Compositions comprising methylphenidate prodrugs, methods of making and using same

Abstract

Compositions comprising methylphenidate prodrugs, methods of making and using the same are disclosed. Specifically disclosed is a process for the preparation of dexmethylphenidate chloride compounds of formula I. The invention also discloses a method for preparing the dexmethylphenidate chloride and dexmethylphenidate hydrochloride capsule. (I)

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180017581.8, filed on February 13, 2021, entitled "Composition containing methylphenidate prodrug, preparation and use thereof".

[0002] Federally funded research or development

[0003] [not applicable] background

[0004] Methylphenidate is a psychoactive substance, a chain-substituted derivative of amphetamine. Similar to amphetamine and cocaine, methylphenidate targets the central nervous system, particularly the dopamine transporter (DAT) and norepinephrine transporter (NET). Methylphenidate is thought to act by increasing the concentrations of dopamine and norepinephrine in the synaptic cleft because it possesses binding capacity to both DAT and NET. Although a derivative of amphetamine, methylphenidate differs pharmacologically from amphetamine because amphetamine is a dopamine transport substrate, while methylphenidate acts as a dopamine transport blocker. As an inhibitor of norepinephrine and dopamine reuptake, methylphenidate thus blocks the reuptake of dopamine and norepinephrine (nomethylepinephrine) into presynaptic neurons (and may stimulate the release of dopamine from dopamine nerve endings at high doses), thereby increasing the levels of dopamine and norepinephrine at the synapse. In some in vitro studies, methylphenidate has shown to be more potent as an inhibitor of norepinephrine uptake / reuptake than dopamine. However, some in vivo studies have shown that methylphenidate is more potent than norepinephrine in enhancing extracellular dopamine concentrations. Unlike amphetamine, methylphenidate has been suggested in the scientific and / or clinical research community not to significantly promote the release of these two monoamine neurotransmitters at therapeutic doses.

[0005] Four isomers of methylphenidate are known to exist: d-erythrophenidate, l-erythrophenidate, d-threophenidate, and l-threophenidate. Initially, methylphenidate was marketed as a mixture of two racemic isomers, d / l-erythrophenidate and d / l-threophenidate. Subsequent studies showed that most of the desired pharmacological activity of the mixture was associated with the threo-isomer, leading to the marketing of the isolated racemic threophenidate. Later, the scientific community determined that the d-threo-isomer was primarily responsible for the stimulant activity. Therefore, a new product containing only d-threophenidate (also known as "d-threo-MPH") was developed.

[0006] Stimulants, including methylphenidate (“MPH”), are believed to enhance the activity of the sympathetic nervous system and / or the central nervous system (CNS). Stimulants, such as MPH and their various forms and derivatives, are used to treat a range of conditions and disorders, primarily including, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety, and / or insomnia.

[0007] Methylphenidate is currently approved by the U.S. Food and Drug Administration (“FDA”) for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Methylphenidate has also shown efficacy for several off-label indications, including depression, obesity, and narcolepsy. In some respects, prodrugs of this technology can be administered to treat ADHD and narcolepsy, or any condition requiring blocking of norepinephrine and / or dopamine transporters.

[0008] Attention deficit hyperactivity disorder (ADHD) in children has been treated with stimulants for many years. However, recently, the increase in prescriptions for ADHD treatment in the adult population has occasionally outpaced the growth of the pediatric market. Although a variety of medications are currently available for treating ADHD, including some stimulants and some non-stimulants, methylphenidate (from, for example, Novartis International AG (located in Basel, Switzerland) under the trademark Ritalin) is commonly prescribed. ® (Purchase from retail stores). Furthermore, during classroom trials, non-stimulants showed lower effectiveness than amphetamine derivatives in improving behavior and attention in children with ADHD.

[0009] As medication wears off, typically in the afternoon or evening, a significant proportion of children with ADHD experience a deterioration in behavior (rebound or "breakdown"). Rebound symptoms include, for example, irritability, paranoia, hyperactivity worse than the untreated state, sadness, crying, and, in rare cases, psychotic episodes. Symptoms can subside rapidly or last for several hours. Some patients may experience severe rebounds / breakdowns, necessitating discontinuation of treatment. The rebound / breakdown effect can also induce addictive behavior by inducing patients to administer additional doses of stimulants intended to prevent the anticipated negative consequences and side effects of the rebound / breakdown.

[0010] As has been demonstrated in conventional techniques, stimulants, such as methylphenidate and amphetamine, exhibit norepinephrine and dopaminergic effects, which can lead to cardiovascular events, including, in individual cases, increased heart rate, hypertension, palpitations, tachycardia, and cardiomyopathy, stroke, myocardial infarction, and / or sudden death. Therefore, currently available stimulants expose patients with pre-existing structural cardiac abnormalities or other serious cardiac indications to even greater health risks and are frequently not used or used with caution in this patient population.

[0011] Methylphenidate, like other stimulants and amphetamine derivatives, is addictive and readily abused. Oral abuse has been reported, and euphoria can be achieved through intranasal and intravenous administration.

[0012] Due to their potent euphoric effects, dependence on stimulants or cocaine can occur even after very short periods of use. For example, early signs of cocaine dependence include difficulty in quitting cocaine use when it is present or available. Cocaine, or many stimulants, have short elimination half-lives and therefore require frequent administration to maintain the "high." Prolonged use of such stimulants above therapeutic doses can lead to a variety of mental and / or physical problems. Effects on mood can include anxiety, restlessness, feelings of superiority, euphoria, panic, agitation, and fear. Behavioral symptoms include, but are not limited to, excessive talkativeness, increased energy, stealing or borrowing money, bizarre or strange behavior, violence, lack of participation in previously enjoyable activities, and reckless and dangerous behavior. Examples of physical symptoms of stimulant dependence may include one or more of the following: decreased need for sleep, headache, nosebleeds, hoarseness, increased heart rate, muscle twitching, malnutrition, fever, nasal perforation, arrhythmia, chronic runny nose, vasoconstriction, increased heart rate, increased blood pressure, sexual dysfunction, decreased appetite, dilated pupils, increased risk of HIV, hepatitis C, and other bloodborne diseases, intestinal gangrene, cravings, and tremors. Examples of psychological symptoms of stimulant dependence may include one or more of the following: severe paranoia, dramatic mood swings, dissociation from reality, lack of motivation, psychosis, hallucinations, inability to use rational judgment, and rationalization of drug use. A variety of factors can trigger or play a role in stimulant use disorder or stimulant dependence. These factors can generally be categorized into three types: genetic, biological, and environmental. Studies have shown that individuals with relatives who have addiction problems are more likely to develop addictions, including cocaine dependence. The likelihood of becoming stimulant dependent is even higher if the relative is a parent. Changes in brain function may be a biological factor associated with addiction problems. For example, low dopamine levels in the brain can lead to substance abuse for a pleasurable feeling. Environmental factors include, but are not limited to, unpredictable situations in an individual's family life; stressors such as child abuse, loss of a loved one, or other traumatic events. There is a need in the art for methylphenidate in the form of blood / brain concentrations that increase slowly and gradually until peak concentration is reached, or that decreases slowly and gradually after peak concentration, or both. Without being bound by any particular theory, it is possible that a slow onset of stimulant concentrations can reduce cardiovascular side effects, and slow elimination can reduce rebound effects. It has also been proposed that a greater increase in synaptic dopamine / time units (i.e., a higher rate of dopamine increase) leads to a more robust and intense euphoric effect. A slow increase in methylphenidate brain concentration results in a low rate of increase in synaptic dopamine, and therefore can lead to less reward and enhancement effects. Without being bound by any particular theory, it has also been proposed that a high occupancy of dopamine transporter receptors can reduce the reward and enhancement effects of additional doses of stimulants or cocaine.This can be achieved, for example, by repeated administration of large doses of a slow-acting form of methylphenidate that does not cause euphoria.

[0013] There is also a need in the art for methylphenidate forms that can provide a faster onset of action at blood / brain concentrations. Without being bound by any theory, some indications may require a large and rapid initial peak in blood and / or brain concentrations of methylphenidate to provide adequate efficacy to the subject, while other indications may require lower blood / brain concentrations of methylphenidate. However, small therapeutic doses of a rapidly onset form of methylphenidate can still be beneficial in providing rapid efficacy when needed.

[0014] There is a further need in the art for methylphenidate forms that offer flexibility in dosing regimens. For example, a single-day dose form of methylphenidate in a composition that can provide both immediate release and extended release PK profiles would be highly desirable.

[0015] There is also a need in the art for methylphenidate forms that, when administered, particularly or orally, maintain the pharmacological benefits, but which, when administered by injection or intranasal route, preferably have no or significantly reduced pharmacological activity.

[0016] Overview

[0017] This technology provides a specific d-threo-methylphenidate (“d-MPH”, “d-methylphenidate”, “d-methylphenidate”) conjugate, or a pharmaceutically acceptable salt thereof, to provide, for example, at least one single-day dose form of a d-methylphenidate conjugate in a composition having unconjugated methylphenidate, which, when compared to unconjugated d-methylphenidate, can provide both immediate release and prolonged release pharmacokinetic profiles. In some instances, the release characteristics provide the ability to administer a prodrug or composition using dosing regimens that are not readily compatible with unconjugated d-methylphenidate. In some aspects, the unconjugated methylphenidate in the composition can be d-methylphenidate, l-methylphenidate, or a mixture thereof, and / or a therapeutically or pharmaceutically acceptable salt thereof.

[0018] On the other hand, this technology provides a prodrug composition comprising at least one d-methylphenidate conjugate having the structure of Formula I:

[0019]

[0020] And unconjugated methylphenidate, wherein the unconjugated methylphenidate comprises d-methylphenidate.

