FIELD OF THE INVENTION

[0001] The present invention relates, in part, to processes of purification of a levodopa amide pharmaceutically acceptable salt, and processes of making a substantially purified pharmaceutically acceptable 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 solubility and/or stability of the drug. For example, mixtures of various impure levodopa amide (L-dopamide) 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. Amides are known as much more stable molecules than esters and salts, and the hydrolysis rate of amides by amido peptidases is significantly reduced as compared with the corresponding hydrolysis of ester or salts. Efficient processes for preparing pure L-dopamide and pharmaceutically acceptable salts thereof are desirable for providing Parkinson's disease patients with more effective treatments.

SUMMARY

[0007] The present disclosure provides, in part, processes of purification (e.g., large scale purification) of a L-dopamide pharmaceutically acceptable salt, processes of making a purified pharmaceutically acceptable L-dopamide free base substantially free of L-dopa, and processes of preparing a purified L-dopamide hydrochloride salt. The processes of the present disclosure may not require, for example, chromatographic purification to remove L- dopa and/or a L-dopa salt from a pharmaceutically acceptable L-dopamide salt or L- dopamide free base. [0008] The purified products obtained by any of the disclosed processes are useful for the preparation of drug substances and pharmaceutical compositions. These purified products may be, for example, in their crystalline form.

[0009] 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.

DETAILED DESCRIPTION

[0010] The present disclosure provides, in part, a process of purification, for example, large scale purification, of a L-dopamide pharmaceutically acceptable salt, and a process of preparing a substantially purified pharmaceutically acceptable L-dopamide free base.

[0011] The processes disclosed herein are, in part, based on the discovery that L-dopamide free base that is substantially free of L-dopa may be obtained by purifying a crude L- dopamide salt product by precipitation (e.g., one or two subsequent precipitations) from an acidic solution at a certain pH, and then neutralizing the purified L-dopamide salt.

[0012] The term "levodopa amide" is used herein interchangeably with the terms "L- dopamide", "LDA", "L-dopamide free base", "LDA free base" or, simply, "LDA FB", all of which terms refer to the chemical compound, L-2-amino-3-(3,4-dihydroxyphenyl) propanamide, represented by:

[0013] Salts of L-dopamide, for example, pharmaceutically acceptable salts or pharmaceutical salts are collectively and interchangeably referred to herein as "L-dopamide pharmaceutically acceptable salts", "pharmaceutically acceptable L-dopa salts", "LDA pharmaceutically acceptable salts", pharmaceutically acceptable LDA salt or, simply, "LDA salts". Particular examples include, LDA HC1 salt, LDA lactate salt, LDA phosphate salt, LDA acetate salt, and the like.

[0014] L-dopamide is derived from levodopa also interchangeably referred to herein as "L- dopa" or "LD", or from a levodopa salt (LD salt). In some embodiments, LDA or LDA salt are useful as prodrugs of L-dopa. L-dopa is represented by the formula:

[0015] Embodiments described herein concern processes for making or producing LDA FB and/or a LDA salt such as LDA HC1 salt, and processes for purification of crude LDA FB and/or a crude LDA salt, optionally in their crystalline form. In some embodiments the LDA FB and/or LDA salts obtained by disclosed production and purification processes are substantially pure products, for example, substantially pure crystalline products.

[0016] 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.

[0017] A pure product, in the context of some embodiments described herein, is a chemical product obtained by any of the processes contemplated herein, for example, LDA free base and/or a pharmaceutically acceptable LDA salt, collectively referred to herein as "active pharmaceutical ingredients" or "APIs", produced or made by a disclosed process, for example, purification process, which contains, besides the principle API molecules, small amounts of impurities as defined herein, particularly, but not exclusively, remains of LDA salts, L-dopa and/or L-dopa salt, reaction solvent, anion and/or cations e.g., of salts or buffers used in the purification process. Herein, a "small amount" of impurities is defined as a total amount of impurities which is less than 10% of total content or total composition of the product.

[0018] Thus, a pure product according to embodiments described herein, is LDA FB or LDA salt product, for example, crystalline LDA FB and/or LDA HC1 salt, containing less than 10% 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.

[0019] For example, a pure product obtained by a contemplated process may comprise residual amounts of L-dopa and/or a salt thereof in total amounts of from about 3% to about 10%, from about 3% to about 10%, from about 3% to about 5%, or from about 8% to about 10%, of total product, and any ranges, subranges or individual values therebetween.

[0020] For example, a pure pharmaceutically acceptable LDA free base or a pure pharmaceutically acceptable LDA salt may contain less than 10%, less than 8%, less than 5%, or less than 3%, of LD or a LD salt.

[0021] 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.

[0022] A substantially pure LDA FB or LDA salt, in accordance with embodiments described herein, will typically contain trace amounts of impurities in a total amount which is less than 5.0% of total composition of the product. For example, the amount of impurities may be less than 5.0%, 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% or less than 0.01%, of total product.

[0023] A contemplated substantially pure LDA FB or LDA salt may comprise, for example, between 0.00% to about 0.03%, between 0.00% to about 0.01%, of impurities in total product or total substance.

[0024] In some embodiments, a substantially pure product is essentially devoid or free of any impurities.

[0025] In some embodiments, a disclosed substantially pure LDA free base or LDA salt 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, assessed, for example, by HPLC or any other known means.

