CN116783164A

CN116783164A - Process for preparing apremilast citrate and intermediates thereof

Info

Publication number: CN116783164A
Application number: CN202180091229.9A
Authority: CN
Inventors: Z·张; M·雷德; E·V·卡斯滕森; M·波普; A·佩尔泽
Original assignee: Zevela Denmark GmbH
Current assignee: Zevela Denmark GmbH
Priority date: 2020-11-19
Filing date: 2021-11-19
Publication date: 2023-09-19

Abstract

The present disclosure relates to a process for preparing apremilast, apremilast citrate and key intermediates thereof, such as ORZY-01. The disclosure also relates to methods of preparing high purity apricots citrate and methods of use thereof.

Description

Process for preparing apremilast citrate and intermediates thereof

Technical Field

The present disclosure relates to a process for preparing apricots (arimoclomol), citric acid apricots and key intermediates thereof, such as ORZY-01. The disclosure also relates to methods of preparing high purity apricots citrate and methods of use thereof.

Background

Apremilast citrate is an Active Pharmaceutical Ingredient (API) for the treatment of lysosomal storage disorders (lysosomal storage disorder), including Niemann-pick type C (Niemann-Pick Disease Type C).

Disclosure of Invention

The present disclosure provides an optimized four-step process for preparing an ultrapure composition comprising apricots citrate (arimoclomol citrate), i.e., N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate. The optimized process includes a plurality of optimized sub-steps, each of which contributes to an overall improved process, providing an ultrapure composition comprising apricots citrate. Ultrapure compositions comprising apricots citrate meet the stringent regulatory requirements of the pharmaceutical agency. The following summaries the four-step process:

Step 1: overview of the method for preparing ORZY-01

Step 2: overview of the method for preparing ORZY-03

Step 3: overview of the method for preparing crude BRX-345 (ORZY-04)

Step 4: overview of the method for preparing BRX-345 (ORZY-05)

The disclosed methods facilitate control of the chiral purity (i.e., enantiomeric excess) of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate above a threshold set by regulatory authorities and the ultrapure compositions are substantially free of previously identified by-products such as RRT 0.74 and N-nitrosopiperidine.

The chiral purity of the ultrapure composition comprising apricots citrate is the result of the chiral resolution step (i.e., the process according to "step 2" of the present disclosure). The present disclosure provides a correlation between the cooling rate of the crude reaction mixture in step 2 and the chiral purity of ORZY-03 (see examples 4 and 5). The chiral purity of the ORZY-03 obtained in step 2 is preserved in the final product but can be further improved by recrystallization.

The present disclosure identifies byproduct RRT 0.74, shown below, which is formed during the salt exchange of step 3, where "crude BRX-345" is prepared from ORZY-03.

( RRT 0.74; (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid methyl ester 1-oxide )

The present disclosure provides an improved process comprising washing with water and adding a catalytic amount of citric acid. In some embodiments, the addition of additional washing and catalytic amounts of citric acid results in the removal of RRT 0.74 by-products without significant loss of yield of the desired product.

Furthermore, the present disclosure provides an optimized method of preparing ORZY-01:

it provides ORZY-01 in high (up to 80%) yields and high purity while reducing the risk of large scale processes.

The previously reported two-step synthesis of ORZY-01 shown below involved refluxing in step 1A for 2 hours, followed by purification of intermediate compound (V) to improve batch quality.

Furthermore, the subsequent steps from compound (V) to ORZY-01, as reported previously at-5 ℃ to 0 ℃, require several additions of sodium nitrite to drive the reaction to completion and result in delayed exothermic reactions and gas release, which raise safety issues at scale up.

The process of the present disclosure provides an improved reaction in step 1A, allowing subsequent direct conversion to ORZY-01 without isolation of compound (V). Furthermore, step 1B of the present disclosure proceeds to completion in a single addition of sodium nitrite in a safe and controlled operation without delayed gas release and process chemistry risks.

In a first aspect, a method of preparing ORZY-01 is provided,

wherein the method comprises the following steps:

step 1A) combining a compound of formula (I);

and a compound of formula (II);

mixing in a first solvent at a first temperature for more than 2 hours to provide an intermediate; then is

Step 1B), the intermediate is reacted with in a second solvent at a second temperatureNaNO ₂ Reacted to provide an ORZY-01,

thereby providing an ORZY-01.

In a second aspect, there is provided a composition comprising ORZY-01,

one or more impurities selected from the group consisting of:

in a third aspect, there is provided a process for the preparation of apricots citrate,

(apricots citrate),

which includes the method of providing ORZY-01 as defined herein,

then precipitation of ORZY-01 with dibenzoyl L-tartaric acid to provide ORZY-03,

the ORZY-03 is reacted with a base and the resulting ORZY-03 free base is then precipitated with citric acid to provide apricots citrate.

In a fourth aspect, there is provided a process for preparing apricots citrate,

(apricots citrate),

which includes a method of providing ORZY-01 as defined herein.

In one aspect, the present disclosure relates to an oral formulation comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutically acceptable salt of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide is N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In one aspect, the present disclosure provides a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, having a purity of greater than or equal to 98.0%.

In one aspect, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of an oral formulation, pharmaceutical composition or unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is administered to the subject.

In one aspect, the present disclosure provides an oral formulation, pharmaceutical composition or unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of Niman pick disease form C in a subject in need thereof.

In one aspect, the present disclosure provides the use of an oral formulation, pharmaceutical composition or unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In one aspect, the present disclosure provides the use of an oral formulation, pharmaceutical composition or unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-yl-propyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof for the treatment or prevention of niemann pick disease form C in a subject in need thereof.

Unless defined otherwise, 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 disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the disclosure will become apparent from the following detailed description and claims.

Detailed Description

Definition of the definition

In order to facilitate understanding of the following description, some definitions are given in the following paragraphs.

As used herein, the term "polar protic solvent" refers to a polar solvent capable of exchanging protons with a reagent and containing polarizable protons. Examples of polar protic solvents are butanol, 2-propanol, ethanol, methanol, water and mixtures thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to salts commonly used in the pharmaceutical arts. Examples of pharmaceutically acceptable salts include, but are not limited to, sodium, hydrochloride, magnesium, calcium, trifluoroacetate and potassium salts. Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate (olcate), tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate (gentisinate), fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

The term "chlorinated hydrocarbon" refers to a hydrocarbon in which one or more hydrogen atoms have been replaced with chlorine. Examples of chlorinated hydrocarbons are intended to include, without limitation, methylene chloride, chloroform, carbon tetrachloride, and ethylene dichloride. Dichloromethane is also known as DCM or CH ₂ Cl ₂ 。

The term "ethanol" as used herein should be understood to include ethanol having a purity of at least 95% by weight, denatured ethanol, and aqueous ethanol containing 20 to 5% by weight water. One example of denatured ethanol is 95 wt% ethanol mixed with 5 wt% isopropanol, and one example of aqueous ethanol is 83 wt% ethanol mixed with 17 wt% purified water.

The term "PCO-N-oxide" as used herein refers to the compound N-hydroxy-1-oxo-3-pyridinecarboxamidine. The structure of PCO-N-oxide is shown as formula (I) herein.

The term "Azonia" as used herein refers to the compound Azonia-spiro [3,5] nonane chloride. The structure of azonia is shown as formula (II) herein.

The term "boiling point" as used herein refers to the boiling point of a liquid at 760mm/Hg or a deviation from it of + -2 deg.C.

As used herein, the term "about" refers to the recited amount, value, or duration of ± 10% or less of the recited amount, value, or duration. In some embodiments, "about" refers to the recited amount, value, or duration of ± 10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1% or ± 0.5%. In other embodiments, "about" refers to the recited amount, value, or duration of ± 10%, ±8%, ±6%, ±5%, ±4% or ± 2%. In other embodiments, "about" refers to the recited amount, value, or duration ± 5%. In some embodiments, "about" refers to the listed amount, value, or duration of ±2% or ±1%. For example, in some embodiments, when the term "about" is used in reference to a temperature or temperature range, the terms refer to the temperature or temperature range mentioned ± 5 ℃, ±2 ℃, or ± 1 ℃. In other embodiments, the term "about" refers to the temperature or temperature range mentioned ± 2 ℃.

As used herein, "apremilast" refers to a compound having the following structure:

which is also referred to herein as N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide.

As used herein, "apremimod S-enantiomer" refers to a compound having the structure:

which is also referred to herein as N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide.

As used herein, "apremilast citrate" refers to a compound having the following structure:

it is also referred to herein as "N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azoyl chloride 1-oxide citrate", "ORZY-05" or "BRX-345".

As used herein, "RRT 0.74" refers to a compound having the structure:

which is also referred to herein as (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid methyl ester 1-oxide.

The term "vessel" as used herein refers to all or part of a manufacturing facility unit in which a chemical reaction that forms a molecule (e.g., ORZY-01, ORZY-03, ORZY-04, or ORZY05 as described herein) occurs.

As used herein, "treatment" or "treatment" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes administration of a compound of the present disclosure (e.g., N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate) to alleviate symptoms or complications of, or eliminate, the disease, condition, or disorder. The term "treatment" may also include the treatment of cells or animal models in vitro.

The compounds of the present disclosure (e.g., N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate) may also be used for the prevention of a disease, condition or disorder or for the identification of suitable candidates for this purpose. As used herein, "prevention" or "prevention" describes reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

Process and conditions

Preparation of seed crystals

Seeds of any of ORZY-01, ORZY-03 and ORZY-05 can be prepared by preparative High Performance Liquid Chromatography (HPLC) or Supercritical Fluid Chromatography (SFC) of the racemic mixture to isolate enantiomerically enriched ORZY-01 which provides greater than about 95% chiral purity. The enantiomerically enriched seeds of ORZY-01 obtained from HPLC or SFC can be grown from a suitable solvent. The enantiomerically enriched ORZY-01 can then be precipitated with L-DBTA in a suitable solvent to provide seeds for ORZY-03. The enantiomerically enriched ORZY-01 may be further precipitated with citric acid in a suitable solvent to provide seeds of ORZY-05.

In some embodiments, the methods disclosed herein further comprise adding one or more ORZY-01 seeds to the vessel. In some embodiments, the methods disclosed herein further comprise adding one or more ORZY-03 seeds to the vessel. In some embodiments, the methods disclosed herein further comprise adding one or more ORZY-05 seeds to the vessel.

In some embodiments, the seed crystals are added during the preparation of the disclosed intermediates.

In some embodiments, the methods disclosed herein further comprise adding one or more ORZY-01 seeds to the vessel as a first step. In some embodiments, the methods disclosed herein further comprise adding one or more ORZY-03 seeds to the vessel as a first step. In some embodiments, the methods disclosed herein further comprise adding one or more ORZY-05 seeds to the vessel as a first step.

Step 1 (ORZY-01)

As demonstrated in example 1 of the present disclosure, optimization of reaction conditions, reactant ratios, reaction times, and temperatures allowed the product ORZY-01 to be isolated in 79.6% yield without intermediate isolation. The yield is higher than previously reported.

In some embodiments, a method of preparing ORZY-01 is provided,

wherein the method comprises the following steps:

step 1A) reacting a compound of formula (I)

With a compound of formula (II)

Mixing in a first solvent at a first temperature for more than 2 hours to provide an intermediate; step 1B) then follows, wherein the intermediate is reacted with NaNO in a second solvent at a second temperature ₂ React to provide ORZY-01.

In some embodiments, the process for preparing ORZY-01 is carried out in a vessel. Thus, the steps described in the method may be performed within a container. The skilled person can select the appropriate container according to the batch size.

In some embodiments, a method of preparing ORZY-01 is provided,

wherein the method comprises

Step 1A) in a vessel a compound of formula (I)

With a compound of formula (II)

Mixing in a first solvent at a first temperature to provide an intermediate; then is

Step 1B), intermediate with NaNO in a second solvent at a second temperature ₂ React to provide ORZY-01.

In some embodiments, the method is provided wherein the intermediate is isolated, optionally purified, prior to step 1B).

In some embodiments, the method is provided wherein the first solvent is a polar protic solvent or a mixture of polar protic solvents.

In some embodiments, the first solvent is selected from ethanol, water, methanol, 2-propanol, and any mixtures thereof. In some embodiments, the first solvent is a mixture of ethanol and water.

In some embodiments, the method is provided wherein step 1A is performed under alkaline conditions, for example by adding a hydroxide, such as NaOH or KOH. NaOH is, for example, aqueous NaOH (50% wt).