[0021] On the other hand, the present technology provides at least one prodrug composition comprising at least one conjugate and unconjugated methylphenidate, wherein the at least one conjugate is d-methylphenidate-CO2CH2-nicotinyl-L-serine (Formula I) or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, the present technology provides a composition comprising unconjugated methylphenidate and at least one conjugate, wherein the at least one conjugate has at least two or more chiral centers, and the composition is optically active.

[0023] In another aspect, this technology provides a method for chemically synthesizing the d-methylphenidate-CO2CH2-nicotinyl-L-serine conjugate of this technology by performing appropriate steps to conjugate d-methylphenidate to a -CO2CH2-nicotinyl-L-serine ligand.

[0024] In another aspect, some aspects of compositions of the present technology comprising (a) a conjugate of formula I and / or one or more pharmaceutically acceptable salts thereof and (b) unconjugated methylphenidate (containing d-methylphenidate) and / or a pharmaceutically acceptable salt thereof are described in T max (Or later) unexpectedly, increased plasma concentrations of d-methylphenidate were observed, producing controlled or prolonged release profiles compared to equimolar doses of unmodified d-methylphenidate.

[0025] On the other hand, some aspects of compositions of this technology comprising (a) a conjugate of formula I and / or one or more pharmaceutically acceptable salts thereof and (b) unconjugated methylphenidate (containing d-methylphenidate) and / or its pharmaceutically acceptable salts show that, about 0 to about 4 hours after oral administration, the concentration of methylphenidate from Concerta is equivalent to that obtained by oral administration of an equimolar dose. ® The plasma concentration of released unconjugated d-methylphenidate was increased compared to that of d-methylphenidate.

[0026] In another aspect, some aspects of compositions of the present technology comprising (a) a conjugate of formula I and / or one or more pharmaceutically acceptable salts thereof and (b) unconjugated methylphenidate (containing d-methylphenidate) and / or a pharmaceutically acceptable salt thereof show that, up to about 4 hours after oral administration, compared with an equimolar dose from Concerta administered orally... ® The plasma concentration of released unconjugated d-methylphenidate was increased compared to that of d-methylphenidate.

[0027] In yet another aspect, some aspects of compositions of the art comprising (a) a conjugate of formula I and / or one or more of its pharmaceutically acceptable salts and (b) unconjugated d-methylphenidate and / or its pharmaceutically acceptable salts unexpectedly show smaller inter-patient variability in oral pharmacokinetic (PK) curves when compared with unconjugated d-methylphenidate.

[0028] On another aspect, some aspects of the compositions of this technology are provided in amounts sufficient to provide an increased AUC when compared with unconjugated d-methylphenidate when administered orally at equimolar doses.

[0029] In another aspect, some aspects of the composition of this technology are provided in an amount sufficient to release d-methylphenidate at T max (Or later) in the following time period, it provides a surprisingly lower C compared to unconjugated d-methylphenidate when administered orally at equimolar doses. max And a lower AUC but a significantly increased partial AUC.

[0030] In another aspect, some aspects of the composition of this technology are provided in an amount sufficient to release d-methylphenidate at T max (Or later) it provides a lower C-value compared to unconjugated d-methylphenidate when administered orally at equimolar doses over a subsequent time period. max Similar to AUC but with a significantly increased partial AUC.

[0031] In another alternative aspect, some aspects of the compositions of this technology are considered to provide fewer side effects compared to unconjugated d-methylphenidate when administered in equimolar doses, and in some alternative aspects are also considered to provide a reduced likelihood of abuse compared to unconjugated d-methylphenidate.

[0032] Furthermore, some aspects of the compositions of this technology are also considered to unexpectedly provide an amount sufficient, when compared with unconjugated d-methylphenidate when administered in equimolar doses, to provide a prolonged Tg. max And / or provides equivalent T when compared with unconjugated d-methylphenidate when administered orally at equimolar doses. max .

[0033] Furthermore, when compared with an equimolar dose from Concerta administered orally ® Compared to the released unconjugated d-methylphenidate, some aspects of the compositions of this technique are also considered to unexpectedly provide sufficient time to deliver a shorter Tg. max The amount.

[0034] Additionally, when compared with the equimolar dose from Concerta administered orally ® Compared to the released unconjugated d-methylphenidate, some aspects of the compositions of this technique are also considered to unexpectedly provide a longer half-life (T0). 1 / 2 The amount of ).

[0035] Furthermore, some aspects of the compositions of this technology are also considered to unexpectedly provide sufficient T to provide a longer duration of action compared to unconjugated d-methylphenidate when administered orally at equimolar doses. 1 / 2 The amount.

[0036] Furthermore, this technology provides at least one method for treating one or more subjects (humans or animals) or patients (humans or animals) suffering from at least one disease, disorder, or condition mediated by control, prevention, restriction, or inhibition of neurotransmitter uptake / reuptake or hormone uptake / reuptake, comprising orally administering to one or more subjects or patients a pharmaceutically and / or therapeutically effective amount of a composition of this technology, the composition comprising unconjugated methylphenidate and / or a pharmaceutically acceptable salt thereof, as well as a conjugate of Formula I and / or a pharmaceutically acceptable salt thereof.

[0037] In another aspect, the present technology provides at least one method for treating a subject (human or animal) suffering from at least one disorder or condition of the central nervous system requiring stimulation of the subject, comprising oral administration of a pharmaceutically effective amount of a composition of the present technology comprising unconjugated methylphenidate and / or a pharmaceutically acceptable salt thereof, and a conjugate of formula I and / or a pharmaceutically acceptable salt thereof, wherein the administration treats at least one disorder or condition of the central nervous system requiring stimulation of the subject.

[0038] In another aspect, the present technology provides at least one method for treating a subject (human or animal) suffering from at least one disorder or condition of the central nervous system requiring stimulation of the subject, comprising oral administration of a therapeutically effective amount of a composition of the present technology, the composition comprising unconjugated methylphenidate and / or a pharmaceutically acceptable salt thereof, and a conjugate of Formula I and / or a pharmaceutically acceptable salt thereof, wherein the administration treats at least one disorder or condition of the central nervous system requiring stimulation of the subject.

[0039] In another aspect, the present technology provides one or more methods of administering to a subject a composition comprising at least one d-methylphenidate conjugate and an unconjugated methylphenidate, wherein the administration reduces the number and / or amount of metabolites produced when compared to unconjugated d-methylphenidate. In other aspects, this one or more methods of administering the compositions of the present technology are considered to reduce the subject's exposure to ritalinic acid when compared to unconjugated d-methylphenidate. It is desirable to minimize exposure to metabolites, such as ritalinic acid, that do not significantly contribute to the intended therapeutic effect due to potential side effects or toxicities that may still occur as a result of potential secondary pharmacological effects of the metabolites. In some aspects, the compositions of the present technology can reduce overall exposure to ritalinic acid by about 25% to about 75%.

[0040] In another aspect, the compositions of this technology are considered to provide increased water solubility of the d-methylphenidate-based conjugates or prodrugs compared to unconjugated d-methylphenidate. Furthermore, the increased water solubility is thought to allow the compositions to be formed into certain dosage forms at higher concentrations, dose strengths, or dose-loading capacities than unconjugated d-methylphenidate. In some aspects, such dosage forms include, for example, oral films or strips.

[0041] In another respect, administration of d-methylphenidate-based compositions comprising d-methylphenidate conjugates and unconjugated methylphenidate to patients (humans or animals) has been considered to provide reduced inter-patient variability in d-methylphenidate plasma concentrations and is considered to have improved safety when compared with unconjugated d-methylphenidate.

[0042] In yet another alternative aspect, the present technology provides at least one method for treating attention deficit hyperactivity disorder, comprising administering to a subject or patient a pharmaceutically and / or therapeutically effective amount of a composition comprising at least one d-methylphenidate conjugate and an unconjugated methylphenidate, wherein the administration treats attention deficit hyperactivity disorder in the subject.

[0043] In another alternative aspect, the technology provides at least one method of treating a subject or patient with an eating disorder, bulimia, obesity, narcolepsy, chronic fatigue, sleep disorder, excessive daytime sleepiness (EDS), cocaine dependence, or stimulant dependence, comprising administering to the subject or patient a pharmaceutically and / or therapeutically effective amount of a composition comprising at least one d-methylphenidate conjugate and an unconjugated methylphenidate, wherein the administration treats the subject or patient with an eating disorder, bulimia, obesity, narcolepsy, chronic fatigue, sleep disorder, excessive daytime sleepiness (EDS), cocaine dependence, or stimulant dependence.

[0044] In another aspect, the present technology provides a composition for treating at least one subject or patient suffering from a disorder or condition of the central nervous system requiring stimulation, wherein the composition comprises unconjugated methylphenidate and a d-methylphenidate conjugate, and wherein the composition has a reduced likelihood of abuse upon administration compared to unconjugated d-methylphenidate.

[0045] In another respect, compositions of the present technology exhibit reduced or blocked pharmacological activity when administered via the parenteral route, or reduced plasma or blood concentrations of d-methylphenidate when administered intranasally, intravenously, intramuscularly, subcutaneously, or rectally, compared to free, unconjugated d-methylphenidate when applied in equimolar amounts.

[0046] In some respects, the compositions of this technology, when compared with unconjugated d-methylphenidate administered orally at equimolar doses, have a prolonged or controlled release profile as measured by the plasma concentration of released d-methylphenidate. In some respects, when compared with unconjugated d-methylphenidate, the plasma concentration of d-methylphenidate released from the conjugate of the composition will increase more slowly and over a longer period after oral administration, resulting in a delayed peak plasma concentration of released d-methylphenidate and a longer duration of action. In other respects, the controlled release profile of d-methylphenidate from the composition will have a Tg approximately equal to that of unconjugated d-methylphenidate. max However, it provides plasma concentrations of d-methylphenidate for a longer period of time.