[0026] Substantially pure LDA FB obtained by a contemplated process is also referred to herein as "pharmaceutically acceptable L-dopamide free base substantially free of L-dopa or a salt thereof or "LDA free base substantially free of L-dopa and/or L-dopa salt". Substantially pure LDA salt obtained by a contemplated process is also referred to herein as "pharmaceutically acceptable L-dopamide salt substantially free of L-dopa or a salt thereof or "LDA salt substantially free of L-dopa and/or L-dopa salt". In exemplary embodiments, a pharmaceutically acceptable LDA salt substantially free of L-dopa and/or a salt thereof is a substantially pure LDA HC1 salt.

Purification of a L-dopamide pharmaceutically acceptable salt (LDA salt)

[0027] The present disclosure, in an aspect thereof, provides a process of purification of a crude L-dopamide salt. For example, a large-scale purification process. Such a purification process is effective in providing, e.g., substantially pure L-dopamide pharmaceutically acceptable salt (LDA salt). [0028] In some embodiments, a process for purification of a crude LDA salt is provided, comprising the following steps:

(a) providing a first crude LDA salt product comprising: a LDA salt, L-dopa (LD), and/or a L-dopa salt (LD salt);

(b) contacting the first crude LDA salt product with a first acid composition, thereby obtaining a first acidic solution comprising LDA salt, LD, and/or a LD salt;

(c) precipitating the LDA salt from the first acidic solution, thereby obtaining a second crude LDA salt product comprising a LDA salt, LD, and/or a LD salt;

(d) contacting the second crude LDA salt product with a second acid composition, thereby obtaining a second acidic solution comprising a LDA salt, LD, and/or a LD salt; and

(e) re-precipitating the LDA salt from the second acidic solution, thereby obtaining the purified L-dopamide pharmaceutically acceptable salt.

[0029] In some embodiments, the pH of the first and/or second acidic solution is between about 2.0 and about 3.0. In exemplary embodiments, the pH of the first and/or second acidic solution is from about 2.5 to about 2.7 at 25 °C.

[0030] In some embodiments, the first and second acid are the same. For example, the first and second acid is hydrochloric acid (HC1).

[0031] In exemplary embodiments, the first or the second acid is HC1.

[0032] The purity of a pharmaceutically acceptable LDA salt and/or pharmaceutical acceptable LDA free base may be above 80%. For example, above 87%, above 88%, above 90%, above 92%, above 94%, above 95%, above 96%, above 97%, above 98%, above 99%, or higher.

[0033] In certain embodiments, the purity of the purified LDA salt is above 99% by HPLC.

[0034] The term "by HPLC" as used herein refers to identification and quantification of a product (e.g., LDA free base or LDA salt) obtained by HPLC.

[0035] In exemplary embodiments, the described process reduces the content of LD and/or LD salt in the purified LDA pharmaceutically acceptable salt, such that the content of LD and/or LD salt in the purified LDA salt is less than about 0.5% by HPLC, for example, less than about 0.3% by HPLC.

[0036] Purification in accordance with processes described herein is mainly effected by crystallization, particularly repeating crystallization cycles, each time with a fresh crystallization medium. Prior to crystallization, the liquid reaction mixture is often contacted with activated carbon. Activated carbon, also called activated charcoal, is charcoal that has been treated with oxygen to open up millions of tiny pores between the carbon atoms. A contemplated process employs a carbon filtering method that uses a bed of activated carbon to remove contaminants and impurities. Each particle/granule of carbon provides a large surface area/pore structure, allowing contaminants the maximum possible exposure to the active sites within the filter media. Activated carbon works via a process called adsorption, whereby pollutant molecules in the fluid to be treated are trapped inside the pore structure of the carbon substrate. Active charcoal carbon filters are most effective at removing chlorine, sediments, and volatile organic compounds (VOCs). Activated carbon is particularly useful is large-scale processes as described herein to purify reaction solutions containing unwanted impurities. The carbon may either be mixed with the solution then filtered off or immobilized in a filter.

[0037] In some embodiments, the purified LDA salt is L-dopamide hydrochloride salt (LDA HC1 salt).

[0038] Also provided herein is a process of large scale purification of a L-dopamide pharmaceutically acceptable salt.

[0039] In some embodiments, a large-scale process for the production of purified pharmaceutically acceptable L-dopamide salt comprises the following steps:

(a) providing a crude L-dopamide salt product comprising: a L-dopamide salt, (LDA salt), L-dopa (LD), and/or a L-dopa salt (LD salt);

(b) contacting the crude L-dopamide salt product with an acid composition, thereby obtaining an acidic solution comprising: LDA salt, LD, and/or a LD salt; and

(c) precipitating the LDA salt from the acidic solution, thereby obtaining the purified L-dopamide pharmaceutically acceptable salt. [0040] In some embodiments, the purity of the purified LDA pharmaceutically acceptable salt is above 98% by HPLC.

[0041] In exemplary embodiments, the content of LD and/or a LD salt in the purified LDA pharmaceutically acceptable salt is less than about 1.0% by HPLC.

[0042] In some embodiments, the purified LDA pharmaceutically acceptable salt is L- dopamide hydrochloride salt (LDA HC1 salt).