In some embodiments, there is provided a method as defined herein, wherein the second solvent is a chlorinated hydrocarbon or a mixture containing a chlorinated hydrocarbon. In some embodiments, the second solvent is a mixture of dichloromethane and water.

In some embodiments, the method is provided wherein the first solvent is different from the second solvent.

In some embodiments, the method is provided wherein the first temperature is at the boiling point of the solvent.

In some embodiments, the method is provided wherein the first temperature is higher than the second temperature.

In some embodiments, the first temperature is from about 70 ℃ to about 90 ℃, such as from about 72 ℃ to about 88 ℃, such as from about 74 ℃ to about 86 ℃, such as from about 76 ℃ to about 84 ℃, such as from about 78 ℃ to about 82 ℃, such as about 80 ℃. In some embodiments, the first temperature is about 75 ℃ to about 85 ℃, such as about 80 ℃. In some embodiments, the first temperature is maintained for about 3.5 hours or more.

In some embodiments, the second temperature is from about 0 ℃ to about 15 ℃, such as from about 6 ℃ to about 14 ℃, such as from about 7 ℃ to about 13 ℃, such as from about 8 ℃ to about 12 ℃, such as from about 9 ℃ to about 11 ℃, such as about 10 ℃.

In some embodiments, the second temperature is about 0 ℃ or greater, such as greater than about 0 ℃. In one embodiment, the second temperature is about 15 ℃ or less.

In some embodiments, the second temperature is from about 0 ℃ to about 15 ℃, such as from about 0 ℃ to about 1 ℃, such as from about 1 ℃ to about 2 ℃, such as from about 2 ℃ to about 3 ℃, such as from about 3 ℃ to about 4 ℃, such as from about 5 ℃ to about 6 ℃, such as from about 6 ℃ to about 7 ℃, such as from about 7 ℃ to about 8 ℃, such as from about 8 ℃ to about 9 ℃, such as from about 9 ℃ to about 10 ℃, such as from about 10 ℃ to about 11 ℃, such as from about 11 ℃ to about 12 ℃, such as from about 12 ℃ to about 13 ℃, such as from about 13 ℃ to about 14 ℃, such as from about 14 ℃ to about 15 ℃.

In some embodiments, the second temperature is maintained for about 1 hour.

In some embodiments, there is provided a method as defined herein, wherein the compound of formula (II)

Mixing with a compound of formula (I) in a molar ratio of 1.3:1.0,

in some embodiments, the molar ratio of the compound of formula (II) to the compound of formula (I) is from 1.2:1.0 to 2.0:1.0, such as from 1.2:1.0 to 1.3:1.0, such as from 1.3:1.0 to 1.4:1.0, such as from 1.4:1.0 to 1.5:1:0, such as from 1.5:1.0 to 1.6:1.0, such as from 1.6:1.0 to 1.7:1.0, such as from 1.7:1.0 to 1.8:1.0, such as from 1.8:1.0 to 1.9:1.0, such as from 1.9:1.0 to 2.0:1.0.

In some embodiments, in combination with NaNO ₂ The intermediate was not isolated prior to the reaction. In some embodiments, in combination with NaNO ₂ Intermediate that is not isolated prior to reaction refers to compound (V) as disclosed herein and which is directly obtainable from step 1A. In some embodiments, the intermediate has formula (V);

or a pharmaceutically acceptable salt thereof.

In some embodiments, the intermediate is reacted with 1.2 to 1.6 equivalents of NaNO ₂ The reaction is, for example, from 1.2 to 1.3 equivalents, for example, from 1.3 to 1.4 equivalents, for example, from 1.4 to 1.5 equivalents, for example, from 1.5 to 1.6 equivalents.

In some embodiments, the intermediate is reacted with at least 1.2 equivalents of NaNO ₂ And (3) reacting.

In some embodiments, the first temperature provides reflux of the first solvent, optionally wherein the first temperature provides reflux of the first solvent for 2.5 hours or more, such as 3 hours or more, such as 4 hours or more, such as 5 hours or more, such as 6 hours or more. In this regard, "first temperature provides reflux" refers to a system in which the first temperature is such that the first solvent is at or close enough to the boiling point to produce condensed vapor to provide condensate and return of condensate to its origin.

In some embodiments, the first solvent is heated at about 75 ℃ to about 85 ℃ for at least 3.5 hours.

In some embodiments, the first solvent is heated at about 75 ℃ to about 85 ℃ for 3.5 hours to 4.5 hours, such as 3.5 hours to 4.0 hours, such as 4.0 hours to 4.5 hours. In one embodiment, the first temperature is 75 ℃ to 85 ℃ for 3.5 hours to 4.5 hours, such as 3.5 hours to 4.0 hours, such as 4.0 hours to 4.5 hours.

In some embodiments, the first solvent is ethanol (optionally denatured); and water, and the first solvent is maintained at 80 ℃ for more than 2 hours. In some embodiments, the first solvent is ethanol (optionally denatured); and water, and the first solvent is maintained at about 80 ℃ for at least 3 hours.

Ethanol may be used in denatured and non-denatured forms. In example 1 of the present disclosure, the denatured form was successfully used. Non-denatured forms have also been found to be effective. Data in non-denatured form are not shown herein.

In some embodiments, the first solvent is ethanol (optionally denatured); and water, and the first solvent is maintained at about 80 ℃ for more than 2 hours; and wherein the second solvent is a mixture of dichloromethane and water. In one embodiment, the first solvent is ethanol (optionally denatured); and water, and the first solvent is maintained at about 80 ℃ for at least 3 hours; and wherein the second solvent is a mixture of dichloromethane and water.

Drying of ORZY-01

In some embodiments, the wet product obtained from the process for preparing ORZY-01 is dried under vacuum. In some embodiments, the wet product is dried at less than 45 ℃ for at least 8 hours, e.g., overnight. In some embodiments, the wet product is dried at 40 ℃ for at least 8 hours, e.g., overnight.

Concentration of solvent

In some embodiments, the concentration of the first solvent used in the methods of the present disclosure is from 0.1M to 1.5M relative to "PCO-N-oxide". For example, the first solvent may be a mixture of water (215 mL) and ethanol (1000 mL) for reacting 112g, 653mmol of "PCO-N-oxide" with 153g (1.3 eq.) of "Azonia". This will provide a PCO-N-oxide concentration of 0.5M relative to the first solvent. The solvent concentration can be scaled linearly to accommodate different batch sizes.

ORZY-01 composition

In some embodiments, a composition is provided comprising ORZY-01,

one or more impurities selected from the group consisting of:

in some embodiments, the impurity is present in the provided compositions comprising ORZY-01 in an amount of less than about 1 weight percent. In some embodiments, an additional recrystallization step may reduce the weight percent of impurities in the provided compositions comprising ORZY-01.

In some embodiments, (a) is present in an amount of 0.1% to 0.5% by weight and/or (B) is present in an amount of 0.1% to 0.5% by weight.

In some embodiments, (a) is present in an amount of 0.1% to 0.5%, such as 0.1% to 0.2%, such as 0.2% to 0.3%, such as 0.3% to 0.4%, such as 0.4% to 0.5% by weight.

In some embodiments, (B) is present in an amount of 0.1% to 0.5%, such as 0.1% to 0.2%, such as 0.2% to 0.3%, such as 0.3% to 0.4%, such as 0.4% to 0.5% by weight.

Step 2 (ORZY-03)

As demonstrated in example 4 of the present disclosure, high chiral purity as well as chemical purity is achieved in the formation of ORZY-03 by using an amount of L-DBTA and a cooling rate of at least 15K/h for chiral resolution. The chiral purity of the ORZY-03 obtained in step 2 remains unchanged in the final product ORZY-05 and can be further improved by recrystallization. An improved chiral resolution step, including a cooling rate of at least 15K/h, is capable of providing an ultrapure composition comprising apricots citrate (ORZY-05). In some embodiments, the ultrapure compositions meet regulatory requirements of pharmaceutical institutions (e.g., FDA and EMA).

In some embodiments, a method of preparing ORZY-03 is provided,

wherein the method comprises the following successive steps:

a) ORZY-01

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Mixing with dibenzoyl L-tartaric acid (L-DBTA) in a first step 2 solvent in a vessel and heating the first step 2 solvent to a first step 2 temperature, optionally stirring the first step 2 solvent;

b) Cooling the first step 2 solvent to a second step 2 temperature at a cooling rate of 15K/h or greater to provide a solid composition comprising ORZY-03; wherein the temperature of the first step 2 is higher than that of the second step 2; and

c) Separating the first step 2 solvent and the solid composition comprising ORZY-03, optionally wherein the separating is by filtration;

thereby providing ORZY-03.

In some embodiments, the method further comprises the steps of:

d) The solid composition comprising ORZY-03 is washed one or more times with a first predetermined volume of the first step 2 solvent.

In some embodiments, the method further comprises the steps of:

e) The solid composition comprising ORZY-03 was dried under reduced pressure.

In some embodiments, the method further comprises step a 1) prior to step b), wherein the first step 2 solvent is cooled to a third step 2 temperature; wherein the temperature of the third step 2 is higher than that of the second step 2.

Step 2:cooling rate

The cooling rate in step 2 provides enantiomerically enriched salt ORZY-03. In some embodiments, the chiral purity of ORZY-03 is increased using a cooling rate of 15K/h or greater.

In some embodiments, the cooling rate is selected from: 15K/h;16K/h;17K/h;18K/h;19K/h;20K/h;21K/h;22K/h;23K/h;24K/h;25K/h;26K/h;27K/h;28K/h;29K/h;30K/h;31K/h;32K/h;33K/h;34K/h;35K/h;36K/h;37K/h;38K/h;39K/h;40K/h;41K/h;42K/h;43K/h;44K/h;45K/h;46K/h;47K/h;48K/h;49K/h; and 50K/h.

In some embodiments, the cooling rate is 15K/h to 50K/h, e.g., 15K/h to 16K/h; for example 16K/h to 17K/h; for example 17K/h to 18K/h; for example 18K/h to 19K/h; for example 19K/h to 20K/h; for example 20K/h to 21K/h; for example 21K/h to 22K/h; for example 22K/h to 23K/h; for example 23K/h to 24K/h; for example 24K/h to 25K/h; for example 25K/h to 26K/h; for example 26K/h to 27K/h; for example 27K/h to 28K/h; for example 28K/h to 29K/h; for example 29K/h to 30K/h; for example 30K/h to 31K/h; for example 31K/h to 32K/h; for example 32K/h to 33K/h; for example 33K/h to 34K/h; for example 34K/h to 35K/h; for example 35K/h to 36K/h; for example 36K/h to 37K/h; for example 37K/h to 38K/h; for example 38K/h to 39K/h; for example 39K/h to 40K/h; for example 40K/h to 41K/h; for example 41K/h to 42K/h; for example 42K/h to 43K/h; for example 43K/h to 44K/h; for example 44K/h to 45K/h; for example 45K/h to 46K/h; for example 46K/h to 47K/h; for example 47K/h to 48K/h; for example 48K/h to 49K/h; or for example 49K/h to 50K/h.

In some embodiments, the cooling rate is 15K/h to 50K/h. In some embodiments, the cooling rate is 15K/h to 40K/h. In some embodiments, the cooling rate is 15K/h to 30K/h. In some embodiments, the cooling rate is 17K/h to 30K/h.

Step 2: solvent(s)

In some embodiments, the first step 2 solvent is a polar protic solvent or a mixture of polar protic solvents.

In some embodiments, the first step 2 solvent is selected from ethanol, water, methanol, 2-propanol, and any mixtures thereof.

In some embodiments, the first step 2 solvent is a mixture of ethanol and water.

In some embodiments, the first step 2 solvent is 20.5 to 23.5kg of water per 55kg of ORZY-01; and 200 to 240kg EtOH per 55kg ORZY-01.

In some embodiments, the first step 2 solvent is about 55kg of ORZY-01 and 22kg of water per unit; and 220kg EtOH per 55kg ORZY-01.

Step 2:temperature (temperature)

In some embodiments, the first step 2 temperature is from about 60 ℃ to about 75 ℃, such as from about 61 ℃ to about 74 ℃, such as from about 62 ℃ to about 73 ℃, such as from about 63 ℃ to about 72 ℃, such as from about 64 ℃ to about 71 ℃, such as from about 65 ℃ to about 70 ℃, such as about 65 ℃.