[0047] In other respects, compared with unconjugated d-methylphenidate administered orally once daily, the composition has a lower AUC and lower C when administered orally once daily. max However, in the second half of the day, it has an equivalent T max And higher plasma concentrations of d-methylphenidate.

[0048] On the other hand, this technology provides a pillbox containing a specified amount of individual doses within a package, each dose containing a pharmaceutically and / or therapeutically effective amount of a composition comprising at least one conjugate of d-methylphenidate and unconjugated methylphenidate. The pillbox also includes instructions for use.

[0049] On the other hand, this technology provides an oral formulation. The oral formulation may comprise a therapeutic dose of (a) a d-threo-methylphenidate (S)-serine conjugate and / or a pharmaceutically acceptable salt thereof, and (b) unconjugated methylphenidate and / or a pharmaceutically acceptable salt thereof.

[0050] In some aspects, compositions of the present invention comprising unconjugated methylphenidate and at least one d-methylphenidate conjugate can be used in neonates, children, adolescents, adults, and / or elderly subjects with ADHD. For example, in some aspects, the compositions of the present invention can be used for once-daily administration, with potentially improved onset and longer duration of action, which may be beneficial to neonates, children, and / or adolescent subjects with ADHD. Brief description of the attached diagram

[0051] Various aspects of this application will now be described by way of example only with reference to the accompanying drawings, in which:

[0052] Figure 1A flowchart 100 is shown for the synthesis of tert-butyl (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate according to some aspects. According to one aspect, nicotinic acid is reacted with L-Ser('Bu)O'Bu HCl (O-tert-butyl-L-serine tert-butyl ester hydrochloride) in MTBE and acetonitrile in the presence of triethylamine.

[0053] Figure 2 A flowchart is shown for the synthesis of the first serdex methylphenidate chloride intermediate (first SDX intermediate) according to one aspect.

[0054] Figure 3 A flowchart is shown for the synthesis of the second methylphenidate chloride intermediate (second SDX intermediate) according to one aspect.

[0055] Figure 4 A flowchart is shown for the synthesis of methylphenidate chloride from one aspect.

[0056] Figure 5 A flowchart of the first recrystallization for purifying and separating SDX pharmaceutical substances is shown according to one aspect.

[0057] Figure 6 A flowchart is shown for the second recrystallization of SDX pharmaceutical substances according to one aspect.

[0058] Figure 7 The re-slurrying of crystalline SDX solids according to one aspect is shown.

[0059] Figure 8 A method for preparing SDX / d-MPH capsules according to one aspect is shown. Invention Details

[0060] Various aspects will be described in detail with reference to the accompanying drawings, wherein like reference numerals throughout several views denote like parts and assemblies. It should be understood that this application is not limited to the specific methods, schemes, and reagents described herein, and therefore can be varied. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of this application or the appended claims.

[0061] Unless the context clearly indicates otherwise, the singular forms “a”, “an”, and “the” as used herein and in the appended claims include plural references.

[0062] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0063] This technology provides one or more compositions comprising methylphenidate chloride (SDX). The compositions have beneficial properties as further described herein.

[0064] As used herein, the term "methylphenidate" is intended to include any stereoisomer of methylphenidate, including four stereoisomers: d-erythro-methylphenidate, l-erythro-methylphenidate, d-threo-methylphenidate, and l-threo-methylphenidate, as well as their salts and derivatives. Methylphenidate is interchangeable with methyl phenyl(piperidin-2-yl)acetate. The term "methylphenidate" includes all salt forms. The trade name for methylphenidate is also known as Concerta. ® (Commercially available from Janssen Pharmaceuticals, Inc., Beerse, Belgium), Ritalin ® Ritalin ® SR, Methylin ® Methylin ® ER (all commercially available from Novartis International AG, of Basil, Switzerland). Methylphenidate used in this technology can be any stereoisomer of methylphenidate, including but not limited to d-erythrophenidate, l-erythrophenidate, d-threophenidate, and l-threophenidate. In a preferred aspect, the conjugate contains a single d-threophenidate isomer. In another aspect, the prodrug conjugate is a single isomer of its optical activity.

[0065] The term "unconjugated methyl ester" refers to methyl 2-phenyl-2-(piperidin-2-yl)acetate and its salts.

[0066] As used below, stereoisomers refer to two molecules composed of the same atoms connected in the same order, but with atoms in different spatial positions; these molecules are described as stereoisomers of each other. The differences between two stereoisomers can only be observed when considering the three-dimensional arrangement of the molecules.

[0067] Bioavailability, as used below, refers to the proportion of a drug or other substance that, when introduced into the body, enters circulation over time and is thus able to exert its active effect.

[0068] The C used below max It is a term used in pharmacokinetics and refers to the maximum (or peak) plasma concentration of a drug in a designated compartment or test area of ​​the body after the drug has been administered and before the administration of a second dose.

[0069] The T used below max In pharmacokinetics, it is used to describe the observed Cmax The term "time" refers to the duration of intravenous administration. Following intravenous administration, C... max and T max It is highly dependent on the experimental protocol, as the concentration continues to decrease after administration.

[0070] As is known to those skilled in the art, the term "steady state" refers to a state in which total drug intake and elimination are in approximately dynamic equilibrium. At steady state, total drug exposure does not change significantly during continuous dosing. Steady state is typically reached after a period of approximately 4–5 times the drug's half-life following the initiation of routine dosing.

[0071] The term “dosage” refers to the total amount of drug or active ingredient administered to an individual subject at one time.

[0072] As used herein, the term “subject” refers to a person or animal, including but not limited to human or animal patients.

[0073] The term "patient" refers to a human or animal subject who requires treatment.

[0074] The term "inter-patient variability" refers to an estimate of the level of pharmacokinetic variability among different individuals receiving the same dose of the same drug. For example, this can be achieved by calculating certain pharmacokinetic parameters (including, for example, C). max AUC last AUC inf and T max The coefficient of variation (CV) is used to estimate the inter-patient variability. When comparing inter-patient variability between different drugs or between one or more of the same drugs in different formulations, a lower CV indicates decreased inter-patient variability, while a higher CV indicates increased inter-patient variability.

[0075] "Coefficient of variation" (CV) is a statistical term and is calculated based on the following formula: CV = standard deviation / mean * 100.

[0076] AUC last In pharmacokinetics, the term refers to the area under the curve in a graph used to describe the concentration of a drug in blood, serum, or plasma relative to the time from time = 0 (or before administration) to the last measurable drug concentration.

[0077] AUC inf In pharmacokinetics, this is a term used to describe the area under a curve in a graph of the concentration of a drug in blood, serum, or plasma relative to time = 0 (or before administration) to infinity.

[0078] The molar equivalent used below refers to the number of moles of a substance that is equal to the number of moles in a mass (weight) or volume. For example, a dose of d-methylphenidate hydrochloride of about 0.1 mg per day will provide the same number of moles of d-methylphenidate as 0.1 mg of d-methylphenidate hydrochloride.

[0079] As used herein, phrases such as “decreased,” “reduced,” “diminished,” or “lowered” refer to changes in pharmacological activity, area under the curve (AUC), and / or peak plasma concentration (C) compared to unconjugated methylphenidate. max A change of at least about 10% is preferred to reduce the likelihood of abuse and overdose of the conjugates of this technology; a larger percentage change is also preferred. For example, the change may also be greater than about 10%, about 15%, about 20%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, about 95%, about 96%, about 97%, about 98%, about 99%, or increments thereof.

[0080] As used herein, “pharmacologically effective amount” refers to an amount that has a pharmacological effect. As used herein, “pharmacologically acceptable salt” is a d-methylphenidate conjugate or an unconjugated methylphenidate or a salt of both, which, when used in a pharmaceutically effective amount, has at least one pharmacological effect.

[0081] As used herein, “therapeutic effective amount” means an amount used to effectively treat a disease or condition. As used herein, “therapeutically acceptable salt” is a pharmaceutically acceptable salt of d-methylphenidate conjugate or unconjugated methylphenidate or both in the composition of the art, which is effective in treating a disease, condition or syndrome when used in a therapeutically effective amount.

[0082] As used herein, the term “attention deficit hyperactivity disorder” (ADHD) encompasses various subtypes of ADHD, including, for example, subjects who do not show or only show mild symptoms of hyperactivity or impulsivity, or subjects who, for example, have primary inattention (formerly attention deficit disorder (ADD)).

[0083] As used herein, the term "prodrug" refers to a substance that is inactive or has reduced pharmacological activity but is converted into an active drug substance through in vivo chemical or biological reactions. In this art, a prodrug is a conjugate of at least one drug substance, d-methylphenidate, a linker group, and a nicotinyl-L-serine moiety. Therefore, the conjugates of this art are prodrugs, and the prodrugs of this art are conjugates.

[0084] Prodrugs are often useful because, in some respects, they may be easier to administer or process than the parent drug. For example, they may have higher bioavailability through oral administration, which the parent drug cannot. Prodrugs may also have improved solubility in water and / or other solvents compared to the parent drug. One aspect of a prodrug is a d-methylphenidate conjugate metabolized into the active moiety. In some respects, upon administration in vivo, a prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically more active form of the compound. In some respects, a prodrug is enzymatically metabolized through one or more steps or processes into a biologically, pharmaceutically, or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon administration in vivo. In some respects, prodrugs are engineered to alter the metabolic or transport properties of a drug—this alteration typically varies depending on the route of administration—to mask side effects or toxicity, to improve bioavailability and / or water solubility, to improve the flavor of the drug, or to alter other characteristics or properties of the drug in other respects.