Processes for obtaining purified L-dopamide hydrochloride salt (LDA HC1)

[0043] In an aspect of the present disclosure, there is provided a process of preparing a purified L-dopamide hydrochloride salt comprising the steps of:

(a) reacting L-dopa (LD) with a chlorinating reagent and an alcohol, R-OH, thereby obtaining a L-dopa ester hydrochloride salt, wherein the L-dopa ester (LD-OR) is a chemical compound, L-3,4-dihydroxy-phenylalanine methyl ester represented by:

wherein R is selected from a lower alkyl, lower alkenyl, alkynyl, aryl or heteroaryl;

(b) reacting the LD-OR hydrochloride salt (LD-OR HC1 salt) with a composition comprising ammonia, thereby obtaining a first crude L-dopamide hydrochloride salt product comprising: L-dopamide hydrochloride salt (LDA HC1 salt), LD, and/or L-dopa hydrochloride salt (LD HC1 salt);

(c) contacting the first crude L-dopamide hydrochloride salt product with a first hydrochloric acid composition, thereby obtaining a first acidic solution comprising: LDA HC1 salt, LD, and/or LD HC1 salt;

(d) precipitating the L-dopamide hydrochloride salt from the first acidic solution, thereby obtaining a second crude L-dopamide hydrochloride salt product comprising: LDA HC1 salt, LD, and/or LD HC1 salt;

(e) contacting the second crude L-dopamide hydrochloride salt with a second hydrochloric acid composition, thereby obtaining a second acidic solution comprising: LDA HC1 salt, LD, and/or LD HC1 salt; and (f) re -precipitating the L-dopamide hydrochloride salt from the second acidic solution, thereby obtaining the purified LDA HC1 salt.

[0044] The alcohol, R-OH, with which LD is reacted in step (a) of the disclosed process, may be, for example, an alcohol of a lower alkyl, namely a straight or branched chain of 1 to 6 carbon atoms (herein "(Ci-C6)alkyl"); or an alcohol of a lower alkenyl or a lower alkynyl, namely a straight or branched chain of 2 to 6 carbon atoms having at least one carbon-carbon double bond, or at least one carbon-carbon triple bond, respectively (herein "(C2-C6)alkenyl" and "(C2-C6)alkynyl", respectively). Optionally any of the lower alkyl, alkenyl or alkenyl moieties may be substituted by at least one substituent. Alternatively, R- OH may be an alcohol of a saturated or partially saturated cyclic moiety of 3 to 6 carbon atoms. For example, R may be cyclopropyl, cyclobutyl, cyclohexyl, cyclobutenyl, cyclohexenyl and the like. R may also be a cyclic non-saturated (i.e., aromatic moiety of 5- 6 carbons (herein "aryl") such as phenyl. Additionally or alternatively, R may be a heterocyclic moiety of 5-6 carbons and at least one heteroatom such as N, S, O or P (herein "heteroaryl"). Optionally, any of the cyclic moieties, whether saturated, partially saturated or aromatic may be substituted by at least one substituent.

[0045] For example, the alcohol R-OH may be an alcohol of a lower alkyl selected from methyl, ethyl, propyl (e.g., isopropyl), butyl (e,g., «-buthyl, teri-butyl, sec-buthyl), heptyl or hexyl.

[0046] In exemplary embodiments, the alcohol is methanol, and the L-dopa ester obtained is LD methyl ester (LD-OMe).

[0047] "Chlorination" as used herein, refers to replacement, in molecules bearing functional groups, such as alcohols, carboxylic acids, of an OH group with CI by the use of a chlorination reagent, to thereby obtain the corresponding chlorides. Carboxylic acid chlorides (also termed acyl chlorides) may be converted, for example, to the corresponding esters by reaction with an alcohol or alkoxide. Non-limiting examples of chlorination reagents useful for a process described herein include thionyl chloride (SOCk), gaseous HC1, osoxalyl chloride (C2O2CI2), phosphoryl chloride (POCI3), phosphorus trichloride (PCb), phosphorus pentachloride (PCI5), sulfuryl chloride (SO2CI2) and other chlorinating reagents commonly known in the art for chlorination. [0048] In exemplary embodiments, the chlorinating reagent is thionyl chloride. In some embodiments, the chlorinating reagent is HC1 gas.

[0049] Two standard methods for converting amino acid esters to amino acid amides are known, namely treatment with ammonia in alcohol (typically methanol) or other organic solvent, or, alternatively, with ammonium hydroxide in water. In some embodiments, the ammonia with which LD-OR is reacted in step (b) of a disclosed process, is aqueous ammonium hydroxide, for example, from about 10% to about 40% aqueous ammonium hydroxide, or about 25% ammonium hydroxide in water. In some embodiments, the ammonia is step (b) is ammonia in, for example, methanol, tetrahydrofuran (THF), or CH2CI2.

[0050] In some embodiments, the pH of the first and/or second acidic solution is between about 2.0 and about 3.0. In exemplary embodiments, the pH of the first and/or second acidic solution is from about 2.5 to about 2.7 at 25°C.

[0051] In certain embodiments, the purity of the purified LDA HC1 is above 99% by HPLC.

[0052] In certain embodiments, the process reduces the content of LD and/or LD HC1 in the purified LDA HC1 salt, such that the content of LD and/or LD HC1 in the purified LDA HC1 salt is less than about 0.5% by HPLC, for example, less than about 0.3% by HPLC.

Processes for obtaining pharmaceutically acceptable L-dopamide free base (LDA FB)

[0053] In a further aspect, the present disclosure provides a process for obtaining a pharmaceutically acceptable L-dopamide free base (LDA FB) substantially free of L-dopa. Such a process is effective in providing, e.g., substantially pure LDA FB.

