Compositions containing methylphenidate prodrugs, methods for preparing and using the same.

Abstract

The present invention provides compositions containing methylphenidate prodrugs, methods for preparing them, and methods for using them. [Solution] This technology relates to celldexmethylphenidate compounds and methods for synthesizing compounds having the formula. This technology provides specific d-threo-methylphenidate ("d-MPH", "d-methylphenidate", "dexmethylphenidate") conjugates or pharmaceutically acceptable salts thereof, and provides at least one once-daily dosing form of a d-methylphenidate conjugate in a composition containing unbound methylphenidate, which can provide both immediate and sustained-release PK profiles when compared to unbound d-methylphenidate, for example.

Description

[Technical Field]

[0001] Federal government-funded research or development [Not applicable] [Background technology]

[0002] background Methylphenidate is a psychostimulant that is a chain-substituted amphetamine derivative. Like amphetamine and cocaine, methylphenidate targets the central nervous system, particularly the dopamine transporter (DAT) and the norepinephrine transporter (NET). Because methylphenidate has the ability to bind to both dopamine transporters (DAT) and norepinephrine transporters (NET), it is thought to act by increasing the concentrations of dopamine and norepinephrine in the synaptic cleft. Although it is an amphetamine derivative, the pharmacology of methylphenidate and amphetamine differs because amphetamine is a dopamine transporter substrate, while methylphenidate acts as a dopamine transporter blocker. Methylphenidate, thus acting as a norepinephrine and dopamine reuptake inhibitor, blocks the reuptake of dopamine and norepinephrine (noradrenaline) into presynaptic neurons (possibly by stimulating dopamine release from dopamine nerve terminals at high doses), thereby increasing dopamine and norepinephrine levels at the synapse. Several in vitro studies have shown that methylphenidate is a more potent norepinephrine reuptake / reuptake inhibitor compared to dopamine. However, several in vivo studies have shown that methylphenidate is more potent in enhancing extracellular dopamine concentrations than norepinephrine concentrations. Unlike amphetamine, scientific and / or clinical research groups suggest that methylphenidate does not significantly promote the release of these two monoamine neurotransmitters at therapeutic doses.

[0003] Four isomers of methylphenidate are known to exist: d-erythromethylphenidate, l-erythromethylphenidate, d-threomethylphenidate, and l-threomethylphenidate. Initially, methylphenidate was marketed as a mixture of two racemates, d / l-erythromethylphenidate and d / l-threomethylphenidate. Subsequent studies showed that most of the desired pharmacological activity of the mixture was related to the threoiomer, and the racemate of isolated threomethylphenidate became available on the market. Later, the scientific community determined that the d-threoiomer was responsible for most of the stimulating activity. As a result, a new product containing only d-threomethylphenidate (also known as "d-threo-MPH") was developed.

[0004] Stimulants containing methylphenidate ("MPH") are thought to enhance the activity of the sympathetic and / or central nervous system (CNS). Stimulants such as MPH and its various forms and derivatives are used to treat a range of symptoms and disorders, primarily encompassing, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety, and / or arousal disorders.

[0005] Methylphenidate is currently approved by the U.S. Food and Drug Administration ("FDA") for the treatment of attention deficit hyperactivity disorder and narcolepsy. Methylphenidate has also shown efficacy in several off-label uses, including depression, obesity, and lethargy. In some embodiments, the prodrug of this technology may be administered for the treatment of attention deficit hyperactivity disorder and narcolepsy, or any condition requiring blockade of norepinephrine and / or dopamine transporters.

[0006] Childhood attention-deficit hyperactivity disorder (ADHD) has long been treated with stimulants. More recently, however, the increasing number of prescriptions for ADHD treatment in the adult population sometimes outpaces the growth of the pediatric market. There is a variety of medications currently used to treat ADHD, including several stimulants and some non-stimulants, but methylphenidate (e.g., marketed under the trademark Ritalin® by Novartis International AG, located in Basel, Switzerland) is commonly prescribed. Furthermore, classroom trials have shown that non-stimulants are less effective than amphetamine derivatives in improving behavior and attention in children with ADHD.

[0007] A significant portion of children with ADHD experience a behavioral decline (rebound or “crush”), typically in the afternoon or evening, as their medication wears off. Rebound symptoms may include irritability, irritability, hyperactivity worse than when unmedicated, sadness, crying, and, rarely, psychotic episodes. Symptoms may subside rapidly or last for several hours. Some patients may experience very severe rebounds / crushes, requiring discontinuation of treatment. The rebound / crush effect can also lead to addiction, as patients may be tempted to take additional doses of stimulants in an attempt to prevent the negative outcomes and side effects of anticipated rebounds / crushes.

[0008] Stimulants such as methylphenidate and amphetamines have been shown in conventional technology to exhibit noradrenergic and dopaminergic effects that can lead to cardiovascular events, including increased heart rate, hypertension, palpitations, tachycardia, and, in isolated cases, cardiomyopathy, stroke, myocardial infarction, and / or sudden death. As a result, currently available stimulants expose patients with pre-existing structural cardiac abnormalities or other serious cardiac signs to even greater health risks and are therefore not frequently used, or should be used cautiously, in this patient population.

[0009] Methylphenidate, like other stimulants and amphetamine derivatives, can be addictive and is prone to substance abuse. Oral abuse has been reported, and euphoria can be achieved through intranasal and intravenous administration.

[0010] Dependence on stimulants such as cocaine can occur even after very short periods of use due to their potent euphoric effects. For example, early signs of cocaine dependence include difficulty refraining from using cocaine when it is present or available. Many stimulants, including cocaine, have short elimination half-lives, requiring frequent dosing to maintain a "high." Chronic use of such stimulants beyond therapeutic doses can lead to a number of mental and / or physical problems. Mood effects may include anxiety, agitation, dominance, euphoria, panic, irritability, and fear. Behavioral symptoms may include, but are not limited to, extreme talkativeness, increased energy, increased vitality, theft or borrowing of money, unstable or bizarre behavior, violence, abstinence from previously enjoyable activities, and reckless and dangerous behavior. Examples of physical symptoms of stimulant dependence include, but are not limited to, one or more: decreased need for sleep, headache, nosebleeds, hoarseness, increased heart rate, muscle contractions, malnutrition, elevated body temperature, nasal perforation, arrhythmia, chronic runny nose, vasoconstriction, increased heart rate, elevated blood pressure, sexual dysfunction, loss of appetite, dilated pupils, increased risk of HIV infection, hepatitis C and other bloodborne diseases, intestinal gangrene, cravings, and tremors. Examples of psychological symptoms of stimulant dependence include, but are not limited to, one or more: severe paranoia, extreme mood swings, escapism, apathy, psychosis, hallucinations, lack of sound judgment, and justification of drug use. There are various factors that may induce or play a role in stimulant use disorder or stimulant dependence. Generally, these factors can be classified into three categories: genetic, biological, and environmental. Studies have shown that individuals with close relatives who have addiction problems are more likely to develop addictions themselves, including cocaine addiction. If the close relative is a parent, the likelihood of developing stimulant addiction is higher. Changes in brain function may be biological factors that correlate with addiction problems. For example, low dopamine levels in the brain may lead an individual to abuse substances for the purpose of achieving pleasure. Environmental factors, though not limited to these, include unpredictable situations in an individual's home life; stressors such as child abuse, loss of a loved one, or other traumatic events.In this field, there is a need for a form of methylphenidate that has a slow, gradual increase in blood / brain concentration of methylphenidate until a peak concentration is achieved, or a slow, gradual decrease in blood / brain concentration of methylphenidate after the peak concentration, or both. While we do not wish to be bound by any particular theory, a slow onset of stimulant concentration may reduce cardiovascular side effects, and a slow withdrawal may reduce rebound effects. It has also been suggested that a greater increase in synaptic dopamine per unit time (i.e., a higher rate of dopamine increase) may result in a more robust and stronger euphoric effect. A slow increase in brain concentration of methylphenidate may produce a lower rate of increase in synaptic dopamine, and therefore less reward and reinforcing effect. While we do not wish to be bound by any particular theory, it has also been suggested that a high occupancy rate of dopamine transporter receptors may reduce the reward and reinforcing effect of additional doses of stimulants such as cocaine. This can be achieved, for example, by repeated administration of large doses of a slow-starting form of methylphenidate that does not produce euphoria.

[0011] In this field, there is also a need for forms of methylphenidate that can provide a more rapid onset of methylphenidate blood / cerebral concentrations. While we do not wish to be bound by any theory, some indications may require a large and rapid initial spike in methylphenidate blood and / or cerebral concentrations to provide sufficient efficacy to the subject, while other indications may require lower blood / cerebral concentrations of methylphenidate. However, a small therapeutic dose of a form of methylphenidate with a rapid onset may still be beneficial to provide rapid efficacy when needed.

[0012] In this field, there is a further need for methylphenidate forms that can offer flexibility in dosing regimens. For example, a once-daily dosing form of methylphenidate in a composition that can provide both immediate-release and sustained-release PK profiles would be highly desirable.