[0085] d-methylphenidate prodrugs can be prepared in various chemical forms, including chemical derivatives or salts. Such d-methylphenidate prodrugs can also be prepared in different physical forms. For example, d-methylphenidate prodrugs can be amorphous, can be polymorphs with different crystallinity, or can exist in different solvation or hydration states, such as hemihydrate, monohydrate, hydrate (nH₂O, when n is 0.5, 1, 2...). Such polymorphs can be prepared, for example, by separating the free base and salt forms using crystallization conditions and / or by ball milling.

[0086] By altering the form of d-methylphenidate prodrugs, their physical properties can be modified. For example, crystalline polymorphs typically exhibit different solubilities, making thermodynamically more stable polymorphs less soluble than those that are less stable. The properties of drug polymorphs can also vary, such as shelf life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Therefore, changing the crystalline state of d-methylphenidate prodrugs is one of many ways to modulate their physical properties.

[0087] A eutectic is a multicomponent crystal containing two or more different molecules, wherein all components are solids under ambient conditions (i.e., 22°C, 1 atmosphere) when in their pure form. These components include the target molecule (i.e., d-methylphenidate prodrug) and molecular eutectic formations, which coexist at the molecular level within the eutectic in a single crystal.

[0088] Cocrystals, which are solids under ambient conditions and contain two or more molecules (eutectic formations) (Jmarsson et al., 2004), represent a class of compounds that have long been known (see Wohler, 1844). However, cocrystals remain relatively unexplored. Surveys in the Cambridge Structural Database (CSD) (Allen et al., 1993) revealed that cocrystals account for less than 0.5% of published crystal structures. Nevertheless, their potential impact on pharmaceutical (e.g., nutritional drug) formulations (Vishweshwar et al., 2006; Li et al., 2006; Remenar et al., 2003; and Childs et al., 2004) and green chemistry (Anastas et al., 1998) is receiving increasing and growing attention. In particular, the fact that all eutectic components are solids under ambient conditions has important practical considerations, as the synthesis of eutectics can be achieved via solid-state techniques (mechanics) (Shan et al., 2002), and chemists can exercise a degree of control over the composition of eutectics because they can induce molecular recognition, particularly hydrogen bonding, during the selection of eutectic formation. These characteristics distinguish eutectics from solvates, which are another broad and well-known group of multicomponent compounds. Solvates are characterized much more extensively than eutectics (e.g., 1652 eutectics versus 10,575 solvates reported in CSD; version 5.27 (May 2006) 3D coordinates, RO.075, non-ionic, organic only).

[0089] Providing novel forms of d-methylphenidate prodrugs with improved properties would be advantageous. Specifically, it is desirable to identify improved forms of d-methylphenidate prodrugs exhibiting significantly improved properties, including increased water and / or solvent solubility and stability. Furthermore, improved processability or preparation of pharmaceutical formulations is desired. For example, even in compositions in which d-methylphenidate prodrugs are mixed with other substances, the needle-like crystalline form or crystal habit of the d-methylphenidate prodrug can cause aggregation, resulting in an inhomogeneous mixture. It is also desirable to increase or decrease the dissolution rate of pharmaceutical compositions containing d-methylphenidate prodrugs in water or other solvents, increase or decrease the bioavailability of orally administered compositions, and provide a faster or more delayed onset of therapeutic effect. It is also desirable to have forms of d-methylphenidate prodrugs that, when administered to subjects, reach peak plasma levels more quickly or more slowly, have longer sustained therapeutic plasma concentrations, and result in higher or lower total exposure compared to an equivalent amount of d-methylphenidate prodrug in its currently known forms. The improved properties discussed above can be altered in the most beneficial way for a specific d-methylphenidate prodrug to achieve a specific therapeutic effect.

[0090] The d-methylphenidate prodrug or conjugate and unconjugated methylphenidate of this technology can be positively charged (cationic) molecules, or pharmaceutically acceptable anionic or cationic salts, or salt mixtures having any ratio between positive and negative components. These anionic salt forms can include, but are not limited to, acetates, L-aspartate, benzenesulfonates, bicarbonates, carbonates, d-camphorsulfonates, L-camphorsulfonates, citrates, ethanedisulfonates, formates, fumarates, gluconates, hydrobromide / bromine, hydrochloride / chloride, d-lactate, L-lactate, d,L-lactate, d,L-malate, L-malate, methanesulfonates, bis(hydroxynaphthyl)ate, phosphates, succinates, sulfates, and hydrogen sulfates. d-tartrate, l-tartrate, d,l-tartrate, meso tartrate, benzoate, glucohepanoate, d-glucuronate, hybenzate, hydroxyethyl sulfonate, malonate, methyl sulfate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, stearate, toluene sulfonate, thiocyanate, acefyllinate, acetylglycine, aminosalicylic acid, ascorbate, borate, butanediol Camphorates, camphor carbonates, decanoates, hexanoates, cholates, cyclopentylpropionate, dichloroacetate, edentate, ethyl sulfate, furate, furate, mucilage, galacturonate, gallate, gentianate, glutamate, glutamate, glycerol phosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodides, sine, lacturonate, laurate, maleate, mandelate Methanesulfonate, myristate, naphthalene disulfonate, oleate, oxalate, palmitate, picrate, neopentanoate, propionate, pyrophosphate, salicylate, salicylsulfonate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribromophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camphor sulfonate, octanoate, etolate, ethanesulfonate, glycolate, thiocyanate, or undecenoate. In a preferred embodiment, the anionic salt form is selected from the group consisting of: chlorides, bicarbonates, iodides, bromides, citrates, acetates, formates, salicylates, hydrogen sulfates, hydroxides, nitrates, hydrogen sulfites, propionates, benzenesulfonates, hypophosphites, phosphates, bromates, iodates, chlorates, fluorides, and nitrites.

[0091] In some respects, the salt form of the conjugate is selected from: chloride, bicarbonate, iodide, bromide, citrate, acetate, formate, salicylate, bisulfate, hydroxide, nitrate, bisulfite, propionate, benzenesulfonate, hypophosphite, phosphate, bromate, iodate, chlorate, fluoride, and nitrite. In some respects, the salt form of the unconjugated methylphenidate is selected from: hydrochloride, hydrobromide, hydroiodate, formate, methanesulfonate, tartrate, salicylate, sulfate, citrate, nitrate, bisulfite, propionate, benzenesulfonate, and acetate.

[0092] The cation salt form may include, but is not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, lithium salts, cholinate, lysine onium salts, or ammonium salts.

[0093] It is not intended to be limited to the following theory that the prodrug / conjugate of this technology undergoes rate-determining enzymatic hydrolysis in vivo, which subsequently leads to a cascade reaction resulting in the rapid formation of d-methylphenidate and its corresponding ligands, metabolites, and / or derivatives thereof. The prodrug conjugate of this technology is non-toxic or has very low toxicity at a given dose level, and is preferably a known drug, natural product, metabolite, or GRAS (Generally Recognized As Safe) compound (e.g., preservatives, dyes, flavoring agents, etc.) or a non-toxic analogue or derivative thereof.

[0094] Synthetic scheme for preparing methylphenidate chloride

[0095] The abbreviations for the components of the composition of this technology include: SDX for methylphenidate chloride; MPH for methylphenidate; d-MPH for methylphenidate hydrochloride; CMCF for methyl chloroformate; MTBE for methyl tert-butyl ether; and MIBK for 4-methyl-2-pentanone. t Bu represents tert-butyl; Ph represents phenyl; T3P represents propylphosphonic anhydride; ACN represents acetonitrile.

[0096] In some respects, the methyl methacrylate conjugate is represented by the ionic salt methyl methacrylate chloride of formula I:

[0097]

[0098] In a preferred aspect of the composition of this technology, the d-methylphenidate active ingredient is derived from two sources: methylphenidate chloride and unconjugated methylphenidate and / or its pharmaceutically acceptable salt.

[0099] In some respects, methylphenidate hydrochloride (d-MPH), chloromethyl chloroformate (CMCF), and (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate tert-butyl ester were synthesized in four stages, as shown below:

[0100]

[0101] Preparation of (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate tert-butyl ester

[0102] In some respects, tert-butyl (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate was prepared according to scheme 1.

[0103] Option 1:

[0104]

[0105] (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate tert-butyl ester was synthesized by reacting O-tert-butyl-L-serine tert-butyl ester hydrochloride and nicotinic acid in MTBE and acetonitrile in the presence of triethylamine (Et3N). Propylphosphonic anhydride (T3P) in acetonitrile was added to the reaction mixture and stirred. The resulting slurry was quenched with water, and the organic layer was washed with aqueous sodium bicarbonate solution, twice with aqueous ammonium chloride solution, and once more with water. The final MTBE solution was distilled to reduce the water content. The (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate tert-butyl ester – MTBE solution was crystallized using MTBE and n-heptane to produce S)-3-(tert-butoxy)-2-(nicotinamide)-propionate tert-butyl ester as a separated solid.