[0054] Purified LDA free base, e.g., pharmaceutically acceptable LDA FB, may be obtained by several routes. For example, LDA free base may be obtained from a purified LDA salt, for example, obtained as described herein by a contemplated process. Alternatively or additionally, purified LDA FB, e.g., substantially pure pharmaceutically acceptable LDA FB, may be obtained by a process in which crude LDA salt is first produced from L-dopa (LD) by amidation, for example, by a contemplated process described herein, followed by purification, e.g., substantial purification of the LDA salt, for example by a contemplated purification process described herein. Then the purified LDA salt is converted to purified LDA free base ubder basic conditions. Various exemplary process for obtaining or making LDA FB disclosed herein are designated herein Processes I, Process II and Process III.

Process I for making pure LDA free base

[0055] In some embodiments, a contemplated process for making a purified pharmaceutically acceptable LDA FB comprises the following steps:

(a) providing a first crude LDA salt product comprising a LDA salt, LD, and/or a LD salt;

(b) contacting the first crude LDA salt product with a first acid composition, thereby obtaining a first acidic solution comprising LDA salt, LD, and/or a LD salt;

(c) precipitating the LDA salt from the first acidic solution, thereby obtaining a second crude LDA salt product comprising a LDA salt, LD, and/or a LD salt;

(d) contacting the second crude LDA salt product with a second acid composition, thereby obtaining a second acidic solution comprising a LDA salt, LD, and/or a LD salt;

(e) re-precipitating the LDA salt from the second acidic solution, thereby obtaining a purified LDA salt;

(f) contacting the purified LDA salt with a base composition, thereby obtaining a basic solution comprising a purified LDA free base; and

(g) precipitating the purified LDA free base from the basic solution, thereby obtaining the purified pharmaceutically acceptable LDA FB.

[0056] In some embodiments, the pH of the first and/or second acidic solution is between about 2.0 and about 3.0. In exemplary embodiments, the pH of the first and/or second acidic solution is between about 2.5 and about 2.7 at 25 °C.

[0057] In some embodiments, the first and second acid are the same. For example, both the first and second acid are hydrochloric acid (HC1).

[0058] In some exemplary embodiments, the first or second acid is HC1. Process II for making pure LDA free base

[0059] In some embodiments, a contemplated process of making a purified pharmaceutically acceptable LDA FB substantially free of L-dopa, comprises the following steps:

(a) providing a purified LDA salt;

(b) contacting the purified LDA salt with a base composition, thereby providing a basic solution comprising a purified LDA FB ; and

(c) precipitating the purified LDA FB base from the basic solution, thereby providing the purified pharmaceutically acceptable LDA FB.

Process III for making pure LDA free base

[0060] In some embodiments, a contemplated process for making a purified pharmaceutically acceptable LDA FB comprises the following steps:

(a) reacting L-dopa (LD) with a chlorinating reagent and an alcohol, R-OH, thereby obtaining a L-dopa ester hydrochloride salt, wherein the L-dopa ester (LD-OR) is the chemical compound, L-3,4-dihydroxy-phenylalanine methyl ester represented by:

wherein R is selected from a lower alkyl, lower alkenyl, lower alkynyl, aryl or heteroaryl;

(b) reacting the LD-OR hydrochloride salt (LD-OR HC1 salt) with a composition comprising ammonia, thereby obtaining a first crude L-dopamide hydrochloride salt product comprising: L-dopamide hydrochloride salt (LDA HC1 salt), LD, and/or L-dopa hydrochloride salt (LD HC1 salt);

(c) contacting the first crude L-dopamide hydrochloride salt product with a first hydrochloric acid composition, thereby obtaining a first acidic solution comprising: LDA HC1 salt, LD, and/or LD HC1 salt;

(d) precipitating the L-dopamide hydrochloride salt from the first acidic solution, thereby obtaining a second crude L-dopamide hydrochloride salt product comprising: LDA HC1 salt, LD, and/or LD HC1 salt; (e) contacting the second crude L-dopamide hydrochloride salt with a second hydrochloric acid composition, thereby obtaining a second acidic solution comprising: LDA HC1 salt, LD, and/or LD HC1 salt;

(f) re -precipitating the L-dopamide hydrochloride salt from the second acidic solution, thereby obtaining a purified LDA HC1 salt;

(g) contacting the purified LDA HC1 salt with a base composition, thereby obtaining a basic solution comprising a purified L-dopamide free base (LDA FB); and

(h) precipitating the purified LDA FB from the basic solution, thereby providing the purified pharmaceutically acceptable LDA FB.

[0061] In some embodiments, the alcohol R-HO, the chlorinating reagent and the ammonia are as defined herein.

Process IV for making pure LDA free base

[0062] The present disclosure provides a further process for making a purified pharmaceutically acceptable L-dopamide free base substantially free of L-dopa. This process may be particularly suitable for large-scale production of purified pharmaceutically acceptable LDA FB. This process resembles Process I herein, but instead of purifying LDA salt by 2 subsequent precipitations before contacting it with a base solution, LDA salt is precipitated only once from an acidic solution.

[0063] In some embodiments, a process, e.g., large-scale process, for making a purified pharmaceutically acceptable L-dopamide free base comprises the following steps:

(a) providing a crude L-dopamide salt product comprising: a L-dopamide salt (LDA salt), L-dopa (LD), and/or a L-dopa salt (LD salt);

(b) contacting the crude L-dopamide salt product with an acid composition, thereby obtaining an acidic solution comprising: LDA salt, LD, and/or a LD salt;

(c) precipitating the LDA salt from the acidic solution, thereby obtaining a purified LDA salt;

(d) contacting the purified LDA salt with a base composition, thereby obtaining a basic solution comprising a purified L-dopamide free base (LDA FB); and

(e) precipitating the purified LDA FB from the basic solution, thereby obtaining the purified pharmaceutically acceptable L-dopamide free base. [0064] In some embodiments, the purity of the purified LDA pharmaceutically acceptable free base is above 98% by HPLC.