[0013] There is a further need in the art for forms of methylphenidate that can maintain pharmacological benefit when administered via the oral route, but preferably have no pharmacological activity or substantially reduced pharmacological activity when administered via the injection or intranasal routes. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0014] BRIEF SUMMARY The present technology provides a specific d-threo-methylphenidate ("d-MPH", "d-methylphenidate", "dexmethylphenidate") conjugate or a pharmaceutically acceptable salt thereof, and can provide both immediate and sustained release PK profiles, for example, when compared to unbound d-methylphenidate, and provides at least one once-daily dosage form of a d-methylphenidate conjugate in a composition comprising unbound methylphenidate. The release profile provides, in some examples, the ability of a prodrug or composition to be administered using a dosing schedule that is not readily available with unbound d-methylphenidate. In some embodiments, the unbound methylphenidate in the composition can be d-methylphenidate, l-methylphenidate or a mixture thereof, and / or a therapeutically or pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present technology provides a prodrug composition comprising at least one conjugate of d-methylphenidate having the structure of Formula I:

Chemical formula

[0016] In another aspect, the present technology provides at least one prodrug composition comprising at least one conjugate, wherein the at least one conjugate is d-methylphenidate-CO2CH2-nicotinoyl-L-Ser (Formula I) or a pharmaceutically acceptable salt thereof, and unbound methylphenidate.

[0017] In a further aspect, the present technology provides a composition comprising unbound 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.

[0018] In yet another aspect, the present technology provides a method for chemically synthesizing the d-methylphenidate-CO2CH2-nicotinoyl-L-Ser conjugate of the present technology by performing appropriate steps for binding d-methylphenidate to a -CO2CH2-nicotinoyl-L-Ser ligand.

[0019] In a further aspect, some embodiments of the compositions of the present technology comprising (a) a conjugate of Formula I and / or a pharmaceutically acceptable salt thereof, and (b) unbound methylphenidate (including d-methylphenidate) and / or a pharmaceutically acceptable salt thereof unexpectedly show an increase in the plasma concentration of d-methylphenidate after T max hours (or thereafter) and produce a controlled or sustained release profile.

[0020] In another aspect, some embodiments of the compositions of the present technology comprising (a) a conjugate of Formula I and / or a pharmaceutically acceptable salt thereof, and (b) unbound methylphenidate (including d-methylphenidate) and / or a pharmaceutically acceptable salt thereof show an increase in the plasma concentration of d-methylphenidate at about 0 to about 4 hours after oral administration as compared to an equimolar dose of unbound d-methylphenidate released from Concerta®.

[0021] In further embodiments, several embodiments of the composition of the Art, comprising (a) a conjugate of Formula I and / or a pharmaceutically acceptable salt thereof, and (b) unbound methylphenidate (including d-methylphenidate) and / or a pharmaceutically acceptable salt thereof, show an increase in plasma concentration of d-methylphenidate up to about 4 hours after oral administration compared to the equimolar dose of oral administration of unbound d-methylphenidate released from Concerta®.

[0022] In further embodiments, several embodiments of the composition of the present technology, comprising (a) a conjugate of formula I and / or a pharmaceutically acceptable salt thereof, and (b) unbound methylphenidate and / or a pharmaceutically acceptable salt thereof, surprisingly show less inter-patient variability in the oral pharmacokinetic (PK) profile compared to unbound d-methylphenidate.

[0023] In yet another embodiment, some embodiments of the composition of the present technology are provided in an amount sufficient to provide an increase in AUC compared to unbound d-methylphenidate when administered orally in equimolar doses.

[0024] In further embodiments, some embodiments of the composition of this technology, when administered orally in equimolar doses, exhibit a higher T content of released d-methylphenidate compared to unbound d-methylphenidate. max (or thereafter) over a period of surprisingly low C max And it provides a lower AUC, but is provided in an amount sufficient to provide a significantly increased partial AUC.

[0025] In further embodiments, some embodiments of the compositions of this technology exhibit lower C content compared to unbound d-methylphenidate when administered orally in equimolar doses. max and provides a similar AUC, but the T of released d-methylphenidate max It is provided in an amount sufficient to provide a significantly increased partial AUC for the subsequent (or later) period.

[0026] In an alternative aspect, some embodiments of the compositions of the present technology are thought to result in a reduction of side effects when administered at equimolar dosages, compared to unbound d-methylphenidate, and in some other aspects, a reduction in the potential for abuse is also considered, compared to unbound d-methylphenidate.

[0027] Furthermore, some embodiments of the compositions of the present technology also unexpectedly provide a sustained T max when administered at equimolar dosages, compared to unbound d-methylphenidate, and / or provide an amount sufficient to provide an equivalent T max when administered orally at equimolar dosages, compared to unbound d-methylphenidate.

[0028] Furthermore, some embodiments of the compositions of the present technology also unexpectedly provide an amount sufficient to provide a shorter T max when compared to an equimolar oral dosage of unbound d-methylphenidate released from Concerta®.

[0029] In addition, some embodiments of the compositions of the present technology are also thought to unexpectedly provide an amount sufficient to provide a longer half-life (T 1 / 2 ) when compared to an equimolar oral dosage of unbound d-methylphenidate released from Concerta®.

[0030] In addition, some embodiments of the compositions of the present technology are also thought to unexpectedly provide an amount sufficient to provide a longer T 1 / 2 when administered orally at equimolar dosages, compared to unbound d-methylphenidate.

[0031] Furthermore, the Technology provides at least one method for treating one or more subjects (human or animal) or patients (human or animal) having at least one disease, disorder or condition mediated by controlling, preventing, limiting or inhibiting neurotransmitter uptake / reuptake or hormone uptake / reuptake, the method comprising orally administering a pharmaceutically and / or therapeutically effective amount of the Technology composition to one or more subjects or patients, comprising unbound methylphenidate and / or a pharmaceutically acceptable salt thereof and a conjugate of formula I and / or a pharmaceutically acceptable salt thereof.

[0032] In a further embodiment, the Technology provides at least one method for treating a subject (human or animal) having at least one disorder or condition requiring stimulation of the central nervous system of the subject, comprising orally administering a pharmaceutically effective amount of the Technology composition comprising unbound 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 requiring stimulation of the central nervous system of the subject.

[0033] In a further embodiment, the Technology provides at least one method for treating a subject (human or animal) having at least one disorder or condition requiring stimulation of the central nervous system of the subject, comprising orally administering a therapeutically effective amount of a composition of the Technology comprising unbound 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 requiring stimulation of the central nervous system of the subject.

[0034] In another embodiment, the Technology provides one or more methods of administering a composition comprising at least one conjugate of d-methylphenidate and unbound methylphenidate to a subject, wherein the administration reduces the number and / or amount of metabolites produced compared to unbound d-methylphenidate. In other embodiments, one or more methods of administering a composition of the Technology are considered to reduce the subject's exposure to litalic acid compared to unbound d-methylphenidate. It is desirable to minimize exposure to metabolites such as litalic acid that do not significantly contribute to the intended therapeutic effect due to potential side effects or toxicity that may still occur as a result of the potential secondary pharmacological effects of the metabolites. In some embodiments, the compositions of the Technology can reduce overall exposure to litalic acid by about 25% to about 75%.

[0035] In further embodiments, the compositions of the present technology are considered to provide increased water solubility of d-methylphenidate conjugates or prodrugs compared to unbound d-methylphenidate. In another embodiment, the increased water solubility is considered to allow the compositions to be formed into specific dosage forms at higher concentrations, administration strengths, or higher dose-loading volumes than unbound d-methylphenidate. In some embodiments, such dosage forms may include, for example, oral thin films or strips.

[0036] In a further embodiment, administration of d-methylphenidate compositions containing d-methylphenidate conjugates and unconjugated methylphenidate to patients (humans or animals) is thought to result in a reduction in inter-patient variability of d-methylphenidate plasma concentrations compared to unconjugated d-methylphenidate, and thus an improvement in the safety profile.

[0037] In another alternative embodiment, the 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 unconjugated methylphenidate, wherein the administration treats attention deficit hyperactivity disorder of the subject.

[0038] In another alternative embodiment, the Technology provides at least one method for treating an eating disorder, bulimia, obesity, narcolepsy, chronic fatigue, sleep disorder, excessive daytime sleepiness (EDS), cocaine dependence, or stimulant dependence in a subject or patient, 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 unconjugated methylphenidate, wherein the administration treats the subject or patient an eating disorder, bulimia, obesity, narcolepsy, chronic fatigue, sleep disorder, excessive daytime sleepiness (EDS), cocaine dependence, or stimulant dependence.

[0039] In another further embodiment, the technology provides a composition for treating at least one subject or patient having a disorder or condition requiring stimulation of the central nervous system of the subject, wherein the composition comprises unbound methylphenidate and a d-methylphenidate conjugate, and has a reduced potential for abuse at administration compared to unbound d-methylphenidate.

[0040] In a further embodiment, the composition of the present technology may be considered to exhibit reduced or prophylactic pharmacological activity when administered via parenteral routes compared to free unbound d-methylphenidate when administered in equimolar amounts, or to exhibit a reduction in the plasma or blood concentration of released d-methylphenidate when administered intranasally, intravenously, intramuscularly, subcutaneously, or rectally.