[0106] Figure 1A flowchart 100 is shown for the synthesis of tert-butyl (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate according to some aspects. Nicotinic acid is reacted with L-Ser('Bu)O'Bu HCl (O-tert-butyl-L-serine tert-butyl ester hydrochloride) in MTBE and acetonitrile in the presence of triethylamine. T3P in 50% acetonitrile is then added to the reaction and stirred to produce a reaction mixture. In step 102, the completed reaction is quenched with water and the aqueous phase is extracted with MTBE. The organic layer is washed with Na2CO3, twice with NH4Cl, and once with water to produce a crude solution. The crude solution then undergoes distillation and cooling step 104, filtration and distillation step 106 with activated carbon, and distillation and cooling step 108 with n-heptane. Tert-butyl (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate seed crystals are added in stirring and cooling step 110 to initiate crystallization. Subsequently, a filtration and washing step 112 and a drying step 114 are performed to produce tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propionate for downstream use.

[0107] Preparation of the first intermediate

[0108] In some respects, the first methylphenidate chloride intermediate was prepared according to scheme 2.

[0109] Option 2:

[0110]

[0111] MTBE (349.0 ± 3.0 kg) and 2,6-dimethylpyridine (2.8 equivalents, 52.4 ± 0.5 kg) were added to d-MPH (1.0 equivalent, 47.1 ± 0.2 kg) in a reactor. The reaction mixture was stirred (at 20ºC ± 5ºC for at least 20 min), and then chloromethyl chloroformate (1.6 equivalents, 35.8 ± 0.3 kg) was added to the reactor, ensuring the temperature of the reaction mixture did not exceed 30ºC. The reaction mixture was stirred at 25ºC ± 5ºC for at least 8 h. The reaction mixture was then quenched with approximately 3 volumes of water (relative to d-MPH), ensuring the temperature of the reaction mixture did not exceed 30ºC. The reaction mixture was stirred at 20ºC ± 5ºC for at least 6 h, and the aqueous layer was separated. The MTBE layer was washed with 3 volumes of aqueous sodium bicarbonate solution, followed by 3 volumes of water. The MTBE solution was distilled at atmospheric pressure with an internal temperature of ≤ 59ºC to achieve approximately 4.3 volumes relative to d-MPH and then cooled to ≤ 50ºC. The MTBE solution was then cooled to 20ºC ± 5ºC and the water content was determined. Distillation was completed when the MTBE solution reached a water content of ≤ 0.2%. The yield was 90%–99%.

[0112] Figure 2 A flowchart 200 is shown illustrating the synthesis of a first methylphenidate chloride intermediate (first SDX intermediate) according to some aspects. Methylphenidate HCl is added to a reactor along with MTBE and 2,6-dimethylpyridine. The resulting reaction mixture can then be stirred at 20ºC ± 5ºC in a stirring step 202. In some aspects, the duration of stirring step 202 can be at least 20 minutes. Subsequently, methyl chloroformate is added to the reactor to produce the first intermediate reaction mixture, which can then be stirred at 25ºC ± 5ºC in a stirring step 204. In some aspects, the duration of stirring step 204 can be at least 8 hours. After the reaction is complete, the first intermediate reaction mixture is quenched with water so that the temperature of the first intermediate reaction mixture does not exceed 30ºC. In a stirring step 206, the first intermediate reaction mixture can be stirred at 20ºC ± 5ºC and the aqueous layer separated. In some aspects, the duration of stirring step 206 can be at least 6 hours. In a washing step 208, the MTBE layer of the first intermediate reaction mixture can be washed with an aqueous solution of NaHCO3 and water. In some aspects, the MTBE layer was washed with 3 volumes of NaHCO3 solution and 3 volumes of water. The completion of washing 208 can be determined by the pH of the final aqueous phase, which is ≥ 6.

[0113] In distillation step 210, the MTBE solution / layer of the first intermediate reaction mixture is distilled at atmospheric pressure and cooled to ≤ 50ºC. In some aspects, the MTBE solution is distilled to approximately 4 volumes relative to d-MPH. In distillation step 212, MTBE is added to the MTBE solution of the first intermediate reaction mixture and distillation is repeated. After distillation 212, the first intermediate in the MTBE solution is cooled to 20ºC ± 5ºC.

[0114] In several aspects, synthesis 200 may include process control steps 214, 216, 218, and / or 220. Process control step 214 may occur between stirring steps 204 and 206, and the depletion of the reaction mixture is determined by HPLC analysis. In some aspects, the reaction is complete when the methylphenidate content is less than 4% of the area relative to the first SDX intermediate. Process control step 216 may occur between washing 208 and distillation 210, and the pH of the final aqueous phase is determined. If the pH exceeds 6, the MTBE layer is washed again with an aqueous solution of NaHCO3 and water until the pH of the final aqueous phase is ≥ 6. Process control step 218 occurs after distillation 212, and the water content of the first intermediate in the MTBE solution is measured by Karl Fischer analysis. In some aspects, the water content of the obtained first intermediate in the MTBE solution is ≤ 0.2%. If the KF result exceeds 0.2%, additional MTBE (150 ± 3.0 kg) can be added to the solution and distillation can be repeated until the water content is ≤ 0.2%. During process control step 220, the final first intermediate in the MTBE solution is analyzed to determine the wt.-% and mass of the first SDX intermediate via HPLC. In some respects, the yield of the first SDX intermediate is 90%-99%.

[0115] Preparation of the second intermediate

[0116] In some respects, the second methylphenidate chloride intermediate was prepared according to scheme 3.

[0117] Option 3

[0118]

[0119] A solution of the first methylphenidate chloride intermediate (1.2 equivalents; 48.0–51.2 kg actual mass of the first intermediate) was added to tert-butyl (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate (1.0 equivalent, 39.6–42.2 kg) in the reactor, and the stirrer was started. Nine volumes of acetonitrile were added to the reaction mixture, and the mixture was distilled under vacuum at an internal temperature ≤ 59ºC to approximately eight volumes. The solution was then cooled to 20ºC ± 5ºC, and the water content was determined. Distillation was complete when the solution reached a water content ≤ 0.15%. The reaction mixture was heated to 60ºC ± 3ºC and stirred for at least 45 hours. The reaction was complete when the content of tert-butyl (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate was less than 10% of the area relative to the second methylphenidate chloride intermediate. Cool the reaction mixture to 20ºC ± 5ºC, add a solution of dioxane in 4.0 M HCl (0.15 equivalents, 4.85–5.15 kg), and stir at 20ºC ± 5ºC for at least 5 minutes. Then add 12 volumes of 4-methyl-2-pentanone (MIBK) to the reaction mixture.

[0120] The reaction mixture was distilled at atmospheric pressure and an internal temperature ≤ 45ºC to remove acetonitrile and MIBK, aiming for a target of 10 volumes. After distillation, the temperature of the reaction mixture was adjusted to 50ºC ± 5ºC. To remove solids, 16 volumes of n-heptane were added over a two-hour process to maintain the reaction temperature at 40ºC–55ºC. Once the solids were removed, seed crystals of the second filament dextromethorphan chloride intermediate (theoretical yield of the second filament dextromethorphan chloride intermediate calculated relative to the amount of (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate tert-butyl ester added) were added to the reaction mixture at 50ºC ± 5ºC to initiate crystallization, followed by the addition of n-heptane. After the addition of n-heptane, the reaction mixture was cooled to 20ºC ± 5ºC, stirred for at least 6 hours, and filtered. The solid second filament dextromethorphan chloride intermediate was washed with a mixture of MIBK and n-heptane (3:1 volume ratio) and dried at ≤ 45ºC (≤ 1.0% LOD) for at least 12 hours to produce crystalline solid second filament dextromethorphan chloride intermediate.

[0121] Figure 3A flowchart 300 is shown illustrating the synthesis of a second methylphenidate chloride intermediate (second SDX intermediate) according to some aspects. Tert-butyl (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate is added to a reactor, followed by the addition of a solution of a first methylphenidate chloride intermediate (first SDX intermediate), and the stirrer is started. In distillation step 302, acetonitrile is added to the resulting reaction mixture and distilled under vacuum at an internal temperature ≤ 59ºC. In some aspects, 9 volumes of acetonitrile are added to the reaction mixture and distilled down to approximately 8 volumes. In heating step 304, the reaction mixture is heated to 60ºC ± 3ºC and stirred for at least 45 hours. In some aspects, the reaction mixture is heated to 59ºC. After the reaction is complete, in cooling step 306, the reaction mixture is cooled to 20ºC ± 5ºC, a dioxane solution of HCl is added, the mixture is stirred at 20ºC ± 5ºC for at least 5 minutes, and MIBK is added to the reaction mixture. In some cases, a dioxane solution in 4.0 M HCl can be used and / or 12 volumes of MIBK can be used.

[0122] Then, in distillation step 308, the reaction mixture is distilled at atmospheric pressure and an internal temperature of ≤ 45ºC to remove acetonitrile and MIBK. In some respects, the reaction mixture is distilled to achieve a target of 10 volumes. After distillation, in conditioning step 310, the temperature of the reaction mixture is adjusted to 50ºC ± 5ºC. The solids in the reaction mixture are then checked. In some respects, if solids are detected, n-heptane can be added over at least two hours to maintain a reaction temperature of 40ºC–55ºC. If no solids are detected after distillation step 308, second SDX intermediate seed crystals are added to the reaction mixture in stirring step 312 to promote crystallization, followed by the addition of n-heptane and stirring for at least 5 minutes. The reaction mixture is cooled to 20ºC ± 5ºC while stirring for at least 6 hours (cooling step 314) and filtered (filtration 316). In washing and drying step 318, the second SDX intermediate solids are washed with MIBK and n-heptane and dried at ≤ 45ºC for at least 12 hours to produce a second SDX intermediate in crystalline solid form. In some cases, the second SDX intermediate solid is washed with n-heptane at a 3:1 ratio of MIBK. In other cases, the target drying temperature is 40ºC–45ºC.