In some embodiments, the second step 2 temperature is from about 10 ℃ to about 30 ℃, such as from about 11 ℃ to about 29 ℃, such as from about 12 ℃ to about 28 ℃, such as from about 13 ℃ to about 27 ℃, such as from about 14 ℃ to about 26 ℃, such as from about 15 ℃ to about 25 ℃, such as about 20 ℃.

In some embodiments, the third step 2 temperature is from about 45 ℃ to about 65 ℃, such as from about 46 ℃ to about 64 ℃, such as from about 47 ℃ to about 63 ℃, such as from about 48 ℃ to about 62 ℃, such as from about 49 ℃ to about 61 ℃, such as from about 50 ℃ to about 60 ℃, such as from about 51 ℃ to about 59 ℃, such as from about 52 ℃ to about 58 ℃, such as from about 53 ℃ to about 57 ℃, such as from about 54 ℃ to about 56 ℃, such as about 55 ℃.

Method aspect of step 2

In some embodiments, the third step 2 temperature is maintained for at least 30 minutes, such as at least 60 minutes.

In some embodiments, one or more ORZY-03 seeds are added to the vessel prior to step b. In some embodiments, one or more of the ORZY-03 seeds have a chiral purity of at least 95%.

In some embodiments, the one or more seeds of ORZY-03 have a mass of 0.2 to 0.8kg per 55kg of ORZY-03, e.g., 0.55kg per 55kg of ORZY-03.

In some embodiments, 0.7 to 1.1 equivalents of L-DBTA, such as 0.88 equivalents of L-DBTA, are used in step 2 based on 1 equivalent of ORZY-01. In some embodiments, 0.7 to 1.1 equivalents of L-DBTA, such as 0.7 to 0.8, such as 0.8 to 0.9, such as 0.9 to 1.0, such as 1.0 to 1.1 equivalents of L-DBTA, are used based on 1 equivalent of ORZY-01.

In some embodiments, the first predetermined volume of the first step 2 solvent is from 35 to 55kg per 55kg of ORZY-03. In some embodiments, the first predetermined volume of the first step 2 solvent is from 41 to 45kg per 55kg of ORZY-03.

Step 3 (ORZY-04)

As demonstrated in example 6 of the present disclosure, optimized step 3 includes adding a catalytic amount of citric acid prior to solvent exchange from DCM to MeOH, inhibiting the formation of "methoxylated ORZY-04" (referred to herein as impurity RRT 0.74). Example 6 also demonstrates that washing the combined DCM phases with water further reduces the level of impurities such as RRT 0.74. The modified step 3 is capable of providing an ultrapure composition comprising apricots citrate (ORZY-05). In some embodiments, the ultrapure composition meets regulatory requirements of a pharmaceutical agency (e.g., US or EMA).

In some embodiments, a method of making ORZY-05 is provided,

wherein the method comprises the steps of:

a) Adding a catalytic amount of citric acid to a solution of ORZY-03 in a first step 3 solvent in a vessel;

b) Changing the solvent of the mixture of step a) from a first step 3 solvent to a second step 3 solvent; wherein the first step 3 solvent is different from the second step 3 solvent;

c) Adding about a stoichiometric amount of citric acid to the mixture obtained in step b) to form a suspension;

d) Filtering the suspension provided in step c) to obtain ORZY-04, which is a crude product of ORZY-05; and

e) Purifying the ORZY-04 of step d) to obtain ORZY-05.

In some embodiments, the method of step 3 further comprises the steps of:

f) Mixing the compound ORZY-03 with an aqueous solution of the base of the first step 3; and

g) Extracting the mixture obtained in step a) with a first step 3 solvent to obtain a solution of ORZY-03 in the first step 3 solvent;

the catalytic amount of citric acid according to step a) is then added to a solution of ORZY-03 in the first step 3 solvent.

In some embodiments, the method further comprises washing the first step 3 solvent one or more times with water, wherein one or more byproducts are removed from the first step 3 solvent.

In some embodiments, the method comprises the steps of:

a) Mixing the compound ORZY-03 with an aqueous solution of the base of the first step 3;

b) Solvent extracting the mixture obtained in step a) with a first step 3;

c) Adding a catalytic amount of citric acid to the organic phase of step b);

d) Changing the solvent of the mixture of step c) from a first step 3 solvent to a second step 3 solvent;

e) Adding about a stoichiometric amount of citric acid to the mixture obtained in step d) to form a suspension; and

f) Filtering the suspension provided in step e) to obtain a crude ORZY-05 (ORZY-04).

Step 3: solvent(s)

In some embodiments, the first step 3 solvent mentioned in step 3 is a chlorinated hydrocarbon or a mixture containing a chlorinated hydrocarbon.

In some embodiments, the first step 3 solvent is dichloromethane or dichloroethane, preferably dichloromethane.

In some embodiments, the second step 3 solvent is a polar protic solvent or a mixture of polar protic solvents.

In some embodiments, the second step 3 solvent is selected from the group consisting of methanol, water, ethanol, 2-propanol, and any mixtures thereof. In some embodiments, the second step 3 solvent is methanol.

Step 3: alkali

In some embodiments, the first step 3 base mentioned in step 3 is a carbonate. In some embodiments, the first step 3 base is selected from K ₂ CO ₃ And Cs ₂ CO ₃ Is a carbonate salt of (a). In some embodiments, the first step 3 base is K ₂ CO ₃ . In some embodiments, K ₂ CO ₃ Comprises 16.8% K ₂ CO ₃ 。

Method aspect of step 3

In some embodiments, ORZY-03 and K ₂ CO ₃ For mixtures of (C) CH ₂ Cl ₂ Extraction is carried out three times.

In some embodiments, the solvent is removed from the CH ₂ Cl ₂ Change to CH ₃ OH comprises the following steps:

a. partial distillation of CH ₂ Cl ₂ A solution;

b. adding CH to the distilled solution provided in step a) ₃ OH；

c. Partially distilling the solution provided in step b); and

d. adding CH to the solution provided in step c) ₃ OH。

In some embodiments, the amount distilled in steps a) and c) corresponds at least to the CH that dissolved ORZY-03 prior to the solvent exchange step ₂ Cl ₂ Is a combination of the amounts of (a) and (b). In some embodiments, the above steps are continuous steps.

In some implementationsIn an embodiment, the method further comprises reacting the solvent from CH ₂ Cl ₂ Change to CH ₃ The solution obtained after OH was passed through an activated carbon filter.

In some embodiments, step 3 further comprises the step of drying ORZY-04. In some embodiments, the drying step comprises vacuum drying the ORZY-04 at 45℃for at least 12 hours.

In some embodiments, the method comprises the following successive steps:

a) ORZY-03 was combined with 16.8% K ₂ CO ₃ Mixing the aqueous solution;

b) Subjecting the mixture obtained in step a) to CH ₂ Cl ₂ Extracting one or more times, for example three times; subsequently subjecting the combined organic phases to one or more water washes;

c) Adding a catalytic amount of citric acid to the organic phase of step b);

d) The solvent of the mixture of step c) is removed from CH by ₂ Cl ₂ Change to CH ₃ OH：

i. Partial distillation of CH from step c) ₂ Cl ₂ A solution;

adding CH to the distilled solution provided in step i) ₃ OH；

Partially distilling the solution provided in step ii); and

adding CH to the solution provided in step iii) ₃ OH，

e) Passing the solution obtained in step d) through an activated carbon filter;

f) Adding about a stoichiometric amount of citric acid to the mixture obtained in step e) to form a suspension;

g) Filtering the suspension provided in step e) to obtain ORZY-04;

h) Vacuum drying the ORZY-04 obtained in step g) at 45℃for at least 12 hours, and

i) Purifying the ORZY-04 of step h) to obtain ORZY-05.

Step 4 (ORZY-05)

As demonstrated in example 7 of the present disclosure, recrystallization under a selected set of conditions resulted in high chiral and chemical purity of ORZY-05 apricots citrate.

In some embodiments, the step of purifying ORZY-04 as described herein to obtain ORZY-05 comprises recrystallization of ORZY-04. In some embodiments, the solvent used in the recrystallization is acetone.

In some embodiments, the recrystallization includes the steps of:

a. ORZY-04 is combined with H ₂ O was mixed and the mixture was heated to 70.+ -. 5 ℃ until a clear solution was observed;

b. cooling the solution formed in step a) to 30±5 ℃;

c. adding acetone to the solution of step b);

d. cooling the mixture of step c) to 0±5 ℃;

e. separating ORZY-05 from the mixture of step d) by separating the solid and the solvent; and optionally

The ORZY-05 obtained in step f) is dried in vacuo at 45℃for at least 12 hours.

In some embodiments, the recrystallization includes the steps of:

b. cooling the solution formed in step a) to 30±5 ℃;

c. adding acetone to the solution of step b);

d. cooling the mixture of step c) to 0±5 ℃;

e. stirring the mixture of step d) at 0±10 ℃ for 12 hours to produce a suspension;

f. separating ORZY-05 from the suspension by filtering the suspension of step e); and

In some embodiments, cooling from 30 ℃ ± 5 ℃ to 0 ℃ ± 5 ℃ is accomplished in 5.5 hours or less, such as 5 hours or less, such as 4.5 hours or less, such as 4 hours or less, such as 3.5 hours or less, such as 3 hours or less, such as 2.5 hours or less, such as 2 hours or less.

Preparation of apricots citrate (ORZY-05)

An optimized four-step process for preparing an ultrapure composition comprising apricots citrate, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate is disclosed herein. The optimized process comprises a plurality of optimized sub-steps, each of which contributes to an overall improved process, thereby enabling the provision of an ultrapure composition comprising apricots citrate.

In some embodiments, a method of preparing apricots citrate (ORZY-05) is provided,

(apricots citrate),

which includes one or more of the methods described herein to provide an ORZY-01; ORZY-03; or ORZY-04; thereby providing an ORZY-05.

In some embodiments, a process for preparing apricots citrate is provided,

(apricots citrate),

comprising a method of providing ORZY-01 as defined herein, thereby providing apricots citrate.

In some embodiments, a process for preparing apricots citrate is provided,

(apricots citrate),

which comprises the following steps:

a) The method of providing ORZY-01 as defined herein,

b) Precipitation of ORZY-01 with dibenzoyl L-tartaric acid to provide ORZY-03,

c) The ORZY-03 is reacted with a base followed by precipitation of the free base of the resulting ORZY-03 with citric acid to provide apricots citrate.

In some embodiments, a process for preparing apricots citrate is provided,

(apricots citrate),

which comprises the following successive steps:

a. an ORZY-01 is provided which,

b. the method of providing an ORZY-03 as defined herein,

c. reacting ORZY-03 with a base, followed by precipitation of the free base of the resulting ORZY-03 with citric acid to provide apricots citrate,

thereby providing apricots citrate.

In some embodiments, a process for preparing apricots citrate is provided,

(apricots citrate),

which comprises the following successive steps:

a. an ORZY-01 is provided which,

b. precipitation of ORZY-01 with dibenzoyl L-tartaric acid to provide ORZY-03,

c. a method of providing ORZY-05 as defined herein;

thereby providing apricots citrate.

Pharmaceutical composition

In some embodiments, the present disclosure provides a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide, or a pharmaceutically acceptable salt thereof, in a purity of greater than or equal to 98.0% as determined by HPLC.

In some embodiments, the present disclosure provides a composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide, or a pharmaceutically acceptable salt thereof, in a purity of greater than or equal to 98.0% as determined by HPLC.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a purity of greater than 98.0% as determined by HPLC.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a purity of greater than or equal to 99.0% as determined by HPLC.

In some embodiments, the present disclosure provides a pharmaceutical composition wherein the enantiomeric excess (ee) of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is at least about 94%.

In some embodiments, the present disclosure provides a pharmaceutical composition wherein the ee of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is at least about 95%.

In some embodiments, the present disclosure provides a pharmaceutical composition wherein the ee of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is at least about 96%.

In some embodiments, the present disclosure provides a pharmaceutical composition wherein the ee of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is at least about 97%.

In some embodiments, the present disclosure provides a pharmaceutical composition wherein the ee of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is at least about 98%.

In some embodiments, the present disclosure provides a pharmaceutical composition, wherein the composition comprises:

a) At least about 94% ee of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate, e.g., at least about 95% ee, e.g., at least about 96% ee, e.g., at least about 97% ee, or e.g., at least about 98% ee; and

b) 0.1% or less of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure discloses a pharmaceutical composition, wherein the composition comprises:

a) At least about 94% ee of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate, e.g., at least about 95% ee, e.g., at least about 96% ee, e.g., at least about 97% ee, or e.g., at least about 98% ee;

b) 0.1% or less of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof; and

c) Less than 2ppm of N-nitrosopiperidine.