[0041] In some embodiments, the compositions of the present technology have a sustained-release or controlled-release profile, as measured by the plasma concentration of released d-methylphenidate when administered orally in equimolar doses compared with unbound d-methylphenidate. In some embodiments, the plasma concentration of d-methylphenidate released from the conjugate of the composition increases 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 compared with unbound d-methylphenidate. In further embodiments, the controlled-release profile of d-methylphenidate of the composition is approximately equal to that of unbound d-methylphenidate. max This provides plasma concentrations of d-methylphenidate that are sustained for a longer period compared to unbound d-methylphenidate.

[0042] In other embodiments, the composition, when administered orally once daily, exhibits lower AUC and lower C25 when compared to unbound d-methylphenidate administered orally once daily. max It has an equivalent T in the latter half of the day max and has a higher d-methylphenidate plasma concentration.

[0043] In another embodiment, the technology provides a pharmaceutical kit comprising a specific amount of individual doses in a package, each dose comprising a pharmaceutical and / or therapeutically effective amount of composition comprising at least one conjugate of d-methylphenidate and unbound methylphenidate. The pharmaceutical kit also includes instructions for use.

[0044] In another further embodiment, the technology provides an oral formulation. The oral formulation may comprise a therapeutic dose of (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.

[0045] In some embodiments, compositions of the present technology comprising at least one conjugate of unbound methylphenidate and d-methylphenidate can be used in neonates, children, adolescents, adults, and / or elderly individuals with ADHD. For example, in some embodiments, the compositions can be used in once-daily administration with potentially improved onset and a longer duration of action, which may be beneficial attributes for neonates, children, and / or adolescent individuals with ADHD.

[0046] Aspects of the present disclosure are described herein merely as examples, with reference to the accompanying drawings. [Brief explanation of the drawing]

[0047] [Figure 1] Figure 1 shows a flow chart of the synthesis of (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate according to several embodiments. In one embodiment, nicotinic acid is reacted with L-Ser('Bu)O'Bu HCl (O-tert-butyl-L-serine tert-butyl ester hydrochloride) in the presence of MTBE and triethylamine in acetonitrile.

[0048] [Figure 2] Figure 2 shows a flow chart of the synthesis of the first celldexmethylphenidate chloride intermediate (first SDX intermediate) according to one embodiment.

[0049] [Figure 3] Figure 3 shows a flow chart of the synthesis of the second celdexmethylphenidate chloride intermediate (second SDX intermediate) according to one embodiment.

[0050] [Figure 4] Figure 4 shows a flow chart of crude cellulose methylphenidate chloride synthesis according to one embodiment.

[0051] [Figure 5]Figure 5 shows a flowchart of the first recrystallization for the purification and isolation of the SDX drug substance according to one embodiment.

[0052] [Figure 6] Figure 6 shows a flowchart of a second recrystallization process for the purification and isolation of the SDX drug substance according to one embodiment.

[0053] [Figure 7] Figure 7 shows a reslurry of crystallized SDX solid according to one embodiment.

[0054] [Figure 8] Figure 8 shows one embodiment of a method for manufacturing SDX / d-MPH capsules. [Modes for carrying out the invention]

[0055] Detailed description of the invention Various embodiments are described in detail with reference to the drawings, and similar reference numerals represent similar parts and assemblies across multiple figures. It should be understood that this disclosure is not limited to and is therefore subject to change the specific methodologies, protocols, and reagents described herein. It should also be understood that the terminology used herein is for the sole purpose of describing specific embodiments and is not intended to limit the scope of this disclosure or the appended claims.

[0056] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context otherwise clearly indicates.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains.

[0058] This technology provides one or more compositions comprising celdexmethylphenidate chloride (SDX). The compositions have beneficial properties as further described herein.

[0059] The use of the term "methylphenidate" herein means that it includes any of the stereoisomers of methylphenidate, including the four stereoisomers d-erythromethylphenidate, l-erythromethylphenidate, d-threomethylphenidate, and l-threomethylphenidate, as well as their salts and derivatives. Methylphenidate is interchangeable with methylphenyl(piperidine-2-yl)acetate. The term "methylphenidate" includes all salt forms. Methylphenidate is also known by its trade names Concerta® (marketed by Janssen Pharmaceuticals, Inc. in Beerse, Belgium), Ritalin®, Ritalin® SR, Methylin®, and Methylin® ER (all marketed by Novartis International AG in Basil, Switzerland). The methylphenidate used in this technology includes, but is not limited to, d-erythromethylphenidate, l-erythromethylphenidate, d-threomethylphenidate, and l-threomethylphenidate, and can be any stereoisomer of methylphenidate. In a preferred embodiment, the conjugate comprises a single d-threomethylphenidate isomer. In another embodiment, the prodrug conjugate is its optically active single isomer.

[0060] The use of the term "unbound methylphenidate" refers to methyl 2-phenyl-2-(piperidine-2-yl)acetate and its salts.

[0061] The term "stereoisomer" as used below refers to two molecules that are stereoisomers of each other, meaning they are made up of the same atoms linked in the same arrangement, but the atoms are in different spatial positions. The difference between two stereoisomers can only be seen when considering the three-dimensional arrangement of the molecules.

[0062] As used below, bioavailability refers to the proportion of a drug or other substance that enters the circulation over time after being introduced into the body and therefore may have an active effect.

[0063] C used below max In pharmacokinetics, this term refers to the maximum (or peak) plasma concentration that a drug achieves in a specific compartment or test area of ​​the body after administration and before administration of a second dose.

[0064] T used below max C max This is a term used in pharmacokinetics to describe the point at which C is observed. After intravenous administration, the concentration is always decreasing after administration, so C max and T max This is closely dependent on the experimental protocol.

[0065] As is known to those skilled in the art, the term “steady state” refers to a state in which the total intake of a drug is in near dynamic equilibrium with its elimination. In a steady state, the total drug exposure does not change significantly during a continuous course of medication. A steady state is typically achieved after a period of about 4 to 5 times the half-life of the drug after the start of normal medication.

[0066] The term "dosage" refers to the total amount of drug or active ingredient ingested by an individual subject at each instance.

[0067] As used herein, the term “subject” means human or animal, including but not limited to human or animal patients.

[0068] The term "patient" refers to a human or animal subject requiring treatment.

[0069] The use of the term "inter-patient variability" refers to an estimate of the level of pharmacokinetic variation between different individuals administered the same dose of the same drug. This estimate is, for example, C max AUC last AUCinf and T max This can be done by calculating the coefficient of variation (CV) of a specific pharmacokinetic parameter, including [specific parameter]. When comparing patient-to-patient variability between different drugs or between the same drug in different formulations, a lower CV indicates a decrease in patient-to-patient variability, while a higher CV indicates an increase in patient-to-patient variability.

[0070] The "coefficient of variation" (CV) is a term used in statistics and is calculated based on the following formula: CV = standard deviation / mean * 100.

[0071] AUC last In pharmacokinetics, this term is used to represent the area under the curve in a plot of drug concentration in blood, serum, or plasma against time from time = 0 (or before administration) to the time of the last measurable drug concentration.

[0072] AUC inf In pharmacokinetics, the area under the curve in a plot of drug concentration in blood, serum, or plasma against time from 0 (or before administration) to infinity is a term used to represent the area under the curve.

[0073] In the following, molar equivalent refers to the number of moles of a substance equal to the number of moles in a given mass (weight) or volume. For example, a dose of d-methylphenidate that is the molar equivalent of approximately 0.1 mg of d-methylphenidate hydrochloride per day will provide the same number of moles of d-methylphenidate as 0.1 mg of d-methylphenidate hydrochloride.

[0074] As used herein, phrases such as “reduced,” “reduced,” “attenuated,” or “lowered” refer to pharmacological activity, area under the curve (AUC), and / or peak plasma concentration (C). maxThis means including at least about 10% change in ) and a larger percentage change is preferable to reduce the potential for abuse and overdose of the conjugates of this technology compared to unconjugated methylphenidate. For example, the change may be greater than increments of 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 in between.

[0075] As used herein, “pharmaceutically effective amount” means an amount that has a pharmacological effect. As used herein, “pharmaceutically acceptable salt” is a salt of d-methylphenidate conjugate or unconjugated methylphenidate or both, which, when used in a pharmacochemically effective amount, have at least one pharmacological effect.

[0076] As used herein, “therapeutic effective dose” means an amount effective to treat a disease or symptom. As used herein, “therapeutically acceptable salt” is a pharmaceutically acceptable salt of d-methylphenidate conjugate or unconjugated methylphenidate or both in the composition of this technology, which, when used in a therapeutically effective dose, is effective to treat a disease, symptom, or syndrome.

[0077] As used herein, the term “Attention Deficit Hyperactivity Disorder” (ADHD) encompasses a variety of subtypes of ADHD, including, for example, subjects who exhibit little to no symptoms of hyperactivity or impulsivity, or subjects who are primarily inattentive (formerly known as Attention Deficit Disorder (ADD)).