[0123] In several aspects, synthesis 300 may have process control steps 320, 322, and / or 324. Process control step 320 may occur between distillation step 302 and heating step 304, and the water content of the reaction mixture is measured via Karl Fischer analysis. In some aspects, distillation is considered complete when the water content of the second intermediate reaction mixture is ≤ 0.15%. If the KF result exceeds 0.15%, additional acetonitrile can be added to the solution and distillation can be repeated until the water content is ≤ 0.15%. In some aspects, 2.5 volumes of acetonitrile are added to the solution. Process control step 322 determines the completion of the reaction mixture by HPLC. In some aspects, the reaction is complete when the content of (S)-3-(tert-butoxy)-2-(nicotinamide)-propionate tert-butyl is ≤ 10.0% of the area of ​​the second SDX intermediate. In some aspects, if the sample does not meet the process standard, stirring can continue at 60ºC ± 3ºC for at least 4 hours, followed by resampling. In process control step 324, the drying loss of the second SDX intermediate solid is determined. In some respects, the yield of the second SDX intermediate in crystalline solid form is 70%-85%.

[0124] Preparation of coarse methylphenidate chloride

[0125] In some respects, coarse methylphenidate chloride was prepared according to scheme 4.

[0126] Option 4:

[0127]

[0128] Anhydrous 1,4-dioxane (3.4 v.) and sulfolane (4.6 v.) were added to the solid crystalline form of second-filament dextromethorphan chloride intermediate (63.5–68.8 kg) in the reactor, and the stirrer was started. A dioxane solution of 4.0 M HCl (2.15 equivalents, 53.98–59.86 kg) was added, and the reaction mixture was heated to 58°C ± 3°C, stirred for 12–18 hours, and then cooled to 20°C–25°C. After the reaction was complete, the reaction mixture was heated to 40°C–45°C and 2-butanone was added. SDX seed crystals (0.11 wt.% relative to the theoretical yield of crude SDX calculated for the solid crystalline form of second-filament dextromethorphan chloride intermediate) were added to the reaction mixture, and the mixture was stirred at 40°C–45°C for at least 15 minutes. To remove the solid, additional 2-butanone (19.2 v.) was added over a 3-hour process to promote precipitation. Once the solids were removed, the reaction mixture was cooled to 37°C–39°C, and SDX seed crystals (0.11 wt.%) were added, followed by additional 2-butanone. The reaction mixture was cooled to ≤10°C over a three-hour period and stirred at ≤10°C for 2–8 hours. The resulting solids were filtered, washed with approximately 2 volumes of 2-butanone, and dried at ≤50°C for at least 10 hours to produce crude SDX as a crystalline solid (≤1.0% LOD). The yield of the separated crude SDX solids was 60%–75%.

[0129] Figure 4 A flowchart illustrating the synthesis of crude SDX chloride according to some aspects is shown. A solution of a second SDX chloride intermediate (second SDX intermediate) is added to a reactor, along with anhydrous 1,4-dioxane and sulfolane, and the stirrer is started. In some aspects, anhydrous 1,4-dioxane and sulfolane are added in 3.4 and 4.6 volumes, respectively. A dioxane solution of HCl is then added. In some aspects, a 4.0 M dioxane solution of HCl is used. In heating and stirring step 402, the reaction mixture is heated to 58ºC ± 3ºC and stirred for 12 to 18 hours. In some aspects, the reaction mixture is heated to 59ºC and stirred for 14 hours. In cooling step 404, the reaction mixture is cooled to 20ºC–25ºC to produce a crude SDX reaction mixture. After the reaction is complete, in heating step 406, the crude SDX reaction mixture is heated to 40ºC–45ºC and 2-butanone is added. In some aspects, the crude SDX reaction mixture is heated to 41ºC. SDX seeds were then immediately added to the reaction mixture.

[0130] In stirring step 408, the reaction mixture is stirred at 40ºC–45ºC for at least 15 minutes and the presence of solids is checked. If solids are present, additional 2-butanone is added over a period of at least 3 hours to promote precipitation. If no solids are present, the reaction is cooled to 37ºC–39ºC, and additional SDX seed crystals are added to the reaction mixture to initiate crystallization, followed by the addition of additional 2-butanone. Subsequently, in cooling step 410, the reaction mixture is cooled to ≤10°C for at least 3 hours, and then stirred at ≤10°C for 2–8 hours. In filtration step 412, the resulting solids are filtered and washed with 2-butanone. In some respects, 2 volumes of 2-butanone may be used. In drying step 414, the crude SDX solids are dried. In some respects, the target drying temperature may be 47ºC.

[0131] In several respects, synthesis 400 can have process control steps 416, 418, and 420. Process control step 416 can occur after cooling 404 and the completion of the reaction is determined by HPLC analysis. In some respects, the reaction is complete when the combined area of ​​the mono-tert-butyl ether and mono-tert-butyl ester intermediates in the reaction mixture is ≤ 2.3% relative to SDX. In some respects, if the sample does not meet this standard, the reaction mixture is reheated, stirred for 2, 4, or 6 hours, cooled, and then resampled. If the sample still does not meet the standard, an additional dioxane solution of HCl is added and the reaction mixture is heated to 58ºC ± 3ºC to achieve the completion of the reaction. Process control step 418 determines the loss on drying of the crude SDX solids via USP 731. In some respects, drying is complete when the LOD is ≤ 1.0%. If the LOD exceeds 1.0%, drying can continue at 47ºC. Process control 420 examines the impurity distribution of the obtained crude SDX solids by HPLC prior to purification. In some cases, the yield of crude SDX solids is 60%-75%.

[0132] Purification of methylphenidate chloride

[0133] In some respects, purified and isolated methylphenidate chloride was prepared according to scheme 5.

[0134] Option 5:

[0135]

[0136] First recrystallization (“RX1”)

[0137] Acetone (6.3 v / v) and water (0.69 v / v) were added to the crude SDX solids (37.1–39.8 kg) in the reactor and stirred. The mixture was heated to reflux (≥ 54°C) and stirred for at least 20 min until the solids dissolved. After dissolution, the solution was adjusted to 45°C–48°C and transferred through a filter cartridge. The solution was then cooled to 38°C–45°C and SDX seed crystals (0.15 wt.% relative to the crude SDX feed) were added to initiate crystallization. The mixture was stirred at 38°C–45°C for at least 15 min. To remove the solids, additional acetone (18 v / v) was added over a period of at least 5 h while cooling to 20°C ± 5°C. Once the solids were removed, the mixture was cooled to ≤ 10°C over a period of 2 h and stirred for at least 2 h, then vacuum filtered to separate the SDX RX1 solids. The resulting solids were filtered, washed twice with acetone (3 v / v each time), and impurities were analyzed by HPLC. The separated SDX RX1 solids were dried at ≤ 50ºC for at least 10 hours, and residual acetone was analyzed by GC. Drying was considered complete when residual acetone was ≤ 4500 ppm. The yield of SDX RX1 solids was 75%–85%.

[0138] Figure 5 A flowchart 500 for the first recrystallization of SDX pharmaceutical substances according to some aspects is shown. Crude SDX solids are added to a reactor, acetone and water are added, and the resulting mixture is stirred. In some aspects, 6.3 volumes of acetone and 0.69 volumes of water are added, respectively. In a heating and stirring step 502, the mixture is heated to reflux (≥ 54ºC) and stirred for at least 20 minutes to dissolve the solids. In some aspects, if the solids remain outside the solution, stirring continues for at least an additional 20 minutes. If solids still remain, additional water is added and stirring continues at ≥ 54ºC for at least 20 minutes. In some aspects, if solids persist, an additional 0.01 volume of water is added. In a cooling step 504, the solution is adjusted to 45ºC–48ºC and transferred through a filter cartridge to another reactor.

[0139] In cooling step 506, the solution is stirred and filtered, and further cooled to 38ºC–45ºC, with SDX seed crystals added to initiate the crystallization process. In some aspects, the solution may be cooled to 42ºC in cooling step 506. The mixture is then stirred in stirring step 508 at 38ºC–45ºC for at least 15 minutes, and the presence of solids is checked. If solids are present, additional acetone is added over a period of at least 5 hours while cooling to 20ºC ± 5ºC. If no solids are present, the reaction is cooled to 32ºC–37ºC, and additional SDX seed crystals are added to the reaction mixture to promote crystallization, followed by the addition of additional acetone. In cooling step 510, the mixture is cooled to ≤ 10ºC over a period of 2 hours and then stirred for at least 2 hours, followed by vacuum filtration to separate the SDX RX1 solids. In some aspects, the target temperature in cooling step 510 is 5ºC. In filtration and washing step 512, the SDX RX1 solids are filtered and washed twice with acetone. In some cases, 3 volumes of acetone can be used. In drying step 514, the SDX RX1 solid is dried at ≤ 50ºC.

[0140] In several respects, the first recrystallization 500 may include process control steps 516, 518, and 520. Process control step 516 may occur after filtration and washing step 512 and impurities are determined via HPLC. In some respects, if all specified impurities in the sample are ≤ 0.15%, all unknown impurities are ≤ 0.10%, and total impurities are ≤ 1.0%, the separated SDX RX1 solid is dried at ≤ 50ºC for at least 10 hours, and residual acetone is analyzed by GC in process control step 518. In some respects, the residual acetone content should be ≤ 4500 ppm. If specified impurities exceed 0.15%, unknown impurities exceed 0.10%, and / or total impurities exceed 1.0%, the separated SDX RX1 solid is dried at ≤ 50ºC for at least 10 hours and subjected to an additional recrystallization procedure using isopropanol (second recrystallization). Figure 6 In the process, step 520 controls the drying loss of the SDX RX1 solids via USP731. In some cases, drying is complete when the LOD is ≤ 1.0%. If the LOD exceeds 1.0%, drying can continue, and then a second recrystallization step can be initiated. In some cases, the yield of pure SDX RX1 solids is 75%–85%.