[0065] In exemplary embodiments, the content of L-dopa in the purified LDA pharmaceutically acceptable free base is less than about 1.0% by HPLC.

[0066] In some embodiments, the process does not include purification by chromatography.

[0067] In some of any of the embodiments described herein for the production of purified, e.g., purified pharmaceutically acceptable LDA FB, or substantially purified LDA FB, for example as described in Processes I to IV herein, the pH of the first and/or second hydrochloric acid solution is between about 2.0 and about 3.0. In exemplary embodiments, the pH of the first and/or second hydrochloric acid solution is between about 2.5 and about 2.7 at 25 °C.

[0068] In some of any of the embodiments described herein for the production of purified, e.g., purified pharmaceutically acceptable LDA FB or substantially pure LDA FB obtained by Process I, Process II, Process III and/or Process IV herein, the base composition with which the purified LDA salt, e.g. LDA HC1 salt, is contacted for making a purified LDA free base, may comprise one or more bases such as hydroxide bases (namely, substances that, in aqueous solution, release hydroxide (OH ^" ) ions). Non-limiting examples of hydroxide bases include hydroxides of the alkali metals and the alkaline earth metals such as, but not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), magnesium hydroxide (Mg(OH)2), and calcium hydroxide (Ca(OH)2, or an organic molecules such as ammonium hydroxide (NH ₄ OH).

[0069] In exemplary embodiments, the basic composition comprises the hydroxide base sodium hydroxide.

[0070] In some embodiments, the pH of the basic solution may between about 8.0 to about 9.1. For example, from about 8.0 to about 9.0, from about 8.1 to about 8.3, from about 8.2 to about 8.4, from about 8.3 to about 8.5, from about 8.4 to about 8.6, from about 8.5 to about 8.7, from about 8.5 to about 8.6, from about 8.6 to about 8.8, from about 8.5 to about 8.7, from about 8.7 to about 8.8, from about 8.7 to about 8.9, or from about 8.8 to about 9.0. [0071] In exemplary embodiments, the pH of the basic solution is between about 8.20 to about 8.40. For example, about 8.20, about 8.25, about 8.30, about 8.35, or about 8.40.

[0072] In some of any of the embodiments described herein for the production of purified, e.g., substantially purified pharmaceutically acceptable LDA free base (e.g., Processes I-III herein), the purity of the purified LDA FB is above 99% by HPLC.

[0073] In some embodiments, a contemplated process for making pure LDA FB reduces the content of L-dopa and/or L-dopa salt in the purified pharmaceutically acceptable LDA FB, wherein the content of L-dopa and/or L-dopa salt in the purified LDA FB is less than about 0.5% by HPLC, for example, less than about 0.3% by HPLC.

[0074] In some embodiments of any aspect of the present disclosure related to the production of a purified, e.g., substantially purified product selected from pharmaceutically acceptable LDA free base (e.g., obtained by Process I, Process II, and/or Process III herein), a pharmaceutically acceptable LDA salt, and/or pharmaceutically acceptable LDA HC1 salt, a contemplated process may provide at least about 1.0 gr of purified product e.g., in one batch. In exemplary embodiments, a contemplated process provides at least about 10 gr, at least about 50 gr, at least about 100 gr, at least about 500 gr, at least 1 kg, or at least 5 kg. For example, the amount of purified product obtained by a disclosed process may be between about 1.0 gr to about 50 gr, between about 50 gr to about 500 gr, between about 500 gr to about 1000 gr, between 800 gr to about 1500 gr, between 100 gr to about 2000 gr, between 1500 gr to about 3000 gr, between 2500 gr to about 4000gr, or between 4000 gr to about 10 kg-

[0075] For example, the amount of purified LDA salt and or LDA FB in one batch may be in a range of from about 250 gr to about 550 gr, from about 500 gr to about 800 gr, from about 600 gr to about 900 gr, from about 750 gr to about 1000 gr, from about 850 gr to about 1200 gr, from about 1000 gr to about 1500 gr, from about 1200 gr to about 1700 gr, from about 1500 gr to about 2000 gr, from about 1800 gr to about 2300 gr, from about 2000 gr to about 2500 gr, from about 2200 gr to about 2600 gr, from about 2500 gr to about 3000 gr, from about 3000 gr to about 3700 gr, from about 3500 gr to about 4000 gr, from about 3800 gr to about 4500 gr, or from about 4000 gr to about 8000 gr, and even more of purified LDA salt in one batch. [0076] In some embodiments of any aspect of the present disclosure, a contemplated process is a large-scale process.

[0077] The term "large scale process", as used herein, refers to a process that can produce a wide scope of product quantities, ranging, for example, from e.g., tens or hundreds of grams to kilograms and even to tons of product. A large-scale process, in the context of embodiments described herein, is a process that can produce purified LDA FB and/or purified LDA salt such as purified LDA HC1 salt, in amounts ranging, for example, from 100 gr to 5 kg, or from 1 kg to 10 kg per process cycle. A large-scale process in some embodiments described herein, is also a process that produces a purified product as defined herein in amounts ranging from, for example, 100 gr to 5 kg, or from 1 kg to 10 kg in a single batch.