In some embodiments, the present disclosure provides a pharmaceutical composition wherein the composition has a purity of greater than or equal to 99.0% N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate as determined by HPLC.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a D10 particle size of from about 2.0 μm to about 20.0 μm as determined using Malvern Mastersizer 3000.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a D50 particle size of from about 5.0 μm to about 60.0 μm as determined using Malvern Mastersizer 3000.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a D90 particle size of from about 30.0 μm to about 130.0 μm as determined using Malvern Mastersizer 3000.

a) At least 98.0% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

b) 1.9% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof; and

c) 0.1% or less of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof.

b) 1.9% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

c) 0.1% or less of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof; and

d) Less than 2ppm of N-nitrosopiperidine.

In some embodiments, a pharmaceutical composition is provided comprising an ORZY-05 obtainable by the methods disclosed herein for preparing an ORZY-05.

In some embodiments, the present disclosure provides a composition wherein the composition has a purity of greater than or equal to 99.0% N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate as determined by HPLC.

In some embodiments, the present disclosure provides a composition comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a D10 particle size of from about 2.0 μm to about 20.0 μm as determined using Malvern Mastersizer 3000.

In some embodiments, the present disclosure provides a composition comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a D50 particle size of from about 5.0 μm to about 60.0 μm as determined using Malvern Mastersizer 3000.

In some embodiments, the present disclosure provides a composition comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a D90 particle size of from about 30.0 μm to about 130.0 μm as determined using Malvern Mastersizer 3000.

In some embodiments, the present disclosure provides a composition, wherein the composition comprises:

d) Less than 2ppm of N-nitrosopiperidine.

In some embodiments, a composition comprising ORZY-05 is provided, obtainable by the methods disclosed herein for preparing ORZY-05.

In some embodiments, the pharmaceutical composition or composition has a degree of purity with respect to N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate, which is determined using HPLC.

In some embodiments, the purity of the pharmaceutical composition is about 98.0%.

In some embodiments, the purity of the pharmaceutical composition is about 98.25%.

In some embodiments, the purity of the pharmaceutical composition is about 98.5%.

In some embodiments, the purity of the pharmaceutical composition is about 98.75%.

In some embodiments, the purity of the pharmaceutical composition is about 99.0%.

In some embodiments, the purity of the pharmaceutical composition is about 99.25%.

In some embodiments, the purity of the pharmaceutical composition is about 99.5%.

In some embodiments, the purity of the pharmaceutical composition is about 99.6%.

In some embodiments, the purity of the pharmaceutical composition is about 99.7%.

In some embodiments, the purity of the pharmaceutical composition is about 99.8%.

In some embodiments, the purity of the pharmaceutical composition is about 99.9%.

In some embodiments, the purity of the pharmaceutical composition is greater than about 99.7%.

In some embodiments, the pharmaceutical composition comprises less than 2% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.9% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.8% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.7% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.6% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.5% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.4% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.3% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.2% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.1% impurities.

In some embodiments, the pharmaceutical composition comprises less than 1.0% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.9% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.8% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.7% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.6% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.5% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.4% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.3% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.2% impurities.

In some embodiments, the pharmaceutical composition comprises less than 0.1% impurities.

In some embodiments, the impurity is a chiral impurity.

In some embodiments, the impurity is a chemical impurity.

In some embodiments, the impurity is N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the impurity is (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the impurity is N-nitrosopiperidine.

In some embodiments, the impurity is N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a combination of a pharmaceutically acceptable salt thereof and N-nitrosopiperidine.

In some embodiments, the impurity is a combination of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminocarbonyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the impurity is N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof in combination with N-nitrosopiperidine.

In some embodiments, the impurity is a combination of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof and N-nitrosopiperidine.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof has chiral purity.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate has chiral purity.

In some embodiments, chiral purity refers to a minimum of 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, chiral purity refers to up to 2% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, chiral purity refers to a minimum of 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and a maximum of 2% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, chiral purity refers to a minimum of 99% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, chiral purity refers to up to 1% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, chiral purity refers to a minimum of 99% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and a maximum of 1% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, chiral purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, wherein N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is undetectable.

In some embodiments, chiral purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, wherein N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is undetectable and no other impurities are detected.

In some embodiments, chiral purity refers to a minimum of 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, chiral purity refers to up to 2% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, chiral purity refers to a minimum of 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminocyl chloride 1-oxide citrate and a maximum of 2% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminocyl chloride 1-oxide citrate.

In some embodiments, chiral purity refers to a minimum of 99% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, chiral purity refers to up to 1% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, chiral purity refers to a minimum of 99% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminocyl chloride 1-oxide citrate and a maximum of 1% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminocyl chloride 1-oxide citrate.

In some embodiments, chiral purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminoacyl chloride 1-oxide citrate, wherein N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminoacyl chloride 1-oxide citrate is undetectable.

In some embodiments, chiral purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminoacyl chloride 1-oxide citrate, wherein N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminoacyl chloride 1-oxide citrate is undetectable and no other impurities are detected.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is from about 94% to about 99% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is from about 94% to about 99% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-carboimidoyl chloride 1-oxide, or a pharmaceutically acceptable salt thereof, is about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.1%, about 98.2%, about 98.3%, about 98.4%, about 98.5%, about 98.6%, about 98.7%, about 98.8%, about 98.9%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate is about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.1%, about 98.2%, about 98.3%, about 98.4%, about 98.5%, about 98.6%, about 98.7%, about 98.8%, about 98.9%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, or about 99.9% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is about 96% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is about 96% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is at least about 94% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is at least about 95% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is at least about 96% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is at least about 97% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is at least about 98% ee.

In some embodiments, the enantiomeric excess of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is at least about 99% ee.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is of chemical purity.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate is of chemical purity.

In some embodiments, chemical purity refers to a minimum of 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, chemical purity refers to a minimum of 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, chemical purity refers to up to 2% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or pharmaceutically acceptable salt thereof or N-nitrosopiperidine.

In some embodiments, chemical purity refers to a minimum of 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-methyliminochloride 1-oxide or a pharmaceutically acceptable salt thereof and a maximum of 2% of (Z) -methyl N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid 1-oxide or a pharmaceutically acceptable salt thereof or N-nitrosopiperidine.

In some embodiments, chemical purity refers to a minimum of 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and a maximum of 2% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof or N-nitrosopiperidine.

In some embodiments, chemical purity refers to a minimum of 99% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, chemical purity refers to a minimum of 99% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, chiral purity refers to up to 1% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or pharmaceutically acceptable salt thereof or N-nitrosopiperidine.

In some embodiments, chemical purity refers to a minimum of 99% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-methyliminochloride 1-oxide or a pharmaceutically acceptable salt thereof and a maximum of 1% of (Z) -methyl N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid 1-oxide or a pharmaceutically acceptable salt thereof or N-nitrosopiperidine.

In some embodiments, chemical purity refers to a minimum of 99% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and a maximum of 1% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof or N-nitrosopiperidine.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, wherein (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof is undetectable.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, wherein (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof is undetectable and no other impurities are detected.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, wherein N-nitrosopiperidine is undetectable.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, wherein N-nitrosopiperidine is undetectable and no other impurity is detected.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminoacyl chloride 1-oxide citrate, wherein (Z) -methyl (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine-methyliminonate 1-oxide or a pharmaceutically acceptable salt thereof and N-nitrosopiperidine are undetectable.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate, wherein (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof and N-nitrosopiperidine are undetectable and no other impurity is detected.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate, wherein (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof is undetectable.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate, wherein (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof is undetectable and no other impurity is detected.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate, wherein N-nitrosopiperidine is undetectable.

In some embodiments, chemical purity refers to a composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate, wherein N-nitrosopiperidine is undetectable and no other impurities are detected.

In some embodiments, the impurity is detected by HPLC.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising:

a) N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, having an enantiomeric excess of about 96% ee;

b) Less than about 0.1% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or pharmaceutically acceptable salt thereof;

c) Less than about 2ppm of N-nitrosopiperidine.

a) N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate with an enantiomeric excess of about 96% ee;

c) Less than about 2ppm of N-nitrosopiperidine.

a) About 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

b) About 2% of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

c) Less than about 0.1% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or pharmaceutically acceptable salt thereof;

d) Less than about 2ppm of N-nitrosopiperidine.

a) About 98% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

d) Less than about 2ppm of N-nitrosopiperidine.

In some embodiments, (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or a pharmaceutically acceptable salt thereof is undetectable.

In some embodiments, the N-nitrosopiperidine is undetectable.

b) N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

a) At least 98.2% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

a) At least 98.4% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

a) At least 98.6% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

a) At least 98.8% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

a) At least 99.0% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

a) At least 99.2% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

a) At least 99.4% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

a) At least 99.6% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate; and

a) 97.0 to 99.8% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminoacyl chloride 1-oxide citrate, e.g. 97.2 to 97.4%, e.g. 97.4 to 97.6%, e.g. 97.6 to 97.8%, e.g. 97.8 to 98.0%, e.g. 98.0 to 98.2%, e.g. 98.2 to 98.4%, e.g. 98.4 to 98.6%, e.g. 98.6 to 98.8%, e.g. 98.8 to 99.0%, e.g. 99.0 to 99.2%, e.g. 99.2 to 99.4%, e.g. 99.4 to 99.6%, or e.g. 99.6 to 99.8%; and

a) At least 98.0% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

c) 0.1% or less of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.1% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.8% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.2% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.7% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.3% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.6% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.4% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.5% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.5% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.4% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.6% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.3% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.7% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.2% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.8% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.1% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 98.9% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 1.0% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.0% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.9% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.1% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.8% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide, or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.2% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.7% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.3% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.6% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.4% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.5% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.5% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.4% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.6% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.3% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.7% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.2% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

a) At least 99.8% of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

b) 0.1% or less of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof;

d) Less than 2ppm of N-nitrosopiperidine.

Formulations

In some embodiments, the present disclosure provides an oral formulation comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In some embodiments, the present disclosure provides an oral formulation comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient.

In some embodiments, the oral formulation comprises a capsule.

In some embodiments, the oral formulation comprises a filler.

In some embodiments, the oral formulation comprises a lubricant.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition comprises a capsule.

In some embodiments, the pharmaceutical composition comprises a filler.

In some embodiments, the pharmaceutical composition comprises a lubricant.

In some embodiments, the capsule comprises a capsule shell.

In some embodiments, the capsule comprises hydroxypropyl methylcellulose (HPMC), titanium dioxide, and optionally one or more colorants.

In some embodiments, the capsule shell comprises hydroxypropyl methylcellulose (HPMC), titanium dioxide, and optionally one or more colorants.

In some embodiments, the filler is microcrystalline cellulose (MCC).

In some embodiments, the lubricant is magnesium stearate.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is present at a dosage of about 20mg to about 500 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide is present in a dosage of about 20mg to about 500 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate is present in a dosage of about 20mg to about 500 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is present at a dosage of about 50mg to about 500 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide is present in a dosage of about 50mg to about 500 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate is present in a dosage of about 50mg to about 500 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-carboximide chloride 1-oxide or a pharmaceutically acceptable salt thereof is present at a dose of about 31mg, about 47mg, about 62mg, about 93mg, or about 124 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-carboximide chloride 1-oxide is present at a dose of about 31mg, about 47mg, about 62mg, about 93mg, or about 124 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-carboximide chloride 1-oxide or a pharmaceutically acceptable salt thereof is present at a dose of about 47mg, about 62mg, about 93mg, or about 124 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide is present at a dose of about 47mg, about 62mg, about 93mg, or about 124 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is present at a dosage of about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, or about 400 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is present at a dosage of about 75mg, about 100mg, about 150mg, about 200mg, or about 400 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate is present at a dosage of about 50mg, about 75mg, about 100mg, about 150mg, or about 200 mg.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is present at a dosage of about 75mg, about 100mg, about 150mg, or about 200 mg.

In some embodiments, the oral formulation comprises about 20% to about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the oral formulation comprises about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the oral formulation comprises about 20% to about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the oral formulation comprises about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the oral formulation comprises about 26.3% or about 52.6% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the oral formulation comprises about 40% to about 80% w/w microcrystalline cellulose.

In some embodiments, the oral formulation comprises about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% w/w microcrystalline cellulose.

In some embodiments, the oral formulation comprises about 73.2% or about 46.9% w/w microcrystalline cellulose.

