattern B peaks was a crystalline hydrate containing -1.6 mol. eq. of H2O. The stoichiometry was assumed to be 1:1 LDA:HC1.

[0174] Further unique crystalline HQ salts of LDA exhibiting XRPD peaks pattern herein designated "Salt Pattern A", were isolated from experiments using other crystallization techniques, for example, the slurry technique. The XRPD peaks pattern of Salt Pattern A of L-dopamide HQ salt is shown in Fig. 2A, and the 'H-NMR plot of this crystalline salt is depicted in Fig. 2B.

(ii) L-dopamide sulfuric acid salt

[0175] Unique crystalline solids exhibiting Salt Pattern A XRPD were isolated from experiments with sulfuric acid using, for example, the slow evaporation technique or the sonication technique. The XRPD peaks pattern of Salt Pattern A of L-dopamide sulfate salt is shown in Fig. 3A, and the 'H-NMR plot of this crystalline salt is shown in Fig. 3B. (Hi) L-dopamide lactic acid salt

Unique crystalline solids exhibiting Salt Pattern A XRPD were isolated from experiments with lactic acid using, for example, the slurry technique at 60°C. The XRPD peaks pattern of Salt Pattern A of L-dopamide lactate salt is shown in Fig. 4A, and the 'H-NMR plot of this crystalline salt is shown in Fig. 4B. according to NMR analysis, the stoichiometry LDA:lactate is 1:0.8.

(iv) L-dopamide phosphoric acid salt

[0176] Unique crystalline solids exhibiting Salt Pattern A XRPD peaks were isolated from experiments with phosphoric acid using, for example, the slurry technique at ambient temperature of at 60°C. The XRPD peaks of Salt Pattern A of L-dopamide phosphate salt are in Fig. SA, and the 'H-NMR plot of this crystalline salt is shown in Fig. SB.

[0177] The LDA-phosphate salt was a crystalline anhydrate with assumed stoichiometry of 1:1 LDA:salt former.

(v) L-dopamide fumaric acid salt

[0178] Unique crystalline solids exhibiting Salt Pattern A XRPD were isolated from experiments with fumaric acid using, for example, the slurry technique or sonication technique. The XRPD peaks of Salt Pattern A of L-dopamide fumarate salt are shown in Fig. 6A, and the 'H-NMR plot of this crystalline salt is shown in Fig. 6B. According to NMR analysis, the ratio LDA:fumarate is 1:1.1.

[0179] The LDA fumarate salt was a crystalline EtOH solvate containing -1.2-1.5 mol. eq of EtOH.

(vi) L-dopamide gluceptic acid salt

[0180] Disordered solids were obtained from gluceptic acid sonication and slurry experiments, and XRPD peaks were assigned as free base and extra peaks. The extra peaks matched Salt Pattern A (see Fig. 7). The gluceptic acid salt was hygroscopic.

[0181] In the ¾ NMR spectra of LDA free base, the CH ₂ and CH-NH ₂ proton signals were observed between -2.4-3.2 ppm, and the CH-NH2 peak was observed at -1.6 ppm. In the salts spectra, the CH ₂ and CH-NH ₂ proton signals shifted down field to -2.6-3.6 ppm, and the CH-NH2 peak shifted downfield or disappeared. If a shift in these protons and/or salt former peaks was not observed it was presumed that salt formation had not taken place. ¾ NMR analyses indicated that almost all the isolated solids were salts. Some of the unique solids isolated were assigned by *H NMR as the free base cyclisation product.

EXAMPLE 2

Humidity stress and HPLC analyses

[0182] Stress testing of the LDA crystalline salts helps in identifying the likely degradation products, which, in turn, can help in establishing the degradation pathways and the intrinsic stability of the molecule. Crystalline solids isolated from the salt screen were stressed at 40°C/75% RH, as described in Materials and Methods, for seven days and visually examined for evidence of deliquescence. If solids remained post stressing they were analyzed by XRPD and HPLC, as described in Materials and Methods. The results are shown in Table 4.

Table 4. Humidity stress tests and HPLC results

[0183] As seen in Table 4, for LDA-HCl salt, XRPD peak pattern HC1 Salt Pattern A converted to HQ Salt Pattern B (gained -15% weight), whereas HQ Salt Pattern B remained as HQ Salt Pattern B, indicating that under these conditions LDA hydrochloric salt exhibiting HC1 Salt Pattern B was the most stable HC1 salt of LDA. L-dopamide sulfate exhibiting Sulfate Salt Pattern A XRPD peaks deliquesced and no further analyses was carried out. L-dopamide phosphate exhibiting Salt Pattern A peaks and LDA fumarate salt presenting Salt Pattern A peaks were stable to stressing at 40°C775% RH. L-dopamide lactate salt exhibiting Salt Pattern A XRPD peaks gained - 8% weight after stressing, however XRPD analysis showed no form change had occurred. L-dopamaide gluceptic acid salt presenting Salt Pattern A peaks gained -6% weight post stressing but appeared to have the same form by XRPD analysis (Figure 7). L-dopamide free base exhibiting XRPD peaks of Pattern A was stable to stressing at 40°C/75% RH.

[0184] HPLC analyses showed negligible change for all samples between T = 0 and T = 1 week. L-dopamide phosphate salt showed purity at -98%. Fumarate salt had a lower HPLC purity (-90%), however the actual purity is most likely the same as the other salts and the main impurity observed was due to the salt former fumaric acid being UV visible. Lactate salt was not soluble in the HPLC diluent and therefore was not analyzed by HPLC.

EXAMPLE 3

Solubility and pH of L-dopamide free base and L-dopamide salts in water

[0185] The aqueous kinetic solubilities of L-dopamide FB and L-dopamide salts were tested as described in Materials and Methods. Solution pH was estimated. The results are shown in Table 5.

Table 5. Solubility and solution pH of L-dopamide salts in water

[0186] Most LDA salts showed solubilities of >80 mg/mL. The solubility of LDA free base exhibiting XRPD peaks of Pattern A was substantially lower than that of the salts (<28 mg/mL) except for the solubility of LDA lactate salt.

INCORPORATION BY REFERENCE

[0187] The entire content of all patents, published patent applications, websites, and other references cited herein are hereby expressly incorporated herein in their entireties by reference.