Products obtained by processes of the disclosure

[0078] The present disclosure, in an aspect thereof, provides a purified LDA free base and/or a purified LDA salt, and substantially purified LDA free base and/or LDA salt, collectively referred to herein as "products" or "purified products", prepared or obtained by any of the processes provided herein.

[0079] In some embodiments, the contemplated purified product is a purified or substantially purified pharmaceutically acceptable salt of LDA obtained by a process described herein. In exemplary embodiments, the pharmaceutically acceptable salt of LDA is L-dopamide hydrochloride salt (LDA HC1 salt).

In some embodiments, the contemplated purified product is a purified or substantially purified pharmaceutically acceptable L-dopamine free base (LDA FB) prepared by a process disclosed herein.

[0080] 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 salt 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. [0081] 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.

[0082] In some embodiments, the purity of a contemplated purified or substantially purified pharmaceutically acceptable LDA salt and/or pharmaceutically acceptable LDA FB is above 99% by HPLC.

[0083] In some embodiments, the content of L-dopa and/or a L-dopa salt in the purified or substantially purified pharmaceutically acceptable LDA salt and/or pharmaceutically acceptable LDA FB is less than about 0.5% or less than about 0.3% by HPLC.

Drug substances

[0084] 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 product as defined herein obtained by a contemplated process of the disclosure. A pure or purified product obtained by a contemplated process may be pharmaceutically acceptable and may form a drug substance.

[0085] The terms "pharmaceutically acceptable" as used herein refers to molecular entity, for example LDA FB and/or a LDA salt such as LDA HC1 salt, and compositions comprising it 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, and general safety and purity standards as required by FDA Office of Biologies standards.

[0086] The term "drug substance" as used 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, i.e., the active pharmaceutical ingredient (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.

[0087] In some embodiments, a drug substance comprises a pharmaceutically acceptable LDA free base and/or a pharmaceutically acceptable LDA salt obtained by a contemplated process described herein.

Pharmaceutical compositions and formulations

[0088] In still a further aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable LDA free base and/or a pharmaceutically acceptable LDA salt obtained by a contemplated process described herein, and a pharmaceutically acceptable excipient. In some embodiments, the composition is a formulation for pharmaceutical administration and comprises a pharmaceutically acceptable carrier.

[0089] 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".

[0090] Some embodiments described herein pertain to liquid pharmaceutical compositions, for example aqueous formulations.

[0091] In some embodiments, a contemplated pharmaceutical composition, e.g., formulation, is a suspension.

[0092] 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 or LDA free base as defined herein, for example, at least one of the pure pharmaceutically acceptable LDA salt or LDA free base obtained by a contemplated process.

[0093] 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).

[0094] Contemplated pharmaceutical compositions may include from 1% to about 25%, or more of a disclosed LDA salt or LDA free base obtained by a disclosed process. For example, a disclosed formulation may comprise, pure or substantially pure pharmaceutically acceptable LDA salt or LDA free base 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.

[0095] 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 LDA salt or LDA free base, obtained in their crystalline form.

[0096] A contemplated pharmaceutical composition may, optionally, further comprise one or more physiologically acceptable excipients and/or a physiologically acceptable carrier.

[0097] 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.

[0098] 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).

[0099] 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.

[0100] 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).

[0101] When a contemplated medicinal formulation comprises a pure pharmaceutically acceptable LDA salt or LDA free base 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.

[0102] 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). [0103] 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).

[0104] 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.

[0105] 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.

[0106] 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.

[0107] Contemplated formulations may congtain 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). [0108] 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.

[0109] 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.

[0110] Also contemplated herein is a stable lyophilized powder comprising a LDA salt and/or LDA FB obtained by any of the processes 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.

[0111] 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 and/or 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.

[0112] 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. [0113] In embodiments described herein, the pharmaceutical compositions disclosed are aqueous formulations particularly useful for subcutaneous administration e.g., via an infusion pump.

[0114] 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.

[0115] 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.

[0116] In some embodiments, a contemplated formulation is designed for administration via a dermal patch suitable for transdermal or subcutaneous administration of an active agent.

[0117] 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. [0118] In some embodiments, a pharmaceutical composition as disclosed herein is designed for a slow release of the pharmaceutically acceptable LDA salt or 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.

[0119] All compositions for any form of administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0120] 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.

[0121] According to the present disclosure, the pharmaceutical compositions can be administered over a defined time period, e.g., days, weeks, months, or years.

[0122] 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).

[0123] "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

[0124] 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.

[0125] 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.

[0126] In an exemplary embodiment, the neurological disease is Parkinson's disease.

[0127] 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.

[0128] 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.

[0129] 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 LDA free base obtained by any one of the processes described herein. [0130] 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 or LDA free base obtained by the processes described herein.

[0131] "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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] In some embodiments, a disclosed method features subcutaneous and substantially continuous administration of a disclosed pharmaceutical.

[0136] 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, 21 hours, 24 hours, 12 to 16 hours, 16 to 18 hours, 18 to 20 hours, or 20 to 24 hours.

[0137] 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.

[0138] 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.

[0139] 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 μΐνηοΜ to about 1000 Ι ιθΜ, 300 ± 100 μΙ ιθΜ, or 200 ± 40 μ^ουτ continuously for 24 hours; 440 ± 200 μΐνΐκΜΓ or 200 ± 50 μΐνΐιουΓ continuously for 16 hours (during waking hours) and from 0 to about 80 μΐνΐιουΓ or 0 to 200 μΙΤΙιουΓ for 8 hours (at night).