In some embodiments, the oral formulation comprises about 0.0% to about 1.0% magnesium stearate.

In some embodiments, the oral formulation comprises about 0.0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 1.0% magnesium stearate.

In some embodiments, the oral formulation comprises about 0.5% magnesium stearate.

In some embodiments, the pharmaceutical composition comprises about 20% to about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises about 20% to about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the pharmaceutical composition comprises about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the pharmaceutical composition comprises about 26.3% or about 52.6% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the pharmaceutical composition comprises about 40% to about 80% w/w microcrystalline cellulose.

In some embodiments, the pharmaceutical composition comprises about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% w/w microcrystalline cellulose.

In some embodiments, the pharmaceutical composition comprises about 73.2% or about 46.9% w/w microcrystalline cellulose.

In some embodiments, the pharmaceutical composition comprises about 0.0% to about 1.0% w/w magnesium stearate.

In some embodiments, the pharmaceutical composition comprises about 0.0%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 1.0% magnesium stearate.

In some embodiments, the pharmaceutical composition comprises about 0.5% w/w magnesium stearate.

In some embodiments, the present disclosure provides a unit dosage form of a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the present disclosure provides a unit dosage form of a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the present disclosure provides an oral formulation comprising a unit dose of the present disclosure and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the unit dosage form comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof in a dosage of about 50mg to about 500 mg.

In some embodiments, the unit dosage form comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide in a dosage of about 50mg to about 500 mg.

In some embodiments, the unit dosage form comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 20mg to about 500 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof in a dosage of about 20mg to about 500 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide in a dosage of about 20mg to about 500 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 20mg to about 500 mg.

In some embodiments, the unit dosage form comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 50mg to about 500 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof in a dosage of about 50mg to about 500 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide in a dosage of about 50mg to about 500 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 50mg to about 500 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof at a dosage of about 31mg, about 47mg, about 62mg, about 93mg, or about 124 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide in a dosage of about 31mg, about 47mg, about 62mg, about 93mg or about 124 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof at a dosage of about 47mg, about 62mg, about 93mg, or about 124 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide in a dosage of about 47mg, about 62mg, about 93mg or about 124 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 50mg, about 75mg, about 100mg, about 150mg, about 200mg or about 400 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 50mg, about 75mg, about 100mg, about 150mg, or about 200 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 75mg, about 100mg, about 150mg, about 200mg, or about 400 mg.

In some embodiments, the oral formulation comprises a unit dosage form comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 75mg, about 100mg, about 150mg, or about 200 mg.

In some embodiments, the present disclosure provides a kit comprising a unit dosage form and instructions for administration.

In some embodiments, the kit further comprises prescription information and/or a plurality of unit doses.

In some embodiments of the oral formulation, the capsule is blue, green, yellow, orange or red.

In some embodiments of the pharmaceutical composition, the capsule is blue, green, yellow, orange or red.

In some embodiments of the unit dose, the capsule is blue, green, yellow, orange or red.

In some embodiments of the oral formulation, the capsule has a white body (white body).

In some embodiments of the pharmaceutical composition, the capsule has a white body.

In some embodiments of the unit dose, the capsule has a white body.

In some embodiments of the oral formulation, the capsule size is "0" number.

In some embodiments of the pharmaceutical composition, the capsule size is "0" number.

In some embodiments of the unit dose, the capsule size is "0" number.

In some embodiments, the capsule comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dose of about 31mg, about 50mg, about 75mg, about 100, about 150mg, or about 200 mg.

In some embodiments, the capsule comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 50mg, about 75mg, about 100, about 150mg, or about 200 mg.

In some embodiments, the capsule comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 50mg, about 75mg, or about 100.

In some embodiments, the capsule is filled with a low powder blend (low powder blend) of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azoxychloride 1-oxide citrate.

In some embodiments, the low powder blend comprises 100mg of the powder blend wherein N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is present in an amount of about 26.2% w/w.

In some embodiments, capsules containing a dose of about 50mg, about 75mg, or about 100 of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate are filled with a low powder blend.

In some embodiments, the capsule comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate at a dosage of about 150mg or about 200 mg.

In some embodiments, the capsule is filled with a high powder blend of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the high powder blend comprises 200mg of the powder blend wherein N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is present in an amount of about 52.6% w/w.

In some embodiments, capsules containing a dose of about 150mg or about 200mg of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate are filled with a high powder blend.

In some embodiments, the oral formulation comprises ultrapure N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the pharmaceutical composition comprises ultrapure N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the unit dose comprises ultrapure N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

In some embodiments, the purity is determined by HPLC.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 98.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 98.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 98.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 98.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 98.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 98.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 98.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 98.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 98.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 98.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 98.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 98.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.25%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.25%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.25%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.25%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.25%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.25%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.6%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.6%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.6%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.6%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.6%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.6%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.7%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.7%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.7%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.7%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.7%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.7%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.8%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.8%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a purity of greater than or equal to 99.8%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.8%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.8%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 99.8%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having chiral purity.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having chiral purity.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having chiral purity.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having chiral purity.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate having chiral purity.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having chiral purity.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide having a chiral purity of greater than or equal to 98.0% or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide having a chiral purity of greater than or equal to 98.0% or a pharmaceutically acceptable salt thereof.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide having a chiral purity of greater than or equal to 98.0% or a pharmaceutically acceptable salt thereof.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 98.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 98.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 98.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide having a chiral purity of greater than or equal to 98.5% or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide having a chiral purity of greater than or equal to 98.5% or a pharmaceutically acceptable salt thereof.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide having a chiral purity of greater than or equal to 98.5% or a pharmaceutically acceptable salt thereof.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 98.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 98.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 98.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chiral purity of greater than or equal to 99.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide having a chiral purity of greater than or equal to 99.0% or a pharmaceutically acceptable salt thereof.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide having a chiral purity of greater than or equal to 99.0% or a pharmaceutically acceptable salt thereof.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 99.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 99.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chiral purity of greater than or equal to 99.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having chemical purity.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having chemical purity.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having chemical purity.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having chemical purity.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having chemical purity.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having chemical purity.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 98.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 98.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 98.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity greater than or equal to 98.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 98.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 98.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 98.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 98.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 98.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 98.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 98.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 98.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.0%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.0%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.0%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.25%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.25%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.25%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity greater than or equal to 99.25%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.25%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.25%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.5%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.5%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.5%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.6%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.6%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.6%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity greater than or equal to 99.6%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.6%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.6%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.7%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.7%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.7%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity greater than or equal to 99.7%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.7%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.7%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.8%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.8%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.8%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.8%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.8%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.8%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.9%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.9%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof having a chemical purity of greater than or equal to 99.9%.

In some embodiments, the oral formulation comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.9%.

In some embodiments, the pharmaceutical composition comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.9%.

In some embodiments, the unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a chemical purity of greater than or equal to 99.9%.

In some embodiments, the oral formulation contains less than 2ppm of impurities.

In some embodiments, the pharmaceutical composition comprises less than 2ppm of impurities.

In some embodiments, the unit dose contains less than 2ppm of impurities.

In some embodiments, the oral formulation contains less than 1ppm of impurities.

In some embodiments, the pharmaceutical composition comprises less than 1ppm of impurities.

In some embodiments, the unit dose contains less than 1ppm of impurities.

In some embodiments, the oral formulation does not contain a detectable impurity.

In some embodiments, the pharmaceutical composition does not contain a detectable impurity.

In some embodiments, the unit dose does not contain a detectable impurity.

In some embodiments, the oral formulation comprises less than about 0.1% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises less than about 0.1% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or pharmaceutically acceptable salt thereof.

In some embodiments, the unit dose comprises less than about 0.1% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or pharmaceutically acceptable salt thereof.

In some embodiments, the oral formulation comprises less than about 0.05% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises less than about 0.05% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or pharmaceutically acceptable salt thereof.

In some embodiments, the unit dose comprises less than about 0.05% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or pharmaceutically acceptable salt thereof.

In some embodiments, the oral formulation does not comprise detectable (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition does not comprise (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the unit dose does not comprise detectable (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid ester 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the impurity is N-nitrosopiperidine.

In some embodiments, the oral formulation comprises less than about 2ppm of N-nitrosopiperidine.

In some embodiments, the pharmaceutical composition comprises less than about 2ppm of N-nitrosopiperidine.

In some embodiments, the unit dose comprises less than about 2ppm of N-nitrosopiperidine.

In some embodiments, the oral formulation comprises less than about 1.6ppm of N-nitrosopiperidine.

In some embodiments, the pharmaceutical composition comprises less than about 1.6ppm of N-nitrosopiperidine.

In some embodiments, the unit dose comprises less than about 1.6ppm of N-nitrosopiperidine.

In some embodiments, the oral formulation comprises less than about 1ppm of N-nitrosopiperidine.

In some embodiments, the pharmaceutical composition comprises less than about 1ppm of N-nitrosopiperidine.

In some embodiments, the unit dose comprises less than about 1ppm of N-nitrosopiperidine.

In some embodiments, the oral formulation comprises less than about 0.8ppm of N-nitrosopiperidine.

In some embodiments, the pharmaceutical composition comprises less than about 0.8ppm of N-nitrosopiperidine.

In some embodiments, the unit dose comprises less than about 0.8ppm of N-nitrosopiperidine.

In some embodiments, the oral formulation does not comprise a detectable N-nitrosopiperidine.

In some embodiments, the pharmaceutical composition does not comprise N-nitrosopiperidine.

In some embodiments, the unit dose does not contain a detectable N-nitrosopiperidine.

In some embodiments, the impurity is N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminocarbonyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof or N-nitrosopiperidine or a combination thereof.

In some embodiments, the pharmaceutically acceptable salt is N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

Medical use

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of an oral formulation comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is administered to the subject.

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is administered to the subject.

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of a unit dose comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is administered to the subject.

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of an oral formulation comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient is administered to the subject.

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of a pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient is administered to the subject.

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of a unit dose comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient is administered to the subject.

In some embodiments, the present disclosure provides an oral formulation of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment or prevention of niemann pick disease form C in a subject in need thereof.

In some embodiments, the present disclosure provides pharmaceutical compositions of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides a unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for use in the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides an oral formulation of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient for use in treating or preventing niemann pick disease form C in a subject in need thereof.

In some embodiments, the present disclosure provides pharmaceutical compositions of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient for use in the treatment or prevention of Niman pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides a unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient for use in the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of an oral formulation of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminoacyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of a pharmaceutical composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminoacyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of a unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminoacyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment or prevention of niemann-pick type C disease in a subject in need thereof.

In some embodiments, the present disclosure provides the use of an oral formulation of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminoacyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of a pharmaceutical composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminoacyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of a unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminoacyl chloride 1-oxide citrate together with at least one pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of an oral formulation of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of a pharmaceutical composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of a unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of an oral formulation of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of a pharmaceutical composition of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate and at least one pharmaceutically acceptable excipient for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the present disclosure provides the use of a unit dose of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate together with at least one pharmaceutically acceptable excipient for the treatment or prevention of niemann pick disease type C in a subject in need thereof.

In some embodiments, the oral formulation is administered one, two, three, or four times per day.

In some embodiments, the pharmaceutical composition is administered one, two, three, or four times per day.

In some embodiments, the unit dose is administered one, two, three, or four times per day.

In some embodiments, the oral formulation is administered three times per day.

In some embodiments, the pharmaceutical composition is administered three times per day.

In some embodiments, the unit dose is administered three times per day.

In some embodiments, the oral formulation is administered three times per day for six consecutive days.

In some embodiments, the pharmaceutical composition is administered three times per day for six consecutive days.

In some embodiments, the unit dose is administered three times per day for six consecutive days.

In some embodiments, the oral formulation is administered under fasted conditions.

In some embodiments, the pharmaceutical composition is administered under fasted conditions.

In some embodiments, the unit dose is administered under fasted conditions.

In some embodiments, the oral formulation is administered as a single morning dose.

In some embodiments, the pharmaceutical composition is administered as a single morning dose.

In some embodiments, the unit dose is administered as a single morning dose.

In some embodiments, the oral formulation is administered to a subject weighing about 70 kg.

In some embodiments, the pharmaceutical composition is administered to a subject weighing about 70 kg.

In some embodiments, the unit dose is administered to a subject weighing about 70 kg.

In some embodiments, the subject is a human.

In some embodiments, the human is an adult. In some embodiments, the human is a pediatric patient (e.g., two years or more).