[0078] As used herein, the term “prodrug” refers to a substance that is inactive or has reduced pharmacological activity but is converted to an active drug by chemical or biological reactions in the body. In this technology, a prodrug is a conjugate of at least one drug, d-methylphenidate, a linker, and a nicotinoyl-L-serine moiety. Thus, the conjugate in this technology is a prodrug, and the prodrug in this technology is a conjugate.

[0079] Prodrugs are often useful because, in some embodiments, they may be easier to administer or process than the parent drug. For example, a prodrug may have greater bioavailability when administered orally, compared to the parent drug. Prodrugs may also have improved solubility in water and / or other solvents compared to the parent drug. One embodiment of a prodrug may be a d-methylphenidate conjugate that is metabolized to the active moiety. In some embodiments, a prodrug is chemically converted at in vivo administration to a more biologically, pharmaceutically, or therapeutically active form of the compound. In some embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to a biologically, pharmaceutically, or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified so that the active compound is regenerated at in vivo administration. In some embodiments, prodrugs are designed to alter the metabolic or transport properties of a drug, the variation typically varying depending on the route of administration; in other distinct embodiments, they are designed to mask side effects or toxicity, improve bioavailability and / or water solubility, enhance the flavor of the drug, or alter other characteristics or properties of the drug.

[0080] d-methylphenidate prodrugs can be prepared to have various different chemical forms, including chemical derivatives or salts. Such d-methylphenidate prodrugs can also be prepared to have different physical forms. For example, d-methylphenidate prodrugs can be amorphous, have different crystalline polymorphs, or exist in different solvated or hydrated states such as hemihydrate, monohydrate, or hydrate (nH2O, where n is 0.5, 1, or 2). Such polymorphs can be produced, for example, by using crystallization conditions to isolate free base and salt forms, and / or by ball milling such forms.

[0081] By altering the crystalline form of d-methylphenidate prodrugs, their physical properties can be changed. For example, crystalline polymorphs typically have different solubility from each other, so more thermodynamically stable polymorphs have lower solubility than less thermodynamically stable polymorphs. Pharmaceutical polymorphs may also differ in properties 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.

[0082] A cocrystal is a multicomponent crystal containing two or more non-identical molecules, which is solid under ambient conditions (i.e., 22°C, 1 atm) when all components are in their pure form. The components include a target molecule (i.e., d-methylphenidate prodrug) and a molecular cocrystal-forming agent that coexists in the cocrystal at the molecular level within the single crystal.

[0083] Cocrystals (cocrystal-forming agents) containing two or more molecules that are solid under ambient conditions (Jmarsson et al., 2004) represent a long-known type of compound (see Wohler, 1844). However, cocrystals are relatively understudied. A survey of 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 supplement) 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 a topic of discussion and growing interest. In particular, the fact that all cocrystal components are solid under ambient conditions is an important practical consideration because the synthesis of cocrystals can be achieved via solid-state techniques (mechanochemistry) (Shan et al., 2002), and chemists can exercise some control over the composition of the cocrystal, as molecular recognition, especially hydrogen bonding, can be induced during the selection of cocrystal formation. These features distinguish cocrystals from solvates, another widely known group of multicomponent compounds. Solvates are characterized far more broadly than cocrystals (for example, in CSD, 1652 cocrystals have been reported for 10,575 solvates; version 5.27 (May 2006) 3D coordinates, RO.075, no ions, organic only).

[0084] Having a novel form of d-methylphenidate prodrug with improved properties would be advantageous. Specifically, it is desirable to identify an improved form of d-methylphenidate prodrug exhibiting significantly improved properties, including increased aqueous and / or solvent solubility and stability. Furthermore, it is desirable to improve processability or the preparation of pharmaceutical formulations. For example, the needle-shaped crystalline form or crystal habit of d-methylphenidate prodrug can cause aggregation even in compositions in which d-methylphenidate prodrug is mixed with other substances, resulting in a heterogeneous mixture. It is also desirable to increase or decrease the dissolution rate of d-methylphenidate prodrug-containing pharmaceutical compositions in water or other solvents, thereby increasing or decreasing the bioavailability of orally administered compositions and providing a faster or delayed onset of therapeutic effect. It is also desirable to have a form of d-methylphenidate prodrug that, compared to an equivalent amount of currently known forms of d-methylphenidate prodrug, has a therapeutic plasma concentration that reaches peak plasma levels faster or slower, lasts longer, and has a higher or lower total exposure upon administration to a subject. The improved properties described above can be modified in the most beneficial way for specific d-methylphenidate prodrugs to achieve particular therapeutic effects.

[0085] The d-methylphenidate prodrug or conjugate and unconjugated methylphenidate of this technology may be a positively charged (cationic) molecule, a pharmaceutically acceptable anionic or cationic salt form, or a salt mixture having any ratio between positive and negative components.These anionic salt forms include, for example, acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, and bisulfate. T, d-tartrate, l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hibenzate, isethionate, malonate, methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acephylline, acetulate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hex Sanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, flute, fusiderate, galacturate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hyprate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisylate, ole Examples include, but are not limited to, oxalates, palmitates, piclates, pivalates, propionates, pyrophosphates, salicylates, salicyl sulfates, sulfosalicylates, tannates, terephthalates, thiosalicylates, tribrophenates, valerates, valproates, adipates, 4-acetamide benzoates, cansilates, octanoates, estates, esylates, glycoates, thiocyanates, or undecylenates.In a preferred embodiment, the anionic salt form is selected from the group consisting of chloride, hydrogen carbonate (bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate, hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite), propionate, benzenesulfonate, hypophosphate, phosphate, bromate, iodate, chlorate, fluoride, and nitrite.

[0086] In some embodiments, the salt form of the conjugate is selected from the group consisting of chloride, hydrogen carbonate (bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate, hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite), propionate, benzenesulfonate, hypophosphate, phosphate, bromate, iodate, chloride, fluoride, and nitrite. In some embodiments, the salt form of unconjugated methylphenidate is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, formate, mesylate, tartrate, salicylate, sulfate, citrate, nitrate, hydrogen sulfite, propionate, benzenesulfonate, and acetate.

[0087] Examples of cationic salt forms include, but are not limited to, sodium, potassium, calcium, magnesium, lithium, corinate, lysinium, or ammonium.

[0088] While we do not wish to limit ourselves to the following theories, the prodrugs / conjugates of this technology are thought to undergo rate-limiting enzyme hydrolysis in vivo, followed by a cascade reaction resulting in the rapid formation of d-methylphenidate and its respective ligands, metabolites, and / or derivatives. The prodrug conjugates of this technology are non-toxic or have very low toxicity at a given dose level and are preferably known drugs, natural products, metabolites, or GRAS (Generally Recognized As Safe) compounds (e.g., preservatives, dyes, flavorings) or non-toxic mimetic compounds or derivatives thereof. Synthetic scheme for producing cellulose methylphenidate chloride

[0089] The abbreviations for the components of the composition of this technology include: SDX represents methylphenidate chloride; MPH represents methylphenidate; d-MPH represents methylphenidate hydrochloride; CMCF represents chloromethyl chloroformate; MTBE represents methyl-t-butyl ether; MIBK represents 4-methyl-2-pentanone; t Bu represents tert-butyl; Ph represents phenyl; T3P represents propylphosphonic anhydride; ACN represents acetonitrile.

[0090] In some embodiments, the seldexmethylphenidate conjugate is of formula I: [ka] It is the ionic salt celdexmethylphenidate chloride, represented by [the formula shown].

[0091] In a preferred embodiment of the composition of this technology, the d-methylphenidate activity is derived from two sources: celdexmethylphenidate chloride and unbound methylphenidate and / or pharmaceutically acceptable salts thereof.

[0092] In some embodiments, celdexmethylphenidate chloride is synthesized in four steps, starting from dexmethylphenidate hydrochloride (d-MPH), chloromethyl chloroformate (CMCF), and (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate, as shown below. [ka] Preparation of (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate

[0093] In some embodiments, (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate is prepared according to Scheme 1.

[0094] Scheme 1: [ka]

[0095] (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate was synthesized by reacting O-tert-butyl-L-serine tert-butyl ester hydrochloride and nicotinic acid in the presence of MTBE and triethylamine (Et3N) in acetonitrile. 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, washed twice with aqueous ammonium chloride, and washed again with water. The final MTBE solution was distilled to reduce the water content. The (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate-MTBE solution was crystallized using MTBE and n-heptane to obtain S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate as an isolated solid.

[0096] Figure 1 shows a flow chart of the synthesis of (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate in several embodiments. Nicotinic acid is reacted with L-Ser('Bu)O'Bu HCl (O-tert-butyl-L-serine tert-butyl ester hydrochloride) in the presence of MTBE and triethylamine in acetonitrile. Then, T3P in 50% acetonitrile is added to the reactants 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 twice with Na2CO3, 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 using activated carbon, and distillation and cooling step 108 using n-heptane. (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate seed crystals are added in the stirring and cooling step 110 to initiate crystallization. After the filtration and washing step 112 and the drying step 114, S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate for downstream use is produced. Preparation of the first intermediate

[0097] In some embodiments, the first celdexmethylphenidate chloride intermediate is prepared according to Scheme 2.