[0140] 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 μΐνΐιουΓ, or 1 ± 0.5 μΐνΐιουΓ continuously for 24 hours; 1 ± 0.5 μΙΤηοιΐΓ continuously for 16 hours (during waking hours) and from 0 to about 0.5 μΐνΐιουΓ 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.

[0141] In some embodiments, administration includes acute and immediate administration such as inhalation or injection.

[0142] 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.

[0143] 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. [0144] 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 or LDA free base obtained by the processes 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.

[0145] 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.

[0146] Two or more dosage unit forms may be administered to a subject at the same rate, or at different rates.

Kits

[0147] In an aspect of the present disclosure, there is provided a kit comprising a LDA free base and/or LDA salt obtained by a disclosed process, 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.

[0148] In some embodiments, the kit comprises a first pharmaceutical composition comprising one or more pure pharmaceutically acceptable LDA salts or LDA free base obtained by the processes 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 coadministration of the pharmaceutical compositions.

[0149] 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.

[0150] 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.

[0151] As used herein the term "about" refers to ± 10 %.

[0152] The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

[0153] 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.

[0154] 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.

[0155] 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. [0156] 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

EXAMPLE 1

Production of purified L-dopamide free base

[0157] L-dopamide free base (LDA FB) was obtained from L-dopa (LD) and purified according to the process depicted in the scheme below, using the following steps and ingredients.

1. 25% aqueous NH ₃ , -8° C to -12" C, 16-24 h

2. Azeoptrope NH ₃ from 2-propanol hydrochloride salt

11

1. Dissolve in H ₂ 0

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

1. Production of L-dopa methyl ester hydrochloride salt (compound 11)

[0158] Methanol (135.0 kg) was cooled to a temperature of from about -5 °C to about 0 °C under nitrogen. Thionyl chloride (22.6 kg, 190.0 mol, 1.5 eq.) was added while keeping the temperature between -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-phenylalanine 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)

[0159] Aqueous ammonium hydroxide (25%) (81.0 kg) was cooled to a temperature in the range of from about -8 °C to about -12 °C under nitrogen, and compound 11 (3,4-dihydroxy- L-phenylalanine methyl ester hydrochloride; 15.0 kg, 60.6 mol) was added. The reaction mixture was stirred at temperature in of from about -8 °C to -12 °C for 16 - 24 hours until minimum 99.0% conversion of compound 11 to compound 12 was achieved (assessed by HPLC). The excess 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 (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 crude 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 teri-Butyl methyl ether (MTBE) was chosen as the best candidate. teri-Butyl methyl ether (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 salt (LDA HC1 salt, compound 13) (85%) as a white to off-white solid.

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

[0160] 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 LDA HC1 salt 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 pure LDA HC1 salt, compound 14 (74%) as a white to off-white solid.

4. Production of L-dopamide free base (LDA FB, compound 15)

[0161] Compound 14 (LDA HC1 salt, 9.30 kg, 40.0 mol) was dissolved in purified water (27.9 kg). The mixture was treated with activated carbon (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 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 purified L- dopamide free base (LDA FB), compound 15 as a white to off-white solid.

[0162] 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).

[0163] 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

Screening of reaction conditions for obtaining purified L-dopamide free base

(i) The amidation step: conversion of compound 11 to compound 12

[0164] Two standard methods for converting amino acid esters to amino acid amides are known, namely treatment with ammonia in alcohol (typically methanol) or with ammonium hydroxide in water. These two methods were tested in attempts to effect amidation of both free amine of L-dopa methyl ester and the hydrochloride salt thereof (compound 11). It was found that 25% ammonium hydroxide at 5 °C was superior to ammonia in methanol with regard to reaction rate and content and afforded the best results for amidation of both the hydrochloride salt of L-dopa methyl ester (11) and its corresponding free base results.

[0165] For example, reaction of 1 gr and 10 gr of 11 with aqueous solution of NH4OH (12 eq. and 10 eq., respectively), provided 100% amidation (conversion to 12) overnight at 5 °C, and 5% L-dopa impurity, and reaction of 5 gr of L-dopa methyl ester free base with aqueous NH4OH (1 eq.) at 5 °C during 21 hours, provided 100% amidation product (12) having 5.2% L-dopa impurity. On the other hand, reaction of 1 gr and 10 gr of 11 with NH3 in methanol (17 eq. each), provided 97% amidation (conversion to 12) over 5 and 8 days, respectively at 5 °C and then at room temperature, and the L-dopa impurities were low (0.2% and 0.8%, respectively). However, reaction of 5 gr of L-dopa methyl ester free base with NH3 in methanol resulted in lower conversions to 12 and necessitated varying reaction conditions. For example, 81% conversion obtained over 6 days at room temperature, with 3.2% L-dopa impurity, or 100% conversion obtained over 4 days at 40 °C, and 3.3% L-dopa impurity. Mixing NH3 with other organic solvents such as tetrahydrofuran (THF) or CH2CI2 resulted in only 1 % conversion of the free base.

(ii) The precipitation steps

[0166] Results obtained from small scale precipitation tests of crude L-dopamide (LDA free base, compound 12) and the corresponding crude hydrochloride salt (LDA HC1 salt, compound 13) were more promising for LDA HC1 salt both with regard to ease of precipitation and reducing the level of L-dopa (LD) impurity. This is mainly because LD has a lower solubility than LDA free base. Thus, two precipitation septs of LDA HC1 salts form acidic solutions were conducted before purified LDA free base was collected.