In some embodiments, the oral formulation is administered as described in table a.

In some embodiments, the pharmaceutical composition is administered as described in table a.

In some embodiments, unit doses are administered as described in table a.

In some embodiments, the oral formulation is administered as described in table B.

In some embodiments, the pharmaceutical composition is administered as described in table B.

In some embodiments, unit doses are administered as described in table B.

Table A

Weight of the subject	Dosage (free base)	Dosage (citrate)	Application schedule
				8kg to 15kg	31mg	50mg	t.i.d
15kg to 22kg	47mg	75mg	t.i.d
				22kg to 38kg	62mg	100mg	t.i.d
38kg to 55kg	93mg	150mg	t.i.d
				>55kg	124mg	200mg	t.i.d

Table B

Weight of the subject	Dosage of	Dosage (citrate)	Application schedule
				8kg to 15kg	47mg	75mg	t.i.d
15kg to 30kg	62mg	100mg	t.i.d
				30kg to 55kg	93mg	150mg	t.i.d
>55kg	124mg	200mg	t.i.d

In some embodiments, the oral formulation is administered to a pediatric subject weighing from about 8kg to about 15 kg.

In some embodiments, the pharmaceutical composition is administered to a pediatric subject having a weight of about 8kg to about 15 kg.

In some embodiments, the unit dose is administered to a pediatric subject weighing from about 8kg to about 15 kg.

In some embodiments, the oral formulation is administered to a pediatric subject weighing from about 15kg to about 22 kg.

In some embodiments, the pharmaceutical composition is administered to a pediatric subject having a weight of about 15kg to about 22 kg.

In some embodiments, the unit dose is administered to a pediatric subject having a weight of about 15kg to about 22 kg.

In some embodiments, the oral formulation is administered at a dose of about 31 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 31 mg.

In some embodiments, the unit dose is administered at a dose of about 31 mg.

In some embodiments, the oral formulation is administered at a dose of about 50 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 50 mg.

In some embodiments, the unit dose is administered at a dose of about 50 mg.

In some embodiments, the oral formulation is administered at a dose of about 47 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 47 mg.

In some embodiments, the unit dose is administered at a dose of about 47 mg.

In some embodiments, the oral formulation is administered at a dose of about 75 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 75 mg.

In some embodiments, the unit dose is administered at a dose of about 75 mg.

In some embodiments, the oral formulation is administered to a subject having a weight of about 15kg to about 30 kg.

In some embodiments, the pharmaceutical composition is administered to a subject having a body weight of about 15kg to about 30 kg.

In some embodiments, the unit dose is administered to a subject having a body weight of about 15kg to about 30 kg.

In some embodiments, the oral formulation is administered to a subject weighing from about 22kg to about 38 kg.

In some embodiments, the pharmaceutical composition is administered to a subject having a weight of about 22kg to about 38 kg.

In some embodiments, the unit dose is administered to a subject having a body weight of about 22kg to about 38 kg.

In some embodiments, the oral formulation is administered at a dose of about 62 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 62 mg.

In some embodiments, the unit dose is administered at a dose of about 62 mg.

In some embodiments, the oral formulation is administered at a dose of about 100 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 100 mg.

In some embodiments, the unit dose is administered at a dose of about 100 mg.

In some embodiments, the oral formulation is administered to a subject having a weight of about 30kg to about 55 kg.

In some embodiments, the pharmaceutical composition is administered to a subject having a weight of about 30kg to about 55 kg.

In some embodiments, the unit dose is administered to a subject having a weight of about 30kg to about 55 kg.

In some embodiments, the oral formulation is administered to a subject having a weight of about 38kg to about 55 kg.

In some embodiments, the pharmaceutical composition is administered to a subject having a weight of about 38kg to about 55 kg.

In some embodiments, the unit dose is administered to a subject having a weight of about 38kg to about 55 kg.

In some embodiments, the oral formulation is administered at a dose of about 93 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 93 mg.

In some embodiments, the unit dose is administered at a dose of about 93 mg.

In some embodiments, the oral formulation is administered at a dose of about 150 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 150 mg.

In some embodiments, the unit dose is administered at a dose of about 150 mg.

In some embodiments, the oral formulation is administered to a subject having a body weight greater than about 55 kg.

In some embodiments, the pharmaceutical composition is administered to a subject having a body weight of greater than about 55 kg.

In some embodiments, the unit dose is administered to a subject having a body weight greater than about 55 kg.

In some embodiments, the oral formulation is administered at a dose of about 124 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 124 mg.

In some embodiments, the unit dose is administered at a dose of about 124 mg.

In some embodiments, the oral formulation is administered at a dose of about 200 mg.

In some embodiments, the pharmaceutical composition is administered at a dose of about 200 mg.

In some embodiments, the unit dose is administered at a dose of about 200 mg.

In some embodiments, no less than about 85% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is dissolved into the solution within about 15 minutes.

In some embodiments, not less than 85% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is dissolved into the solution at a pH of about 1.2, about 4.5, or about 6.8 in about 15 minutes.

In some embodiments, not less than about 85% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is dissolved into solution within about 15 minutes.

In some embodiments, not less than 85% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is dissolved into solution at a pH of about 1.2, about 4.5, or about 6.8 in about 15 minutes.

In some embodiments, no less than about 80% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is dissolved into the solution within about 30 minutes.

In some embodiments, no less than 80% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is dissolved into the solution at a pH of about 1.2, about 4.5, or about 6.8 in about 30 minutes.

In some embodiments, no less than about 80% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is dissolved into solution within about 30 minutes.

In some embodiments, not less than 80% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is dissolved into solution at a pH of about 1.2, about 4.5, or about 6.8 in about 30 minutes.

In some embodiments, the capsule ingredients are mixed with a liquid for oral administration as a liquid.

In some embodiments, the liquid is less than or equal to 20mL. In some embodiments, the liquid is less than or equal to 15mL.

In some embodiments, the liquid is water. In some embodiments, the liquid is apple juice.

In some embodiments, the capsule ingredients are mixed with a soft serve for oral administration.

In some embodiments, the present disclosure provides an oral formulation comprising:

About 50mg of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

about 139.05mg microcrystalline cellulose; and

about 0.95mg magnesium stearate.

about 139.05mg microcrystalline cellulose; and

about 0.95mg magnesium stearate.

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of an oral formulation is administered to the subject, the oral formulation comprising:

about 139.05mg microcrystalline cellulose; and

about 0.95mg of magnesium stearate,

wherein the subject has a weight of about 8kg to about 15kg.

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of a pharmaceutical composition is administered to the subject, the pharmaceutical composition comprising:

about 139.05mg microcrystalline cellulose; and

about 0.95mg of magnesium stearate,

wherein the subject is a pediatric subject having a weight of about 8kg to about 15 kg.

about 139.05mg microcrystalline cellulose; and

about 0.95mg of magnesium stearate,

which is useful for treating or preventing niemann pick disease form C in a subject in need thereof, wherein the subject is a pediatric subject having a weight of about 8kg to about 15 kg.

about 139.05mg microcrystalline cellulose; and

about 0.95mg of magnesium stearate,

for use in treating or preventing niemann pick disease type C in a subject in need thereof, wherein the subject is a pediatric subject having a weight of from about 8kg to about 15 kg.

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease type C in a subject in need thereof, comprising administering to the subject an oral formulation comprising:

about 139.05mg microcrystalline cellulose; and

about 0.95mg of magnesium stearate,

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease type C in a subject in need thereof, the method comprising:

about 139.05mg microcrystalline cellulose; and

about 0.95mg of magnesium stearate,

In some embodiments, the present disclosure provides a method of treating or preventing niemann pick disease type C in a subject in need thereof, comprising:

about 139.05mg microcrystalline cellulose; and

about 0.95mg of magnesium stearate,

about 139.05mg microcrystalline cellulose; and

about 0.95mg of magnesium stearate,

about 75mg of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

about 208.57mg microcrystalline cellulose; and

about 1.43mg magnesium stearate.

about 208.57mg microcrystalline cellulose; and

about 1.43mg magnesium stearate.

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 75mg of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate

About 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose;

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject is a pediatric subject having a weight of about 15kg to about 22 kg.

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

which is useful for treating or preventing niemann pick disease type C in a subject in need thereof, wherein the subject is a pediatric subject having a weight of about 15kg to about 22 kg.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising;

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

About 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 208.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 100mg of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

About 278.1mg microcrystalline cellulose; and

about 1.90mg magnesium stearate.

about 278.1mg microcrystalline cellulose; and

about 1.90mg magnesium stearate.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 15kg to about 30kg.

About 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 15kg to about 30kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

which is useful for treating or preventing niemann pick disease type C in a subject in need thereof, wherein the subject has a body weight of greater than about 15kg to about 30kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 15kg to about 30kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 15kg to about 30kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 15kg to about 30kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 15kg to about 30kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 22kg to about 38kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 22kg to about 38kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

which is useful for treating or preventing niemann pick disease type C in a subject in need thereof, wherein the subject has a body weight of greater than about 22kg to about 38kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

About 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 22kg to about 38kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 22kg to about 38kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 22kg to about 38kg.

about 278.1mg microcrystalline cellulose; and

about 1.90mg of magnesium stearate,

wherein the subject has a weight of greater than about 22kg to about 38kg.

about 150mg of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

about 133.57mg microcrystalline cellulose; and

about 1.43mg magnesium stearate.

about 133.57mg microcrystalline cellulose; and

about 1.43mg magnesium stearate.

about 133.57mg microcrystalline cellulose; and

About 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 30kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 30kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

which is useful for treating or preventing niemann pick disease type C in a subject in need thereof, wherein the subject has a body weight of greater than about 30kg to about 55kg.

About 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 30kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 30kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 30kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 30kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 38kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 38kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

which is useful for treating or preventing niemann pick disease type C in a subject in need thereof, wherein the subject has a body weight of greater than about 38kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 38kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 38kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 38kg to about 55kg.

about 133.57mg microcrystalline cellulose; and

about 1.43mg of magnesium stearate,

wherein the subject has a weight of greater than about 38kg to about 55kg.

about 200mg of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate;

about 178.1mg microcrystalline cellulose; and

about 1.9mg magnesium stearate.

About 178.1mg microcrystalline cellulose; and

about 1.9mg magnesium stearate.

about 178.1mg microcrystalline cellulose; and

about 1.9mg of magnesium stearate,

wherein the body weight of the subject is greater than about 55kg.

about 178.1mg microcrystalline cellulose; and

about 1.9mg of magnesium stearate,

wherein the body weight of the subject is greater than about 55kg.

About 178.1mg microcrystalline cellulose; and

about 1.9mg of magnesium stearate,

which is useful for treating or preventing niemann pick disease type C in a subject in need thereof, wherein the subject has a body weight of greater than about 55kg.

about 178.1mg microcrystalline cellulose; and

about 1.9mg of magnesium stearate,

about 178.1mg microcrystalline cellulose; and

about 1.9mg of magnesium stearate,

wherein the body weight of the subject is greater than about 55kg.

about 178.1mg microcrystalline cellulose; and

about 1.9mg of magnesium stearate,

wherein the body weight of the subject is greater than about 55kg.

about 178.1mg microcrystalline cellulose; and

about 1.9mg of magnesium stearate,

wherein the body weight of the subject is greater than about 55kg.

about 178.1mg microcrystalline cellulose; and

about 1.9mg of magnesium stearate,

wherein the body weight of the subject is greater than about 55kg.

In some embodiments, the oral formulation comprises a capsule.

In some embodiments, the pharmaceutical composition comprises a capsule.

In some embodiments, geometric mean C _max Measured in comparison to a 70kg male.