[0141] Optional second recrystallization (“RX2”)

[0142] Isopropanol (7.4 v / v) and water (0.60 v / v) were added to the impure SDX RX1 solids (28.2–30.4 kg) in the reactor and stirred. The mixture was heated to reflux (≥ 75°C) and stirred for at least 20 minutes until the solids dissolved. After dissolution, the solution was adjusted to 63–66°C and transferred through a filter cartridge. The solution was then cooled to 58–63°C and SDX seed crystals (0.15 wt.% relative to the SDX RX1 solids feed) were added to initiate crystallization.

[0143] The mixture was stirred at 58ºC–63ºC for at least 15 minutes. To remove solids, additional isopropanol (13.8 wt%) was added over a period of at least 5 hours while cooling to 25ºC ± 5ºC. If no solids were detected, the mixture was cooled to 52ºC–56ºC, and then additional SDX seed crystals (0.15 wt%) were added, followed by additional isopropanol. The mixture was further cooled to ≤ 10ºC over a period of 2 hours and stirred for at least 2 hours, then vacuum filtered to separate the SDX RX2 solids.

[0144] The obtained solid was filtered, washed twice with isopropanol (3 volumes each time), and impurities were analyzed by HPLC. The separated SDX RX2 solid was dried at ≤ 50ºC for at least 10 hours, and residual acetone and isopropanol were analyzed by GC. Drying was considered complete when residual acetone and isopropanol were ≤ 4500 ppm. The yield of SDX RX2 solid (i.e., the purified SDX drug substance) was 84%–94%.

[0145] Figure 6 A flowchart 600 for the second recrystallization of SDX pharmaceutical substances according to some aspects is shown. Impure SDX RX1 solid is added to a reactor, isopropanol and water are added, and the resulting mixture is stirred. In some aspects, 7.4 volumes of isopropanol and 0.60 volumes of water are added, respectively. In the heating and stirring step 602, the mixture is heated to reflux (≥ 75ºC) and stirred for at least 20 minutes to dissolve the solid. In some aspects, if the solid remains outside the solution, stirring continues for at least another 20 minutes. If the solid still exists, additional water is added and stirring continues at ≥ 75ºC for at least 20 minutes. In some aspects, if the solid persists, an additional 0.01 volume of water is added. In the cooling step 604, the solution is adjusted to 63ºC–66ºC and transferred through a filter cartridge to another reactor.

[0146] In cooling step 606, the solution is stirred and filtered, then further cooled to 58ºC–63ºC, and SDX seed crystals are added to initiate the crystallization process. In some embodiments, the solution may be cooled to 60ºC in cooling step 606. The mixture is then stirred in stirring step 608 at 58ºC–63ºC for at least 15 minutes, and the presence of solids is checked. If solids are present, additional isopropanol is added over a period of at least 5 hours while cooling to 25ºC ± 5ºC. If no solids are present, the reaction is cooled to 52ºC–56ºC, and additional SDX seed crystals are added to the reaction mixture to promote crystallization, followed by the addition of additional isopropanol. In some embodiments, if no solids are present, the reaction is cooled to 54ºC. In cooling step 610, the mixture is cooled to ≤ 10ºC over a period of 2 hours and then stirred for at least 2 hours, followed by vacuum filtration to separate the SDX RX2 solids. In some embodiments, the target temperature in cooling step 610 is 5ºC. In the filtration and washing step 612, the SDX RX2 solid is filtered and washed twice with isopropanol. In some cases, 3 volumes of isopropanol may be used. In the drying step 614, the SDX RX2 solid is dried at ≤ 50ºC.

[0147] In several respects, the second recrystallization 600 may include process control steps 616 and 618. Process control step 616 may occur after filtration and washing step 612 and impurities are determined by HPLC. In some respects, when the sample has all specified impurities ≤ 0.15%, all unknown impurities ≤ 0.10%, and total impurities ≤ 1.0%, the separated SDX RX2 solid is dried at ≤ 50ºC for at least 10 hours, and residual acetone and isopropanol are analyzed by GC in process control step 618. In some respects, the residual acetone and isopropanol content should be ≤ 4500 ppm. In some respects, the yield of pure SDX RX2 solid is 84%–94%.

[0148] In some respects, if the residual solvent does not meet the process standards (≤ 4500 ppm), the SDX RX2 solids can be subjected to the re-slurrying process described below.

[0149] Resizing of optional crystalline SDX solids

[0150] The separated SDX RX2 solids and a 3:1 mixture of n-heptane / acetone (12 volumes) were added to the reactor, and the slurry was stirred at 20ºC–25ºC for at least 20 hours. The slurry was filtered, washed with a 5:1 mixture of n-heptane / acetone (5 volumes), and dried at ≤50ºC for at least 10 hours. In-sample GC analysis was used to confirm that the residual solvent levels (acetone, n-heptane, and isopropanol) met process standards before the batch was discharged from the dryer for final packaging and release testing of the SDX drug substance. After the reslurrying step, the yield of the purified SDX drug substance was 95%–100%.

[0151] Figure 7 The reslurrying of crystalline SDX solids is illustrated in step 700. Crystallized SDX solids are added to a reactor along with a mixture of n-heptane and acetone. In some cases, the n-heptane / acetone ratio is 3:1. In heating and stirring step 702, the slurry is stirred at 20°C–25°C for at least 20 hours. The slurry is then filtered in filtration step 704 and washed with the n-heptane / acetone mixture. In some cases, the n-heptane / acetone ratio is 5:1. The slurry is then dried at ≤ 50°C for at least 10 hours to obtain SDX solids. In some cases, the slurry is dried at 47°C. In process control step 708, the residual solvent content is analyzed via GC. In some cases, the yield of SDX solids is 95%–100%.

[0152] In some respects, if impurity analysis of the SDX RX2 solid determines that specified impurities exceed 0.15%, unknown impurities exceed 0.10%, and / or total impurities exceed 1.0%, reprocessing may be performed. In these respects, the separated SDX RX2 solid can be subjected to further recrystallization using aqueous acetone according to the first recrystallization 500 procedure, but with 9 volumes of 91:9 acetone:water and 15 volumes of the antisolvent acetone used to further remove residual process impurities.

[0153] Preparation of capsules containing methylphenidate chloride and methylphenidate hydrochloride

[0154] In some respects, the pharmaceutical product contains dextromethorphan chloride and dextromethorphan hydrochloride (SDX / d-MPH) in capsules. In some respects, the capsules contain 42 wt% SDX and 9 wt% d-MPH. In some respects, the SDX / d-MPH capsules are prepared by method 800. Figure 8 The text shows:

[0155] Preparation of preblators

[0156] In some cases, the allocated amounts of SDX and d-MPH pharmaceutical substances are sieved using a vibrating screen equipped with a 20-mesh sieve and added to a handheld mixer. In some cases, a portion of the microcrystalline cellulose is passed through a 20-mesh sieve into the handheld mixer. In some cases, 50% of the batch of microcrystalline cellulose is added. The SDX-d-MPH-cellulose premix is ​​then mixed. In some cases, the API premix (mixture #1) is mixed at 130 rpm.

[0157] Preparation of intraparticle primary blends and intraparticle lubricating blends

[0158] In some cases, the remaining portion of the microcrystalline cellulose and a certain amount of cropovidone are passed through a 20-mesh sieve and added to the pre-blend, and the resulting intra-particle primary blend (blend #2) is mixed. In some cases, the intra-particle primary blend is mixed at 260 rpm. A portion of the magnesium stearate is passed through a 30-mesh sieve and added to the blender. In some cases, 50% of the bulk magnesium stearate is added. The resulting intra-particle lubricating blend (blend #3) is mixed. In some cases, blend #3 is mixed at 130 rpm.

[0159] Dry granulation step 802 and milling step 804

[0160] In some cases, the intragranular lubricated blend is granulated by roller compaction followed by milling to improve the density of the resulting particles and the flow properties of the blend. In other cases, a roller compactor with two rollers is used, and the resulting strip is passed through a screening mill to obtain milled particles for extragranular blending.

[0161] Preparation of primary blends and lubricating blends with particulate matter

[0162] After milling 804, a certain amount of colloidal silica and talc are passed through a 30-mesh sieve and added to the blender along with the milled particles of the intragranular lubricating blend. This extragranular primary blend (blend #4) is mixed, and the remaining magnesium stearate is passed through a 30-mesh sieve and added to the blender to obtain the extragranular lubricating blend (blend #5). In some cases, the extragranular primary blend is mixed for 260 rpm. The extragranular lubricating blend is then mixed for another 130 rpm.

[0163] Encapsulation

[0164] The final particulate external lubricant blend is added to the encapsulator product hopper and filled into capsules. In some respects, the capsules are size 3 HPMC capsules.

[0165] In some aspects, additional processing steps 810 include capsule dust removal / metal detection, weight sorting, and / or bulk packaging.

[0166] In some aspects, method 800 includes a process control step 812, which includes PSD sieving analysis of the particulate external lubricant blend. In some aspects, process control step 814 is part of method 800 and includes visual inspection and / or weight inspection of the resulting capsules. The invention is further described in the following paragraphs.

[0167] A method for preparing methylphenidate chloride compounds having Formula I:

[0168] ,

[0169] The method includes:

[0170] (a) Synthesis of compounds having formula II:

[0171] ,

[0172] (b) Synthesis of the first intermediate compound having Formula III:

[0173] ,

[0174] (c) Synthesis of the second intermediate compound having formula IV:

[0175] ,

[0176] (d) Synthesize the crude product of the methylphenidate chloride compound.