[0167] Attempts to precipitate crude LDA HC1 salt by addition of ethanol to an aqueous solution at pH 4.5 - 5.5 followed by distillation at reduced pressure provided variable content of LD impurities. However, when the pH of the aqueous solution of crude L-dopamide (12) was adjusted to pH 2.5 - 2.7 with concentrated hydrochloric acid that ensured a monohydrochloride was formed, LDA HC1 salt precipitation was readily achieved by first reducing the amount of water to approx. 8% w/w by azeotropic distillation with 2-propanol followed by addition of teri-butyl methyl ether. By this precipitation procedure, the content of LD dropped from approx. 5% in the crude material to 1.1% in the isolated precipitate.

(Hi) L-dopa impurities

[0168] The content of LD impurities was dependent on the reaction temperature. A reaction temperature of -10 °C provided a reaction mixture with acceptable conversion and a satisfying content of LD at 2.0%. Some exemplary results of temperature dependency tests are shown in Table 1 (amidation step was conducted with 25% NH4OH). Table 1. Dependency ofL-dopa content in purified LDA free base on the reaction temperature

Scale = amount of starting material (compound 10)

(iv) Exemplary reaction conditions for obtaining compounds 13, 14 and 15

[0169] Exemplary experimental conditions and results for obtaining compounds 13-15 are shown in Tables 2-4 herein. Table 2 depicts experimental data of the amidation step, namely, production of crude LDA HCl salt (13) obtained from 4 different exemplary batches. Table 3 depicts experimental data of the re-precipitation step, namely, production of purified LDA HCl salt (14) obtained from 2 exemplary batches. Table 4 depicts experimental data of production of L-dopamide free base (15) obtained from 3 different exemplary batches. Batches 1 and 2 of Table 2 correspond to batches 1 and 2 of Table 3. Batches 2, 3, and 4 of Table 3 correspond to batches 2, 3, and 4 of Table 4.

Table 2. Experimental data for production of crude L-dopamide hydrochloride salt (13)

Table 3. Experimental data for producing of purified L-dopamide hydrochloride salt (14)

Overall yield L-dopa

Batch No. Yield of 14 HPLC purity from 11 content

1 78.9% 64.5% 0.23% 99.5%

2 74.7% 67.9% 0.20% 99.2% Table 4. Experimental data for production of L-dopamide free base (15)

EXAMPLE 3

Analytical data of L-dopamide hydrochloride salt (14) and L-dopamide free base (15)

[0170] Analytical data and purity of LDA HC1 salt (14) and LDA free base (15) produced by the process described in Example 1 where collected from exemplary batches and are listed in Table 5 and 6 herein, respectively. The products were analyzed by their appearance, as well as by analytical means such as liquid chromatography-mass spectroscopy (LC-MS), ^J H NMR and specific optical rotation. Purity was assessed, e.g., by HPLC, gas chromatography (GC) and ion chromatography (IC).

Table 5. Analytical data of L-dopamide hydrochloride salt (14)

Test Batch 1 (78.9 gr scale) Batch 2 (374 gr scale)

Appearance of solids Off-white Off-white

[M+l] 197.20, [M+l] 197.05,

LC-MS

[M-l] 194.95 [M-l] 195.10

¾ NMR Consistent with structure Consistent with structure

Purity (HPLC) 99.5% 99.2%

Content of L-dopa 0.23% 0.20%

Area % and relative retention RRT 1.55: N/A, RRT RRT 1.55: 0.17%, RRT time (RRT) of any impurities 2.29: N/A, RRT 2.62: 2.28: 0.08%, RRT 2.62:

> 0.05% (by HPLC) 0.18%, RRT 2.67: 0.10% 0.11%, RRT 2.67: 0.28%

Total impurities 0.51% 0.84%

Water content (KF, % w/w) 1.06% 2.25%

Solubility in water 201.08 mg/mL 213.62 mg/mL

pH 3.0 3.0 Chloride content by ion

15.0% 16.3% chromatography (IC) (w/w)

Methanol <250 ppm Methanol <250 ppm, (n.d.), acetonitrile <250 acetonitrile <250 ppm

Residual solvents by gas

ppm (n.d.), tert-butyl (n.d.), tert-butyl methyl chromatography (GC) (ppm)

methyl ether <250 ppm, ether <250 ppm, 2- 2-propanol: 9496 ppm propanol: 11177 ppm

Specific optical rotation +20.5 +20.0

Table 6. Analytical data of L-dopamide free base (15)

Methanol <250 ppm, Methanol <100 ppm

Methanol <250 ppm

acetonitrile <250 (n.d.), acetonitrile <100 (n.d.), acetonitrile <250

ppm (n.d.), tert-butyl ppm (n.d.), tert-butyl

Residual solvents by GC ppm (n.d.), tert-butyl

methyl ether <250 methyl ether <190 ppm, (ppm) methyl ether <250 ppm,

ppm, 2-propanol: 2-propanol: < 100 ppm 2-propanol: <250 ppm,

<250 ppm, ethanol < (n.d.), ethanol: <100 ethanol<250 ppm (n.d.)

250 ppm (n.d.) ppm (n.d.)

Melting range 171.6-172.7 °C N/A N/A

INCORPORATION BY REFERENCE

[0171] 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.