[0098] Scheme 2: [ka]

[0099] MTBE (349.0 ± 3.0 kg) and 2,6-lutidine (2.8 equivalents, 52.4 ± 0.5 kg) were added to dexmethylphenidate hydrochloride (d-MPH) (1.0 equivalent, 47.1 ± 0.2 kg) in the reactor. After stirring the reaction mixture (at 20°C ± 5°C for at least 20 minutes), chloromethyl chloroformate (1.6 equivalents, 35.8 ± 0.3 kg) was added to the reactor so that the temperature of the reaction mixture did not exceed 30°C. The reaction mixture was stirred at 25°C ± 5°C for at least 8 hours. Then, the reaction mixture was quenched with approximately 3 volumes of water (relative to d-MPH) so that the temperature of the reaction mixture did not exceed 30°C. The reaction mixture was stirred at 20 ± 5°C for at least 6 hours, and the aqueous layer was separated. The MTBE layer was washed with 3 volumes of aqueous sodium bicarbonate, followed by 3 volumes of water. The MTBE solution was distilled at atmospheric pressure at an internal temperature of 59°C or below until it reached approximately 4.3 volumes relative to d-MPH, and then cooled to below 50°C. Next, the MTBE solution was cooled to 20±5°C, and its water content was determined. Distillation was completed when the MTBE solution reached a water content of 0.2% or less. The yield was 90–99%.

[0100] Figure 2 shows a flow chart of the synthesis of the first celdexmethylphenidate chloride intermediate (first SDX intermediate) 200 in several embodiments. Dexmethylphenidate HCl is added to a reactor containing MTBE and 2,6-lutidine. The resulting reaction mixture can then be stirred at 20±5°C in stirring step 202. In some embodiments, the duration of stirring step 202 can be at least 20 minutes. Chloromethyl chloroformate is then added to the reactor to produce the first intermediate reaction mixture, which can then be stirred at 25±5°C in stirring step 204. In some embodiments, the duration of stirring step 204 can be at least 8 hours. Once 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 30°C. In stirring step 206, the first intermediate reaction mixture is stirred at 20±5°C and the aqueous layer can be separated. In some embodiments, the duration of stirring step 206 can be at least 6 hours. In washing step 208, the MTBE layer of the first intermediate reaction mixture can be washed with an aqueous NaHCO3 solution and water. In some embodiments, the MTBE layer is washed with 3 volumes of NaHCO3 solution and 3 volumes of water. Completion of washing 208 can be determined by the pH of the final aqueous phase, which is 6 or higher.

[0101] In distillation step 210, the MTBE solution / layer of the first intermediate reaction mixture is distilled at atmospheric pressure and cooled to below 50°C. In some embodiments, 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 the distillation is repeated. After distillation 212, the first intermediate in the MTBE solution is cooled to 20±5°C.

[0102] In various embodiments, synthesis 200 may have in-process control steps 214, 216, 218 and / or 220. In-process control step 214 may be performed between stirring steps 204 and 206, and the completion of the reaction mixture is determined by HPLC analysis. In some embodiments, the reaction is complete when the dexmethylphenidate content is less than 4% area relative to the first SDX intermediate. In-process control 216 may be performed between washing 208 and distillation 210, and the pH of the final aqueous phase is determined. If the pH is greater than 6, the MTBE layer is washed again with aqueous NaHCO3 solution and water until the pH of the final aqueous phase is 6 or greater. In-process control step 218 is performed after distillation 212, and the water content of the first intermediate in the MTBE solution is measured by Karl Fischer analysis. In some embodiments, the obtained water content of the first intermediate in the MTBE solution is 0.2% or less. 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% or less. In the in-process control step 220, the final first intermediate in the MTBE solution is analyzed, and the weight % and mass of the first SDX intermediate are determined by HPLC. In some embodiments, the yield of the first SDX intermediate is 90–99%. Preparation of the second intermediate

[0103] In some embodiments, the second celdexmethylphenidate chloride intermediate is prepared according to scheme 3.

[0104] Scheme 3 [ka]

[0105] The first celdexmethylphenidate chloride intermediate solution (1.2 equivalents; actual mass of the first intermediate 48.0-51.2 kg) was added to (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate (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 it was distilled under vacuum at an internal temperature of 59°C or less to a volume of approximately 8. The solution was then cooled to 20±5°C, and the water content was determined. Distillation was completed when the water content of the solution reached 0.15% or less. The reaction mixture was heated to 60±3°C and stirred for at least 45 hours. The reaction was complete when the content of (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate was less than 10% of the area relative to the second celdexmethylphenidate chloride intermediate. The reaction mixture was cooled to 20±5°C, and 4.0 M HCl solution in dioxane (0.15 equivalents, 4.85-5.15 kg) was added, and the mixture was stirred at 20±5°C for at least 5 minutes. Then, 12 volumes of 4-methyl-2-pentanone (MIBK) were added to the reaction mixture.

[0106] The reaction mixture was distilled at atmospheric pressure at an internal temperature of 45°C or lower to remove acetonitrile and MIBK, obtaining 10 volumes of the target product. After distillation, the temperature of the reaction mixture was adjusted to 50±5°C. To remove the solid, 16 volumes of n-heptane were added over 2 hours to maintain the reaction temperature at 40-55°C. After the solid was removed, a second celdexmethylphenidate chloride intermediate seed crystal (0.11 wt% of the theoretical yield of the second celdexmethylphenidate chloride intermediate calculated relative to the amount of (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate added) was added to the reaction mixture at 50±5°C to initiate crystallization, after which n-heptane was added. After the addition of n-heptane, the reaction mixture was cooled to 20±5°C, stirred for at least 6 hours, and filtered. The second celdexmethylphenidate chloride intermediate solid was washed with a mixture of MIBK and n-heptane (volume ratio 3:1) and dried at 45°C or below for at least 12 hours (LOD less than 1.0%) to obtain a crystalline solid of the second celdexmethylphenidate chloride intermediate.

[0107] Figure 3 shows a flow chart of the synthesis of the second celdexmethylphenidate chloride intermediate (second SDX intermediate) 300 in several embodiments. (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate is added to the reactor, the first celdexmethylphenidate chloride intermediate solution (first SDX intermediate) is added, and the stirrer is started. In the distillation step 302, acetonitrile is added to the resulting reaction mixture and distilled under vacuum at an internal temperature of 59°C or less. In some embodiments, 9 volumes of acetonitrile are added to the reaction mixture and distilled down to about 8 volumes. In the heating step 304, the reactants are heated to 60±3°C and stirred for at least 45 hours. In some embodiments, the reaction mixture is heated to 59°C. Once the reaction is complete, in cooling step 306 the reaction mixture is cooled to 20±5°C, HCl in the dioxane is added, and the mixture is stirred at 20±5°C for at least 5 minutes, and MIBK is added to the reaction mixture. In some embodiments, 4.0 M HCl in the dioxane may be used and / or 12 volumes of MIBK may be used.

[0108] Next, in distillation step 308, the reaction mixture is distilled at atmospheric pressure at an internal temperature of 45°C or less to remove acetonitrile and MIBK. In some embodiments, the reaction mixture is distilled to obtain 10 volumes of the target product. After distillation, in adjustment step 310, the temperature of the reaction mixture is adjusted to 50±5°C. Next, the reaction mixture is checked for solidity. In some embodiments, if solidity is detected, n-heptane can be added over a period of at least 2 hours to maintain a reaction temperature of 40-55°C. If no solidity is detected after distillation step 308, a second SDX intermediate seed crystal is added to the reaction mixture in stirring step 312 to promote crystallization, then n-heptane is added and stirred for at least 5 minutes. The reaction mixture is cooled to 20±5°C while stirring for at least 6 hours (cooling step 314) and filtered (filtration 316). In the washing and drying step 318, the second SDX intermediate solid is washed with MIBK and n-heptane and dried at 45°C or below for at least 12 hours to obtain the second SDX intermediate as a crystalline solid. In some embodiments, the second SDX intermediate solid is washed with MIBK:n-heptane in a 3:1 ratio. In some embodiments, the target drying temperature is 40-45°C.

[0109] In various embodiments, synthesis 300 may have in-process control steps 320, 322, and / or 324. In-process control step 320 may be performed between distillation step 302 and heating step 304, and the water content of the reaction mixture is measured by Karl Fischer analysis. In some embodiments, distillation is considered complete when the water content of the second intermediate reaction mixture is 0.15% or less. If the KF result is greater than 0.15%, additional acetonitrile may be added to the solution and distillation may be repeated until the water content is 0.15% or less. In some embodiments, 2.5 volumes of acetonitrile are added to the solution. In-process control step 322 determines the completion of the reaction mixture by HPLC. In some embodiments, the reaction is considered complete when the content of (S)-tert-butyl 3-(tert-butoxy)-2-(nicotinamide)-propanoate is 10.0% or less of the area of ​​the second SDX intermediate. In some embodiments, if the sample does not meet the in-process criteria, stirring can be continued at 60±3°C for at least 4 hours before resampling. The in-process control step 324 determines the drying loss of the second SDX intermediate solid. In some embodiments, the yield of the second SDX intermediate as a crystalline solid is 70–85%. Preparation of crude cellulose methylphenidate chloride

[0110] In some embodiments, crude cellulose methylphenidate chloride is prepared according to Scheme 4.