[0177] (e) Purify the compound having formula V to produce the methylphenidate chloride compound having formula I.

[0178] The above method, wherein the synthesis of the compound having Formula II includes reacting O-tert-butyl-L-serine tert-butyl ester hydrochloride and nicotinic acid in methyl tert-butyl ether and acetonitrile in the presence of triethylamine.

[0179] In the above method, after the reaction of O-tert-butyl-L-serine tert-butyl ester hydrochloride and nicotinic acid in methyl tert-butyl ether and acetonitrile in the presence of triethylamine, the resulting solution is crystallized using methyl tert-butyl ether and n-heptane to produce the compound having formula II.

[0180] The above method, wherein the synthesis of the first intermediate compound includes:

[0181] (a) Reaction of methylphenidate HCl with methyl tert-butyl ether and 2,6-dimethylpyridine to obtain a reaction mixture; and

[0182] (b) Add chloromethyl chloroformate to the reaction mixture to produce the first intermediate compound.

[0183] The above method, wherein the synthesis of the second intermediate compound includes:

[0184] (a) Reacting the compound having Formula II with the first intermediate compound in the presence of acetonitrile, a dioxane solution of HCl, and 4-methyl-2-pentanone to obtain a reaction mixture; and

[0185] (b) Add methylphenidate chloride seed crystals to the reaction mixture to produce the second intermediate compound in the form of a crystalline solid.

[0186] The above method, wherein the synthesis of the crude product of the methylphenidate chloride compound having formula V includes:

[0187] (a) Reacting the second intermediate crystalline solid with anhydrous 1,4-dioxane and sulfolane to produce a reaction mixture; and

[0188] (b) Add methyl methacrylate chloride seed crystals to the reaction mixture to produce a crude product of the methyl methacrylate chloride compound having formula V.

[0189] The above methods, wherein the crude product of purifying the methylphenidate chloride compound includes:

[0190] (a) Reacting the crude product with acetone to produce a reaction mixture; and

[0191] (b) Add methyl methacrylate chloride seed crystals to the reaction mixture to produce the methyl methacrylate chloride compound of Formula I as a crystalline solid.

[0192] The above methods further include:

[0193] (f) Determine the purity level of the methylphenidate chloride compound having Formula I.

[0194] In the above method, if impurities are detected, the methylphenidate chloride compound undergoes an additional purification step, which includes:

[0195] (a) Reacting the solid methylphenidate chloride crystals with isopropanol to produce a reaction mixture; and

[0196] (b) Add methyl methacrylate chloride seed crystals to the reaction mixture to produce the methyl methacrylate chloride compound of Formula I as a crystalline solid.

[0197] A method for preparing capsules of methylphenidate chloride and methylphenidate hydrochloride, comprising:

[0198] (a) A certain amount of methylphenidate chloride compound having Formula I:

[0199]

[0200] It is blended with a certain amount of dextromethorphan hydrochloride;

[0201] (b) Add a first amount of microcrystalline cellulose to a blender and mix to produce a preblator;

[0202] (c) A second amount of microcrystalline cellulose and a certain amount of crosspovidone are added to the preblister to produce an intragranular primary blend;

[0203] (d) Mix the primary blend within the particles;

[0204] (e) A first amount of magnesium stearate is added to the primary blend within the particles to produce an in-particle lubricating blend;

[0205] (e) Mix the lubricating blend within the particles;

[0206] (f) Granulate the lubricating blend within the granules using a roller compactor;

[0207] (g) Grind the lubricating blend within the particles;

[0208] (h) A certain amount of colloidal silica and talc are added to the intraparticle lubricating blend of the milled particles to produce an extraparticle primary blend.

[0209] (i) The primary blend of the external particles is mixed with a second amount of magnesium stearate to produce an external lubricant blend;

[0210] (j) Mix the particulate external lubricant blend; and

[0211] (k) Encapsulate the particulate external lubricant blend in a capsule.

[0212] The above method refers to HPMC capsule No. 3.

[0213] The above method involves mixing the pre-blended material at 130 rpm.

[0214] The above method involves mixing the primary blend within the particles at 260 revolutions.

[0215] The above method involves mixing the lubricating blend within the particles at 130 revolutions per minute.

[0216] The above method involves mixing the primary blend of the particles at 260 revolutions.

[0217] The above method involves mixing the external lubricant blend of the particles at 130 revolutions per minute.

[0218] The presently described technology is now described in such complete, clear, concise, and precise terms that any person skilled in the art can practice it. It should be understood that the foregoing describes preferred aspects of the technology, and modifications may be made therein without departing from the spirit or scope of the invention as set forth in the appended claims.

Claims

1. A method for preparing a dexpramipexole chloride compound having Formula I: (I)， the method comprising: (a) synthesizing a compound having Formula II: (I), (II), (b) synthesizing a first intermediate compound having Formula III: (III), (c) synthesizing a second intermediate compound having Formula IV: (IV), (d) synthesizing a crude product of the dexpramipexole chloride compound, (e) purifying the crude product of the dexpramipexole chloride compound in step (d) to produce the dexpramipexole chloride compound having Formula I, wherein purifying the crude product of the dexpramipexole chloride compound in step (d) comprises the steps of: (i) crystallizing the dexpramipexole chloride compound having Formula I from an aqueous solution containing acetone to obtain a first solid form of the dexpramipexole chloride compound having Formula I; (ii) crystallizing the first solid form of the dexpramipexole chloride compound having Formula I from a first aqueous isopropanol solution to obtain a second solid form of the dexpramipexole chloride compound having Formula I; (iii) determining a purity level of the second solid form of the dexpramipexole chloride compound having Formula I; (iv) crystallizing the second solid form of the dexpramipexole chloride compound having Formula I from a second solution containing an aqueous isopropanol solution and dexpramipexole chloride seed crystals to obtain a third solid form of the dexpramipexole chloride compound having Formula I, and (v) reslurrying the third solid form of the dexpramipexole chloride compound having Formula I from a reslurry solution containing heptane and acetone, wherein the ratio of heptane / acetone is about 3:

1.

2. The method of claim 1, wherein, The synthesis of the compound having Formula II comprises reacting O-tert- butyl-L-serine tert-butyl ester hydrochloride and nicotinic acid in the presence of triethylamine in methyl tert-butyl ether and acetonitrile.

3. The method of claim 2, wherein, After reacting O-tert-butyl-L-serine tert-butyl ester hydrochloride and nicotinic acid in the presence of triethylamine in methyl tert-butyl ether and acetonitrile, the resulting solution is crystallized using methyl tert-butyl ether and n-heptane to produce the compound having Formula II.

4. The method of any one of claims 1 to 3, wherein, The synthesis of the first intermediate compound comprises: (a) reacting dexpramipexole HC1 with methyl tert-butyl ether and 2,6- dimethylpyridine to obtain a reaction mixture; and (b) adding chloromethyl chloroformate to the reaction mixture to produce the first intermediate compound.

5. The method of any one of claims 1 to 3, wherein, The synthesis of the second intermediate compound comprises: (a) reacting the compound having Formula II with the first intermediate compound in the presence of acetonitrile, a dioxane solution of HC1, and 4-methyl-2- pentanone to obtain a reaction mixture; and (b) adding second intermediate seed crystals to the reaction mixture to produce the second intermediate compound as a crystalline solid.

6. The method of any one of claims 1 to 3, wherein, The synthesis of the crude product of the dexpramipexole chloride compound in step (d) of claim 1 comprises: (a) reacting the second intermediate crystalline solid with anhydrous 1,4 dioxane and sulfolane to produce a reaction mixture; and (b) adding dexpramipexole chloride seed crystals to the reaction mixture to produce the crude product of the dexpramipexole chloride compound.

7. A method of making a dexmethylphenidate hydrochloride and dexmethylphenidate hydrochloride capsule comprising: (a) blending an amount of dexmethylphenidate hydrochloride compound having Formula I: with an amount of dexmethylphenidate hydrochloride; (I) wherein the dexmethylphenidate hydrochloride compound having Formula I is made by the method of any one of claims 1 to 6; (b) adding a first amount of microcrystalline cellulose to a blender and mixing to produce a pre-blend; (c) adding a second amount of microcrystalline cellulose and an amount of crospovidone to the pre-blend to produce an intra-granular primary blend; (d) mixing the intra-granular primary blend; (e) adding a first amount of magnesium stearate to the intra-granular primary blend to produce an intra-granular lubricated blend; (f) mixing the intra-granular lubricated blend; (g) granulating the intra-granular lubricated blend using a roller compactor; (h) milling the intra-granular lubricated blend; (i) adding an amount of colloidal silicon dioxide and talc to the milled intra-granular lubricated blend to produce an extra-granular primary blend; (j) mixing the extra-granular primary blend with a second amount of magnesium stearate to produce an extra-granular lubricated blend; (k) mixing the extra-granular lubricated blend; and (l) encapsulating the extra-granular lubricated blend in a capsule. The capsule is a size 3 HPMC capsule.

8. The method of claim 7, wherein, The pre-blend is mixed for 130 revolutions.

9. The method of claim 7, wherein, The intra-granular primary blend is mixed for 260 revolutions.

10. The method of any one of claims 7-9, wherein, The intra-granular lubricated blend is mixed for 130 revolutions.

11. The method of any one of claims 7-9, wherein, The extra-granular primary blend is mixed for 260 revolutions.

12. The method of any one of claims 7-9, wherein, The extra-granular lubricated blend is mixed for 130 revolutions.

13. The method of any one of claims 7-9, wherein, ​

Images