In some embodiments, geometric mean C of the oral formulation after administration of a single dose _max At 1749 (CV 49%) ng/mL C _max Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition after administration of a single dose _max At 1749 (CV 49%) ng/mL C _max Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose after administration of a single dose _max At 1749 (CV 49%) ng/mL C _max Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of a single dose _{For 0 to 8 hours} AUC at 5317 (CV 17%) h.ng/mL _{For 0 to 8 hours} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of a single dose _{For 0 to 8 hours} AUC at 5317 (CV 17%) h.ng/mL _{For 0 to 8 hours} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose after administration of a single dose _{For 0 to 8 hours} AUC at 5317 (CV 17%) h.ng/mL _{For 0 to 8 hours} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of a single dose _0-infinity AUC at 6331 (CV 17%) h.ng/mL _0-infinity Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of a single dose _0-infinity AUC at 6331 (CV 17%) h.ng/mL _0-infinity Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral dose after administration of a single dose _0-infinity AUC at 6331 (CV 17%) h.ng/mL _0-infinity Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration _{max, steady state} At C at 2090 (CV 23%) ng/mL _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition at steady state after administration _{max, steady state} At C at 2090 (CV 23%) ng/mL _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration _{max, steady state} At C at 2090 (CV 23%) ng/mL _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration _{For 0-8 hours, steady state} AUC at 7207 (CV 19%) h.ng/mL _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration _{For 0-8 hours, steady state} AUC at 7207 (CV 19%) h.ng/mL _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose after administration _{For 0-8 hours, steady state} AUC at 7207 (CV 19%) h.ng/mL _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is measured in plasma.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration of the oral formulation to a human weighing from about 8kg to about 15kg _{max, steady state} At C of 533ng/mL _{max, steady state} (368-770 ng/mL, 5 th and 95 th percentiles) to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition at steady state after administration of the pharmaceutical composition to a human weighing from about 8kg to about 15kg _{max, steady state} At 533ng/mL (368-770 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration of the unit dose to a human weighing from about 8kg to about 15kg _{max, steady state} At 533ng/mL (368-770 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the method comprises administering to the subjectAfter human administration of an oral formulation weighing from about 8kg to about 15kg, the AUC of the oral formulation _{For 0-8 hours, steady state} AUC at 2916 h.ng/mL (1924-4436 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of the pharmaceutical composition to a human weighing from about 8kg to about 15kg _{For 0-8 hours, steady state} AUC at 2916 h.ng/mL (1924-4436 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose is that after administration of the unit dose to a human weighing from about 8kg to about 15kg _{For 0-8 hours, steady state} AUC at 2916 h.ng/mL (1924-4436 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration of the oral formulation to a human weighing from greater than about 15kg to about 30kg _{max, steady state} At C of 593ng/mL (395-878 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition at steady state following administration of the pharmaceutical composition to a human having a body weight of greater than about 15kg to about 30kg _{max, steady state} At C of 593ng/mL (395-878 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration of the unit dose to a human weighing from greater than about 15kg to about 30kg _{max, steady state} At C of 593ng/mL (395-878 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of the oral formulation to a human weighing from greater than about 15kg to about 30kg _{For 0-8 hours, steady state} AUC at 3043 h.ng/mL (1938-4763 h.ng/mL 5 th and 95 th percentiles) _{Stabilizing for 0-8 hrState of} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of the pharmaceutical composition to a human having a body weight of greater than about 15kg to about 30kg _{For 0-8 hours, steady state} AUC at 3043 h.ng/mL (1938-4763 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose is greater than about 15kg to about 30kg after administration of the unit dose to a human weighing from greater than about 15kg _{For 0-8 hours, steady state} AUC at 3043 h.ng/mL (1938-4763 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration of the oral formulation to a human weighing from greater than about 30 to about 55kg _{max, steady state} At C of 679ng/mL (450-1024 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition at steady state following administration of the pharmaceutical composition to a human having a body weight of greater than about 30 to about 55kg _{max, steady state} At C of 679ng/mL (450-1024 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration of the unit dose to a human having a body weight of greater than about 30 to about 55kg _{max, steady state} At C of 679ng/mL (450-1024 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of the oral formulation to a human weighing from greater than about 30kg to about 55kg _{For 0-8 hours, steady state} AUC at 3149 h.ng/mL (2010-4855 h.ng/mL, 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, after administration of the pharmaceutical composition to a human having a body weight of greater than about 30kg to about 55kg,AUC of the pharmaceutical composition _{For 0-8 hours, steady state} AUC at 3149 h.ng/mL (2010-4855 h.ng/mL, 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose is greater than about 30kg to about 55kg after administration of the unit dose to a human weighing from greater than about 30kg _{For 0-8 hours, steady state} AUC at 3149 h.ng/mL (2010-4855 h.ng/mL, 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration of the oral formulation to a human weighing greater than about 55kg _{max, steady state} At C of 743ng/mL (479-743 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition at steady state following administration of the pharmaceutical composition to a human weighing greater than about 55kg _{max, steady state} At C of 743ng/mL (479-743 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration of the unit dose to a human weighing greater than about 55kg _{max, steady state} At C of 743ng/mL (479-743 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of the oral formulation to a human weighing greater than about 55kg _{For 0-8 hours, steady state} AUC at 3182 h.ng/mL (2057-4921 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of the pharmaceutical composition to a human weighing greater than about 55kg _{For 0-8 hours, steady state} AUC at 3182 h.ng/mL (2057-4921 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodimentsIn, after administration of a unit dose to a human weighing greater than about 55kg, the AUC of said unit dose _{For 0-8 hours, steady state} AUC at 3182 h.ng/mL (2057-4921 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration of the oral formulation to a human weighing from about 8kg to about 15kg _{max, steady state} At 352ng/mL (240-514 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition at steady state after administration of the pharmaceutical composition to a human weighing from about 8kg to about 15kg _{max, steady state} At 352ng/mL (240-514 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration of the unit dose to a human weighing from about 8kg to about 15kg _{max, steady state} At 352ng/mL (240-514 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of the oral formulation to a human weighing from about 8kg to about 15kg _{For 0-8 hours, steady state} AUC at 1918 h.ng/mL (1255-2908 h.ng/mL, 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of the pharmaceutical composition to a human weighing from about 8kg to about 15kg _{For 0-8 hours, steady state} AUC at 1918 h.ng/mL (1255-2908 h.ng/mL, 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose is that after administration of the unit dose to a human weighing from about 8kg to about 15kg _{For 0-8 hours, steady state} AUC at 1918 h.ng/mL (1255-2908 h.ng/mL, 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is included in the (3) is included in the (1) is included in the (3) is included in the (4.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation after administration of the oral formulation to a human weighing from greater than about 15kg to about 22kg _{max, steady state} At 473ng/mL (323-688 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition after administration of the pharmaceutical composition to a human having a body weight of greater than about 15kg to about 22kg _{max, steady state} At 473ng/mL (323-688 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose is greater than about 15kg to about 22kg after administration of the unit dose to a human weighing from the unit dose _{max, steady state} At 473ng/mL (323-688 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of the oral formulation to a human weighing from greater than about 15kg to about 22kg _{For 0-8 hours, steady state} AUC at 2479 h.ng/mL (1640-3771 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of the pharmaceutical composition to a human having a body weight of greater than about 15kg to about 22kg _{For 0-8 hours, steady state} AUC at 2479 h.ng/mL (1640-3771 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose is greater than about 15kg to about 22kg after administration of the unit dose to a human weighing from greater than about 15kg _{For 0-8 hours, steady state} AUC at 2479 h.ng/mL (1640-3771 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration of the oral formulation to a human weighing from greater than about 22kg to about 38kg _{max, steady state} At 522ng/mL (349-770 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition at steady state following administration of the pharmaceutical composition to a human having a body weight of greater than about 22kg to about 38kg _{max, steady state} At 522ng/mL (349-770 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration of the unit dose to a human weighing from greater than about 22kg to about 38kg _{max, steady state} At 522ng/mL (349-770 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of the oral formulation to a human weighing from greater than about 22kg to about 38kg _{For 0-8 hours, steady state} AUC at 2557 h.ng/mL (1663-3942 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of the pharmaceutical composition to a human having a body weight of greater than about 22kg to about 38kg _{For 0-8 hours, steady state} AUC at 2557 h.ng/mL (1663-3942 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose is greater than about 22kg to about 38kg after administration of the unit dose to a human weighing from greater than about 22kg _{For 0-8 hours, steady state} AUC at 2557 h.ng/mL (1663-3942 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration of the oral formulation to a human weighing from greater than about 38kg to about 55kg _{max, steady state} At 651ng/mL (435-974 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some casesIn embodiments, the geometric mean C of the pharmaceutical composition at steady state following administration of the pharmaceutical composition to a human having a body weight of greater than about 38kg to about 55kg _{max, steady state} At 651ng/mL (435-974 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration of the unit dose to a human weighing from greater than about 38kg to about 55kg _{max, steady state} At 651ng/mL (435-974 ng/mL, 5 th and 95 th percentiles) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of the oral formulation to a human weighing from greater than about 38kg to about 55kg _{For 0-8 hours, steady state} AUC at 2954 h.ng/mL (1958-4465 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of the pharmaceutical composition to a human having a body weight of greater than about 38kg to about 55kg _{For 0-8 hours, steady state} AUC at 2954 h.ng/mL (1958-4465 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose is greater than about 38kg to about 55kg after administration of the unit dose to a human weighing from greater than about 38kg _{For 0-8 hours, steady state} AUC at 2954 h.ng/mL (1958-4465 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the oral formulation at steady state after administration of the oral formulation to a human weighing greater than about 55kg _{max, steady state} At C of 739ng/mL (483-1130 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the pharmaceutical composition at steady state following administration of the pharmaceutical composition to a human weighing greater than about 55kg _{max, steady state} At 739ng/mL (483-1130 ng/mL, 5 th and 9 th)5 percentile) C _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the geometric mean C of the unit dose at steady state after administration of the unit dose to a human weighing greater than about 55kg _{max, steady state} At C of 739ng/mL (483-1130 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of an oral formulation after administration of the oral formulation to a human weighing greater than about 55kg _{For 0-8 hours, steady state} AUC at 3191 h.ng/mL (2054-4948 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a pharmaceutical composition after administration of the pharmaceutical composition to a human weighing greater than about 55kg _{For 0-8 hours, steady state} AUC at 3191 h.ng/mL (2054-4948 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, the AUC of a unit dose is that after administration of the unit dose to a human weighing greater than about 55kg _{For 0-8 hours, steady state} AUC at 3191 h.ng/mL (2054-4948 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl following a single oral dose of about 31mg to about 496mg]The exposure to oxy } pyridine-3-azomethionyl chloride 1-oxide citrate increases in proportion to the dose, with an estimate of the proportionality coefficient (90% CI) for C _max 1,149 (1,07-1, 20), for AUC _0-infinity 1,027 (0, 98-1,08).

In some embodiments, the overall median t after administration _max From 0.25 to 3.0 hours.

In some embodiments, median t after administration _max About 0.5 hours.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is metabolized upon ingestion.

In some embodiments, the metabolite of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is a cysteine conjugate.

In some embodiments, the metabolite of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is O-glucuronide.

In some embodiments, the oral formulation has a shelf life of at least 24 months at about 20 ℃ to about 25 ℃.

In some embodiments, the pharmaceutical composition has a shelf life of at least 24 months at about 20 ℃ to about 25 ℃.

In some embodiments, the unit dose has a shelf life of at least 24 months at about 20 ℃ to about 25 ℃.