[0111] Scheme 4: [ka]

[0112] Anhydrous 1,4-dioxane (3.4 vol) and sulfolane (4.6 vol) were added to the second celdex-methylphenidate chloride intermediate crystalline solid (63.5-68.8 kg) in the reactor, and the stirrer was started. 4.0 M HCl (2.15 equivalents, 53.98-59.86 kg) was added to the dioxane, and the reaction mixture was heated to 58 ± 3 °C, stirred for 12-18 hours, and then cooled to 20-25 °C. Once the reaction was complete, the reaction mixture was heated to 40-45 °C, and 2-butanone was added. SDX seed crystals (0.11 wt%) relative to the theoretical yield of crude SDX, calculated relative to the second celdex-methylphenidate chloride intermediate crystalline solid were added to the reaction mixture, and the mixture was stirred at 40-45 °C for at least 15 minutes. To remove the solid, an additional 2-butanone (19.2 vol) was added over 3 hours to promote precipitation. After the solid was removed, the reaction mixture was cooled to 37–39°C, and SDX seed crystals (0.11 wt%) were added, followed by the addition of 2-butanone. The reaction mixture was cooled to below 10°C over a period of 3 hours and stirred below 10°C for 2–8 hours. The resulting solid was filtered, washed with approximately 2 volumes of 2-butanone, and dried below 50°C for at least 10 hours to obtain crude SDX as a crystalline solid (LOD less than 1.0%). The yield of isolated crude SDX solid was 60–75%.

[0113] Figure 4 shows a flow chart of the synthesis of crude celdexmethylphenidate chloride in several embodiments. The second celdexmethylphenidate chloride intermediate solution (second SDX intermediate) is placed in the reactor, anhydrous 1,4-dioxane and sulfolane are added, and the stirrer is started. In some embodiments, 3.4 and 4.6 volumes of anhydrous 1,4-dioxane and sulfolane are added, respectively. Subsequently, HCl in dioxane is added. In some embodiments, 4.0 M HCl in dioxane is used. In heating and stirring step 402, the reaction mixture is heated to 58 ± 3°C and stirred for 12 to 18 hours. In some embodiments, the reaction mixture is heated to 59°C and stirred for 14 hours. In cooling step 404, the reaction mixture is cooled to 20 to 25°C to produce the crude SDX reaction mixture. Once the reaction is complete, in heating step 406, the crude SDX reaction mixture is heated to 40 to 45°C and 2-butanone is added. In some embodiments, the crude SDX reaction mixture is heated to 41°C. Immediately afterward, SDX seed crystals are added to the reaction mixture.

[0114] In stirring step 408, the reaction mixture is stirred at 40-45°C for at least 15 minutes to check for the presence of a solid. If a solid is present, additional 2-butanone is added over a period of at least 3 hours to promote precipitation. If no solid is present, the reaction mixture is cooled to 37-39°C, additional SDX seed crystals are added to the reaction mixture to initiate crystallization, and then additional 2-butanone is added. Subsequently, in cooling step 410, the reaction mixture is cooled to below 10°C for at least 3 hours, and then stirred at below 10°C for 2-8 hours. The resulting solid is filtered and washed with 2-butanone in filtration step 412. In some embodiments, two volumes of 2-butanone can be used. In drying step 414, the crude SDX solid is dried. In some embodiments, the target drying temperature can be 47°C.

[0115] In various embodiments, synthesis 400 may have in-process control steps 416, 418, and 420. In-process control step 416 may be performed after cooling 404, and the completion of the reaction is determined by HPLC analysis. In some embodiments, the reaction is complete when the total area of ​​the mono-t-butyl ether and mono-t-butyl ester intermediates in the reaction mixture is less than or equal to 2.3% relative to SDX. In some embodiments, if the sample does not meet this criterion, the reaction mixture is reheated, stirred for 2, 4, or 6 hours, cooled, and then resampled. If the sample still does not meet the criterion, additional HCl in dioxane is added, and the reaction mixture is heated to 58±3°C to achieve reaction completion. In-process control step 418 determines the loss on drying (LOD) of the crude SDX solid according to USP 731. In some embodiments, drying is complete when the LOD is less than or equal to 1.0%. If the LOD is greater than 1.0%, drying can be continued at 47°C. In-process control 420 examines the impurity profile of the crude SDX solid obtained by HPLC before purification. In some embodiments, the yield of crude SDX solid is 60–75%. Purification of crude cellulose methylphenidate chloride

[0116] In some embodiments, purified and isolated celdexmethylphenidate chloride is prepared according to Scheme 5.

[0117] Scheme 5: [ka] First recrystallization ("RX1")

[0118] Acetone (6.3 vol) and water (0.69 vol) were added to the crude SDX solid (37.1–39.8 kg) in the reactor and stirred. The mixture was heated under reflux (above 54°C) and stirred for at least 20 minutes until the solid dissolved. After dissolution, the solution was adjusted to 45–48°C and transferred through a filter cartridge. The solution was then cooled to 38–45°C, and SDX seed crystals (0.15 wt%) relative to the amount of crude SDX added were added to initiate crystallization. The reaction mixture was stirred at 38–45°C for at least 15 minutes. To remove the solid, additional acetone (18 vol) was added over a period of at least 5 hours while cooling to 20±5°C. Once the solid was removed, the mixture was cooled to below 10°C over a period of 2 hours, stirred for at least 2 hours, and then the SDX RX1 solid was isolated by vacuum filtration. The obtained solid was filtered, washed twice with acetone (3 vol each time), and analyzed for impurities by HPLC. The isolated SDX RX1 solid was dried at a temperature below 50°C for at least 10 hours, and residual acetone was analyzed by GC. Drying was considered complete when the residual acetone level was 4500 ppm or less. The yield of SDX RX1 solid was 75–85%.

[0119] Figure 5 shows a flow chart 500 of the first recrystallization for the purification and isolation of SDX drug substance in several embodiments. Crude SDX solid is placed in a reactor, acetone and water are added, and the resulting mixture is stirred. In some embodiments, 6.3 volumes of acetone and 0.69 volumes of water are added, respectively. In the heating and stirring step 502, the mixture is heated under reflux (above 54°C) and stirred for at least 20 minutes to dissolve the solid. In some embodiments, if solid remains in the solution, stirring is continued for at least another 20 minutes. If solid still remains, additional water is added and stirring is continued at above 54°C for at least 20 minutes. In some embodiments, if solid remains, an additional 0.01 volumes of water is added. In the cooling step 504, the solution is adjusted to 45-48°C and transferred to another reactor through a filter cartridge.

[0120] In cooling step 506, the filtered solution is stirred and further cooled to 38-45°C, and SDX seed crystals are added to initiate the crystallization process. In some embodiments, the solution may be cooled to 42°C in cooling step 506. Then, in stirring step 508, the mixture is stirred at 38-45°C for at least 15 minutes to check for the presence of a solid. If a solid is present, additional acetone is added over a period of at least 5 hours while cooling to 20±5°C. If no solid is present, the reactants are cooled to 32-37°C, additional SDX seed crystals are added to the reaction mixture to promote crystallization, and then additional acetone is added. In cooling step 510, the mixture is cooled to below 10°C over a period of 2 hours, then stirred for at least 2 hours, and then the SDX RX1 solid is isolated by vacuum filtration. In some embodiments, the target temperature in cooling step 510 is 5°C. In filtration and washing step 512, the SDX RX1 solid is filtered and washed twice with acetone. In some embodiments, 3 volumes of acetone may be used. In drying step 514, the SDX RX1 solid is dried at a temperature of 50°C or lower.

[0121] In various embodiments, the first recrystallization 500 may include in-process control steps 516, 518, and 520. The in-process control step 516 may be performed after the filtration and washing step 512, and impurities are determined by HPLC. In some embodiments, for samples where all specific impurities are ≤ 0.15%, all unknown impurities are ≤ 0.10%, and total impurities are ≤ 1.0%, the isolated SDX RX1 solid is dried at ≤ 50°C for at least 10 hours and analyzed for residual acetone by GC in the in-process control step 518. In some embodiments, the residual acetone content should be ≤ 4500 ppm. If specific impurities exceed 0.15%, unknown impurities exceed 0.10%, and / or total impurities exceed 1.0%, the isolated SDX RX1 solid is dried at ≤ 50°C for at least 10 hours and subjected to an additional recrystallization procedure (second recrystallization; Figure 6) using isopropyl alcohol. In-process control step 520 determines the drying loss (LOD) of the SDX RX1 solid according to USP 731. In some embodiments, drying is complete when the LOD is 1.0% or less. If the LOD is greater than 1.0%, drying can be continued before the start of the second recrystallization step. In some embodiments, the yield of pure SDX RX1 solid is 75–85%. Any second recrystallization ("RX2")

[0122] Isopropyl alcohol (7.4 vol) and water (0.60 vol) were added to the impure SDX RX1 solid (28.2-30.4 kg) in the reactor and stirred. The mixture was heated under reflux (above 75°C) and stirred for at least 20 minutes until the solid 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 amount of SDX RX1 solid added were added to initiate crystallization.

[0123] The mixture was stirred at 58–63°C for at least 15 minutes. To remove the solid, additional isopropyl alcohol (13.8 vol) was added over a period of at least 5 hours while cooling to 25±5°C. If no solid was detected, the mixture was cooled to 52–56°C, after which additional SDX seed crystals (0.15 wt%) were added, followed by the addition of additional isopropyl alcohol. The mixture was further cooled to below 10°C over a period of 2 hours, stirred for at least 2 hours, and then the SDX RX2 solid was isolated by vacuum filtration.

[0124] The obtained solid was filtered, washed twice with isopropyl alcohol (3 volumes each time), and analyzed for impurities by HPLC. The isolated SDX RX2 solid was dried at a temperature of 50°C or lower for at least 10 hours, and analyzed for residual acetone and isopropyl alcohol by GC. Drying was considered complete when residual acetone and isopropyl alcohol levels were 4500 ppm or less. The yield of SDX RX2 solid, i.e., purified SDX API, was 84–94%.

[0125] Figure 6 shows a flow chart 600 of a second recrystallization for the purification and isolation of SDX drug substance according to one embodiment. Impure SDX RX1 solid is placed in a reactor, isopropyl alcohol and water are added, and the resulting mixture is stirred. In some embodiments, 7.4 volumes of isopropyl alcohol and 0.60 volumes of water are added, respectively. In heating and stirring step 602, the mixture is heated under reflux (above 75°C) and stirred for at least 20 minutes to dissolve the solid. In some embodiments, if solid remains in the solution, stirring is continued for at least another 20 minutes. If solid still remains, additional water is added and stirring is continued at above 75°C for at least 20 minutes. In some embodiments, if solid remains, an additional 0.01 volumes of water is added. In cooling step 604, the solution is adjusted to 63-66°C and transferred to another reactor through a filter cartridge.

[0126] In cooling step 606, the filtered solution is stirred and further cooled to 58-63°C, and SDX seed crystals are added to initiate the crystallization process. In some embodiments, the solution can be cooled to 60°C in cooling step 606. Next, in stirring step 608, the reaction mixture is stirred at 58-63°C for at least 15 minutes to check for the presence of a solid. If a solid is present, additional isopropyl alcohol is added over a period of at least 5 hours while cooling to 25±5°C. If no solid is present, the reaction mixture is cooled to 52-56°C, additional SDX seed crystals are added to the reaction mixture to initiate crystallization, and then additional isopropyl alcohol is added. In some embodiments, if no solid is present, the reaction mixture is cooled to 54°C. In cooling step 610, the mixture is cooled to below 10°C over a period of 2 hours, then stirred for at least 2 hours, and then the SDX RX2 solid is isolated by vacuum filtration. In some embodiments, the target temperature in cooling step 610 is 5°C. In the filtration and washing step 612, the SDX RX2 solid is filtered and washed twice with isopropyl alcohol. In some embodiments, three volumes of isopropyl alcohol can be used. In the drying step 614, the SDX RX2 solid is dried at a temperature of 50°C or below.

[0127] In various embodiments, the second recrystallization 600 may include in-process control steps 616 and 618. In-process control step 616 may be performed after the filtration and washing step 612, and impurities are determined by HPLC. In some embodiments, for samples having all specific impurities at ≤ 0.15%, all unknown impurities at ≤ 0.10%, and total impurities at ≤ 1.0%, the isolated SDX RX2 solid is dried at ≤ 50°C for at least 10 hours, and analyzed for residual acetone and isopropyl alcohol by GC in in-process control step 618. In some embodiments, the residual acetone isopropyl content should be ≤ 4500 ppm. In some embodiments, the yield of pure SDX RX2 solid is 84–94%.

[0128] In some embodiments, if the residual solvent does not meet the in-process standard (4500 ppm or less), the SDX RX2 solid can be subjected to the reslurry procedure described below. Any reslurry of crystallized SDX solid

[0129] Isolated SDX RX2 solid and a 3:1 mixture of n-heptane / acetone (12 volumes) were placed in a reactor, and the slurry was stirred at 20–25°C for at least 20 hours. The slurry was filtered, washed with a 5:1 mixture of n-heptane / acetone (5 volumes), and dried below 50°C for at least 10 hours. The in-sample process was analyzed using GC to confirm that residual solvent levels (acetone, n-heptane, isopropyl alcohol) met in-process standards before the batch was discharged from the dryer for final packaging and release testing of the SDX API. The yield of purified SDX API was 95–100% after the reslurry procedure.

[0130] Figure 7 shows a reslurry 700 of crystallized SDX solid according to one embodiment. The crystallized SDX solid is placed in a reactor and an n-heptane / acetone mixture is added. In some embodiments, the n-heptane / acetone ratio is 3:1. In heating and stirring step 702, the slurry is stirred at 20-25°C for at least 20 hours. The slurry is then filtered in filtration step 704 and washed with an n-heptane / acetone mixture. In some embodiments, the n-heptane / acetone ratio is 5:1. The slurry is then dried at 50°C or below for at least 10 hours to obtain SDX solid. In some embodiments, the slurry is dried at 47°C. In-process control step 708 analyzes the residual solvent content by GC. In some embodiments, the yield of SDX solid is 95-100%.

[0131] In some embodiments, if impurity analysis of the SDX RX2 solid determines that a specific impurity exceeds 0.15%, an unknown impurity exceeds 0.10%, and / or the total impurities exceed 1.0%, reprocessing may be performed. In these embodiments, the isolated SDX RX2 solid may be subjected to additional recrystallization using aqueous acetone after the first recrystallization 500 procedure, but further removing residual process impurities using 9 volumes of 91:9 acetone:water and 15 volumes of poor solvent acetone. Manufacturing of Celldexmethylphenidate Chloride and Dexmethylphenidate Hydrochloride Capsules

[0132] In some embodiments, the formulation contains seldexmethylphenidate chloride and dexmethylphenidate hydrochloride (SDX / d-MPH) in a capsule. In some embodiments, the capsule contains 42% by weight of SDX and 9% by weight of d-MPH. In some embodiments, a method for producing the SDX / d-MPH capsule 800 is shown in Figure 8. Pre-blend preparation

[0133] In some embodiments, the SDX and d-MPH active pharmaceutical ingredients are sieved using a vibrating sieve with a 20-mesh sieve and added to a tote blender. In some embodiments, a portion of the microcrystalline cellulose is added to the tote blender through a 20-mesh sieve. In some embodiments, 50% of the batch amount of microcrystalline cellulose is added. The SDX-d-MPH-cellulose preblend is mixed. In some embodiments, the API preblend (blend #1) is mixed at 130 rpm. Preparation of primary and lubricating blends within grains

[0134] In some embodiments, a residual portion of microcrystalline cellulose and a certain amount of crospovidone are passed through a 20-mesh sieve and added to the preblend to mix the resulting primary intragranular blend (blend #2). In some embodiments, the primary intragranular blend is eliminated at 260 rpm. A portion of the magnesium stearate is passed through a 30-mesh sieve and added to the blender. In some embodiments, 50% of the batch amount of magnesium stearate is added. The resulting intragranular lubricating blend (blend #3) is mixed. In some embodiments, blend #3 is mixed at 130 rpm. Dry granulation step 802 and grinding step 804

[0135] In some embodiments, roller compression is used to granulate the intragranular lubrication blend, followed by grinding to improve the density and blend flow properties of the resulting fine particles. In one embodiment, a roller compactor consisting of two rollers is used, and the resulting ribbon is passed through a screening mill to obtain ground fine particles for the extragranular blend. Preparation of extragranular primary and lubricating blends

[0136] After grinding 804, a certain amount of colloidal silicon dioxide and talc is passed through a 30-mesh sieve and added to the blender along with the ground fine particles of the in-granular lubrication blend. This extra-granular 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 extra-granular lubrication blend (blend #5). In some embodiments, the extra-granular primary blend is mixed at 260 rpm. The extra-granular lubrication blend is then mixed at 130 rpm. Encapsulation

[0137] The final extragranular lubricant blend is loaded into the encapsulation device product hopper and filled into capsules. In some embodiments, the capsules are size 3 HPMC capsules.

[0138] In some embodiments, the further processing step 810 includes dust removal / metal detection, weight sorting, and / or bulk packaging of the capsules.

[0139] In some embodiments, Method 800 includes an in-process control step 812, which includes PSD sieve analysis of the extragranular lubrication blend. In some embodiments, the in-process control step 814 is part of Method 800 and includes visual inspection and / or weight check of the resulting capsules. The present invention is further described in the following paragraphs.

[0140] Formula I: [ka] A method for producing a celldexmethylphenidate chloride compound having, (a) Formula II: [ka] To synthesize a compound having, (b) Formula III: [ka] To synthesize a first intermediate compound having, (c) Formula IV: [ka] To synthesize a second intermediate compound having, (d) Synthesize the crude product of the seldexmethylphenidate chloride compound. (e) Purify the compound having formula V to produce a celdexmethylphenidate chloride compound having formula I. Methods that include...

[0141] The above method for synthesizing a compound having formula II comprises reacting o-tert-butyl-L-serine tert-butyl ester hydrochloride and nicotinic acid in the presence of methyl-t-butyl ether and triethylamine in acetonitrile.

[0142] The above method involves reacting o-tert-butyl-L-serine tert-butyl ester hydrochloride with nicotinic acid in the presence of methyl-t-butyl ether and triethylamine in acetonitrile, and then crystallizing the resulting solution using methyl-t-butyl ether and n-heptane to obtain a compound having formula II.

[0143] The synthesis of the first intermediate compound was (a) Reacting dexmethylphenidate HCl with methyl t-butyl ether and 2,6-lutidine to obtain a reaction mixture, and (b) The method comprising adding chloromethyl chloroformate to the reaction mixture to obtain a first intermediate compound.

[0144] The synthesis of the second intermediate compound was (a) Reacting a compound having formula II with a first intermediate compound in the presence of acetonitrile, HCl in dioxane, and 4-methyl-2-pentanone to obtain a reaction mixture, (b) The method comprising adding a celdexmethylphenidate chloride seed crystal to the reaction mixture to obtain a second intermediate compound as a crystalline solid.

[0145] The synthesis of the crude product of a celdexmethylphenidate chloride compound having formula V is (a) Reacting a second intermediate crystalline solid with anhydrous 1,4-dioxane and sulfolane to produce a reaction mixture, (b) The method described above, comprising adding a celdexmethylphenidate chloride seed crystal to the reaction mixture to obtain a crude product of a celdexmethylphenidate chloride compound having formula V.

[0146] Purification of the crude product of the seldexmethylphenidate chloride compound (a) Reacting the crude product with acetone to produce a reaction mixture, and (b) The method described above, comprising adding a celdexmethylphenidate chloride seed crystal to the reaction mixture to obtain a celdexmethylphenidate chloride compound having formula I as a crystalline solid.

[0147] (f) The method of the above, further comprising determining the purity level of the celldexmethylphenidate chloride compound having formula I.

[0148] If impurities are detected, the seldexmethylphenidate chloride compound will be detected. (a) Reacting cellulose methylphenidate chloride crystalline solid with isopropyl alcohol to produce a reaction mixture, and (b) The method of the above, further comprising the additional step of adding a celdexmethylphenidate chloride seed crystal to the reaction mixture to obtain a celdexmethylphenidate chloride compound having formula I as a crystalline solid.

[0149] A method for producing seldexmethylphenidate chloride and dexmethylphenidate hydrochloride capsules, (a) Formula I: [ka] Blending a certain amount of a celldexmethylphenidate chloride compound and a certain amount of dexmethylphenidate hydrochloride, (b) Add a first amount of microcrystalline cellulose to the blender and mix to produce a pre-blend. (c) Add a second amount of microcrystalline cellulose and a certain amount of crospovidone to the preblend to produce the primary blend within the granules. (d) Mix the primary blend within the granules. (e) Adding a first amount of magnesium stearate to the primary in-granule blend to produce an in-granule lubricating blend. (e) Mixing the granular lubricant blend, (f) Granulating an intragranular lubrication blend using a roller compactor. (g) Grinding the granular lubrication blend, (h) Adding certain amounts of colloidal silicon dioxide and talc to the crushed granular lubricant blend to produce an extragranular primary blend, (i) Mix the extragranular primary blend with a second amount of magnesium stearate to produce an extragranular lubricating blend. (j) Mixing extragranular lubricant blends, (k) A method comprising encapsulating an extragranular lubricant blend in a capsule.

[0150] The above method, where the capsule is a size 3 HPMC capsule.

[0151] The pre-blend is mixed at 130 RPM using the method described above.

[0152] The above method involves mixing the primary blend within the grains at 260 revolutions per minute.

[0153] The above method involves mixing the granular lubrication blend at 130 revolutions per minute.

[0154] The above method involves mixing the outer primary blend at 260 RPM.

[0155] The above method involves mixing the extragranular lubricant blend at 130 revolutions per minute.

[0156] The technologies described herein are described in complete, clear, concise, and precise terms so that any person skilled in the art of the technology can carry them out. It should be understood that the foregoing describes preferred embodiments of the technology and that modifications can be made without departing from the spirit or scope of the invention as set forth in the appended claims. The present invention provides, for example, the following items: (Item 1) Formula I: [ka] A method for producing a celldexmethylphenidate chloride compound having, wherein the method is (a) Formula II: [ka] To synthesize a compound having, (b) Formula III: [ka] To synthesize a first intermediate compound having, (c) Formula IV: [ka] To synthesize a second intermediate compound having, (d) Synthesize the crude product of the seldexmethylphenidate chloride compound, (e) A method comprising purifying the compound having formula V to produce the celldexmethylphenidate chloride compound having formula I. (Item 2) (f) The method according to item 1, further comprising determining the purity level of the celldexmethylphenidate chloride compound having formula I. (Item 3) If an impurity is detected, the seldexmethylphenidate chloride compound is, (a) Reacting cellulose methylphenidate chloride crystalline solid with isopropyl alcohol to produce a reaction mixture, and (b) Adding a celdexmethylphenidate chloride seed crystal to the reaction mixture to obtain the celdexmethylphenidate chloride compound having formula I as a crystalline solid. The method described in item 1 or item 2, which includes undergoing additional steps. (Item 4) The method according to any of the preceding items, 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 methyl-t-butyl ether and triethylamine in acetonitrile. (Item 5) The method according to item 4, wherein, after the reaction of O-tert-butyl-L-serine tert-butyl ester hydrochloride and nicotinic acid in the presence of methyl-t-butyl ether and triethylamine in acetonitrile, the resulting solution is crystallized using methyl-t-butyl ether and n-heptane to obtain a compound having formula II. (Item 6) The synthesis of the first intermediate compound is (a) Reacting dexmethylphenidate HCl with methyl t-butyl ether and 2,6-lutidine to obtain a reaction mixture, and (b) The method according to any of the preceding items, comprising adding chloromethyl chloroformate to the reaction mixture to obtain the first intermediate compound. (Item 7) The synthesis of the second intermediate compound is (a) Reacting the compound having formula II with the first intermediate compound in the presence of acetonitrile, HCl in dioxane, and 4-methyl-2-pentanone to obtain a reaction mixture, (b) The method according to any of the preceding items, comprising adding a celdexmethylphenidate chloride seed crystal to the reaction mixture to obtain the second intermediate compound as a crystalline solid. (Item 8) The synthesis of the crude product of the celdexmethylphenidate chloride compound having formula V is (a) Reacting the second intermediate crystalline solid with anhydrous 1,4-dioxane and sulfolane to produce a reaction mixture, (b) The method according to any of the preceding items, comprising adding a celdexmethylphenidate chloride seed crystal to the reaction mixture to obtain the crude product of the celdexmethylphenidate chloride compound having formula V. (Item 9) Purification of the crude product of the cellulose methylphenidate chloride compound is (a) Reacting the crude product with acetone to produce a reaction mixture, and (b) The method according to any of the preceding items, comprising adding a celdexmethylphenidate chloride seed crystal to the reaction mixture to obtain the celdexmethylphenidate chloride compound having formula I as a crystalline solid. (Item 10) A method for producing seldexmethylphenidate chloride and dexmethylphenidate hydrochloride capsules, (a) Formula I: [ka] Blending a certain amount of a celldexmethylphenidate chloride compound and a certain amount of dexmethylphenidate hydrochloride, (b) Add a first amount of microcrystalline cellulose to the blender and mix to produce a pre-blend. (c) Add a second amount of microcrystalline cellulose and a certain amount of crospovidone to the preblend to produce an intragranular primary blend. (d) Mixing the primary blend within the granules, (e) Adding a first amount of magnesium stearate to the primary in-granule blend to produce an in-granule lubricating blend, (e) Mixing the in-granule lubricant blend, (f) Granulating the in-granule lubrication blend using a roller compactor, (g) Grinding the granular lubricant blend, (h) Adding a certain amount of colloidal silicon dioxide and talc to the crushed intragranular lubricant blend to produce an extragranular primary blend, (i) Mix the extragranular primary blend with a second amount of magnesium stearate to produce an extragranular lubricating blend. (j) Mixing the extragranular lubricant blend, (k) A method comprising encapsulating the extragranular lubricant blend in a capsule. (Item 11) The method according to item 10, wherein the capsule is a size 3 HPMC capsule. (Item 12) The method according to item 10 or 11, wherein the pre-blend is mixed at 130 revolutions per minute. (Item 13) The method according to any one of items 10 to 12, wherein the primary blend within the granules is mixed at 260 revolutions per minute. (Item 14) The method according to any one of items 10 to 13, wherein the intragranular lubricant blend is mixed at 130 revolutions per minute. (Item 15) The method according to any one of items 10 to 14, wherein the extragranular primary blend is mixed at 260 revolutions per minute. (Item 16) The method according to any one of items 10 to 15, wherein the extragranular lubricant blend is mixed at 130 revolutions per minute.

Claims

[Claim 1] The invention described herein.

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