In some embodiments, the oral formulation comprises ultrapure N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical composition comprises ultrapure N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

In some embodiments, the unit dose comprises ultrapure N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

Particle size distribution

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate forms particles having a preferred particle size distribution. In some embodiments, a pharmaceutical composition is provided comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having the preferred particle size distribution listed herein. Particle Size Distribution (PSD) can be determined using static auto-imaging (morphology 4) in example 8 (table 3A) presented herein. In some embodiments, malvern Mastersizer, e.g., malvern Mastersizer 3000, is used to determine the PSD. The method employed in the present disclosure for determining PSD is described in detail in example 11.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azoxyimide chloride 1-oxide citrate forms particles having a digital CE diameter D10 of about 0.5 μm to about 3.5 μm; for example, the numerical CE diameter D10 of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate particles is about 0.5 μm to about 3.5 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a D10 particle size with a digital CE diameter D10 of about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1.0 μm, about 1.1 μm, about 1.2 μm, about 1.3 μm, about 1.4 μm, about 1.5 μm, about 1.6 μm, about 1.7 μm, about 1.8 μm, about 1.9 μm, about 2.0 μm, about 2.1 μm, about 2.2 μm, about 2.3 μm, about 2.4 μm, about 2.5 μm, about 2.6 μm, about 2.7 μm, about 2.8 μm, about 2.9 μm, about 3.3 μm or about 3.3.3 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D10 particle size with a digital CE diameter D10 of about 0.5 μm to about 3.5 μm, such as about 0.5 μm to about 1.0 μm, such as about 1.0 μm to about 1.5 μm, such as about 1.5 μm to about 2.0 μm, such as about 2.0 μm to about 2.5 μm, such as about 2.5 μm to about 3.0 μm, such as about 3.0 μm to about 3.5 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate forms particles having a D10 particle size with a digital CE diameter D10 of about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1.0 μm, about 1.1 μm, about 2.4 μm or about 2.5 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a volume CE diameter D10 of about 2.0 μm to about 17.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a D10 particle size that is about 2.0 μm, about 2.5 μm, about 3.0 μm, about 3.5 μm, about 4.0 μm, about 4.5 μm, about 5.0 μm, about 5.5 μm, about 6.0 μm, about 6.5 μm, about 7.0 μm, about 7.5 μm, about 8.0 μm, about 8.5 μm, about 9.0 μm, about 9.5 μm, about 10.0 μm, about 10.5 μm, about 11.0 μm, about 11.5 μm, about 12.0 μm, about 12.5 μm, about 13.0 μm, about 13.5 μm, about 14.0 μm, about 14.5 μm, about 15.0 μm, about 16.0 μm or about 15.5 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azoyl chloride 1-oxide citrate forms particles having a D10 particle size with a volumetric CE diameter D10 of about 2.0 μm to about 17.0 μm, such as about 2.0 μm to about 3.0 μm, such as about 3.0 μm to about 4.0 μm, such as about 4.0 μm to about 5.0 μm, such as about 5.0 μm to about 6.0 μm, such as about 6.0 μm to about 7.0 μm, such as about 7.0 μm to about 8.0 μm, such as about 8.0 μm to about 9.0 μm, such as about 9.0 μm to about 10.0 μm, such as about 10.0 μm to about 11.0 μm, such as about 11.0 μm to about 12.0 μm, such as about 12.0 μm to about 13.0 μm, such as about 13.0 μm to about 14.0.0 μm, such as about 15.0 μm, such as about 16.0.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-diimine yl chloride 1-oxide citrate forms particles having a D10 particle size that has a volume CE diameter D10 of about 4.6 μm, about 6.2 μm, about 9.4 μm, about 10.7 μm, about 10.9 μm, about 11.2 μm, about 12.4 μm, about 12.6 μm, or about 13.1 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a digital length D10 of about 0.5 μm to about 5.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a D10 particle size with a digital length D10 of about 0.5 μm, about 0.6 μm, about 0.7 μm, about 0.8 μm, about 0.9 μm, about 1.0 μm, about 1.1 μm, about 1.2 μm, about 1.3 μm, about 1.4 μm, about 1.5 μm, about 1.6 μm, about 1.7 μm, about 1.8 μm, about 1.9 μm, about 2.0 μm, about 2.1 μm, about 2.2 μm, about 2.3 μm, about 2.4 μm, or about 2.5 μm, about 2.6 μm, about 2.7 μm, about 2.8 μm, about 2.9 μm, about 3.3 μm, about 3.4.4.3 μm, about 3.4.3 μm, about 3.4 μm, about 3.4.4 μm, about 3.4 μm, about 3.4.7 μm, about 3.4.4 μm, about 3.4.5 μm, or about 3.4.5 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a D10 particle size with a digital length D10 of about 0.5 μm to about 5.0 μm, such as about 0.5 μm to about 1.0 μm, such as about 1.0 μm to about 1.5 μm, such as about 1.5 μm to about 2.0 μm, such as about 2.0 μm to about 2.5 μm, such as about 2.5 μm to about 3.0 μm, such as about 3.0 μm to about 3.5 μm, such as about 3.5 μm to about 4.0 μm, such as about 4.0 μm to about 4.5 μm, such as about 4.5 μm to about 5.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate forms particles having a D10 particle size with a digital length D10 of about 1.1 μm, about 1.4 μm, about 1.5 μm, about 1.7 μm, about 1.8 μm, about 2.8 μm, about 2.9 μm about 3.5 μm or about 4.2 μm.

In some embodiments, the D10 particle size of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate particles is from about 2.0 μm to about 20.0 μm as determined using Malvern Mastersizer 3000.

In some embodiments, the D10 particle size of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboximide chloride 1-oxide citrate particles is about 2.0 μm, about 2.5 μm, about 3.0 μm, about 3.5 μm, about 4.0 μm, about 4.5 μm, about 5.0 μm, about 5.5 μm, about 6.0 μm, about 6.5 μm, about 7.0 μm, about 7.5 μm, about 8.0 μm, about 8.5 μm, about 9.0 μm, about 9.5 μm, about 10.0 μm, about 10.5 μm, about 11.0 μm, about 11.5 μm, about 12.0 μm, about 12.5 μm, about 13.0 μm, about 13.5 μm, about 14.0 μm, about 14.5 μm, about 15.0 μm, about 16.5 μm, about 17.5 μm, about 19.0 μm, about 17.5 μm.

In some embodiments, the D10 particle size of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate particles is about 2.0 μm to about 20.0 μm, such as about 2.0 μm to about 2.5 μm, such as about 2.5 μm to about 3.0 μm, such as about 3.0 μm to about 3.5 μm, such as about 3.5 μm to about 4.0 μm, such as about 4.0 μm to about 4.5 μm, such as about 4.5 μm to about 5.0 μm, such as about 5.0 μm to about 5.5 μm, such as about 5.5 μm to about 6.0 μm, such as about 6.0 μm to about 6.5 μm, such as about 6.5 μm to about 7.0 μm, such as about 7.0 μm to about 7.0 μm, such as about 7.5 μm to about 7.5 μm, such as about 7.5 μm to about 8.8 μm, such as about 8.0 μm, such as from about 9.0 μm to about 9.5 μm, such as from about 9.5 μm to about 10.0 μm, such as from about 10.0 μm to about 10.5 μm, such as from about 10.5 μm to about 11.0 μm, such as from about 11.0 μm to about 11.5 μm, such as from about 11.5 μm to about 12.0 μm, such as from about 12.0 μm to about 12.5 μm, such as from about 12.5 μm to about 13.0 μm, such as from about 13.0 μm to about 13.5 μm, such as from about 13.5 μm to about 14.0 μm, such as from about 14.0 μm to about 14.5 μm, such as from about 14.5 μm to about 15.0 μm, such as from about 15.0 μm to about 15.5 μm, such as from about 15.5 μm to about 16.0 μm, such as from about 16.0 μm to about 16.5 μm, such as from about 16.5 μm to about 17.5 μm, such as from about 17.5 μm to about 17.18.5 μm, such as from about 17.5 μm to about 18.18.0 μm, such as from about 18.5 μm to about 18.0 μm, such as from about 19.0 μm to about 19.5 μm, such as from about 19.5 μm to about 20.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a digital CE diameter D50 of about 1.0 μm to about 10.0 μm, for example, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate particles have a digital CE diameter D50 of about 1.0 μm to about 10.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D50 particle size, the digital CE diameter D50 of which is about 1.0 μm, about 1.1 μm, about 1.2 μm, about 1.3 μm, about 1.4 μm, about 1.5 μm, about 1.6 μm, about 1.7 μm, about 1.8 μm, about 1.9 μm, about 2.0 μm, about 2.1 μm, about 2.2 μm, about 2.3 μm, about 2.4 μm, about 2.5 μm, about 2.6 μm, about 2.7 μm, about 2.8 μm, about 2.9 μm, about 3.0 μm, about 3.1 μm, about 3.2 μm, about 3.3 μm, about 3.4 μm, about 3.5 μm, about 3.6 μm, about 3.7 μm, about 3.8 μm, about 3.9 μm, about 4.0 μm, about 4.1 μm, about 4.4.1 μm, about 4.4 μm, about 4.8 μm, about 4.4.5 μm, about 4.4.4 μm, about 4.4.5 μm, about 4.4 μm, about 4.0 μm, about 3.3.3 μm, about 3.4.4 μm about 5.1 μm, about 5.2 μm, about 5.3 μm, about 5.4 μm, about 5.5 μm, about 5.6 μm, about 5.7 μm, about 5.8 μm, about 5.9 μm, about 6.0 μm, about 6.1 μm, about 6.2 μm, about 6.3 μm, about 6.4 μm, about 6.5 μm, about 6.6 μm, about 6.7 μm, about 6.8 μm, about 6.9 μm, about 7.0 μm, about 7.1 μm, about 7.2 μm, about 7.3 μm, about 7.4 μm, about 7.5 μm, about 7.6 μm, about 7.7 μm, about 7.8 μm, about 7.9 μm, about 8.0 μm, about 8.1 μm, about 8.2 μm, about 8.3 μm, about 4.4 μm, about 8.4 μm, about 8.5 μm, about 8.1 μm, about 8.9 μm, about 8.3 μm, about 8.9 μm, about 9.1 μm, about 9.2 μm, about 7.3 μm, about 7.4 μm, about 7.5 μm, about 7.5.5 μm, about 7.6 μm, about 7.6.6 μm About 9.4 μm, about 9.5 μm, about 9.6 μm, about 9.7 μm, about 9.8 μm, about 9.9 μm or about 10.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D50 particle size with a digital CE diameter D50 of about 1.0 μm to about 10.0 μm, such as about 1.0 μm to about 2.0 μm, such as about 2.0 μm to about 3.0 μm, such as about 3.0 μm to about 4.0 μm, such as about 4.0 μm to about 5.0 μm, such as about 5.0 μm to about 6.0 μm, such as about 6.0 μm to about 7.0 μm, such as about 7.0 μm to about 8.0 μm, such as about 8.0 μm to about 9.0 μm, such as about 9.0 μm to about 10.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate forms particles having a D50 particle size with a digital CE diameter D50 of about 1.6 μm, about 2.0 μm, about 2.2 μm, about 2.5 μm, about 2.9 μm, about 3.3 μm, about 5.6 μm or about 5.3 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a volume CE diameter D50 of about 10.0 μm to about 39.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate forms particles having a D50 particle size with a volume CE diameter D50 of about 10.0 μm, about 11.0 μm, about 12.0 μm, about 13.0 μm, about 14.0 μm, about 15.0 μm, about 16.0 μm, about 17.0 μm, about 18.0 μm, about 19.0 μm, about 20 μm, about 21.0 μm, about 22.0 μm, about 23.0 μm, about 24.0 μm, about 25.0 μm, about 26.0 μm, about 27.0 μm, about 28.0 μm, about 29.0 μm, about 30.0 μm, about 31.0, about 32.0 μm, about 33.0 μm, about 34.0 μm, about 35.0 μm, about 36.0 μm, about 37.0 μm or about 38.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azoyl chloride 1-oxide citrate forms particles having a D50 particle size with a volumetric CE diameter D50 of about 10.0 μm to about 39.0 μm, such as about 10.0 μm to about 12.0 μm, such as about 12.0 μm to about 14.0 μm, such as about 14.0 μm to about 16.0 μm, such as about 16.0 μm to about 18.0 μm, such as about 18.0 μm to about 20.0 μm, such as about 20.0 μm to about 22.0 μm, such as about 22.0 μm to about 24.0 μm, such as about 24.0 μm to about 26.0 μm, such as about 26.0 μm to about 28.0 μm, such as about 28.0 μm to about 30.0 μm, such as about 30.0 μm to about 32.0 μm, such as about 32.0 μm to about 34.0 μm, such as about 34.0 μm to about 36.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-diimine yl chloride 1-oxide citrate forms particles having a D50 particle size with a volume CE diameter D50 of about 11.1 μm, about 14.0 μm, about 20.6 μm, about 22.7 μm, about 24.7 μm, about 25.0 μm, about 26.0 μm, about 26.4 μm, about 32.1 μm or about 38.9 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a digital length D50 of about 3.0 μm to about 12.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D50 particle size, the digital length D50 is about 3.0 μm, about 3.1 μm, about 3.2 μm, about 3.3 μm, about 3.4 μm, about 3.5 μm, about 3.6 μm, about 3.7 μm, about 3.8 μm, about 3.9 μm, about 4.0 μm, about 4.1 μm, about 4.2 μm, about 4.3 μm, about 4.4 μm, about 4.5 μm, about 4.6 μm, about 4.7 μm, about 4.8 μm, about 4.9 μm about 5.0 μm, about 5.1 μm, about 5.2 μm, about 5.3 μm, about 5.4 μm, about 5.5 μm, about 5.6 μm, about 5.7 μm, about 5.8 μm, about 5.9 μm, about 6.0 μm, about 6.1 μm, about 6.2 μm, about 6.3 μm, about 6.4 μm, about 6.5 μm, about 6.6 μm, about 6.7 μm, about 6.8 μm, about 6.9 μm, about 7.0 μm about 7.1 μm about 7.2 μm, about 7.3 μm, about 7.4 μm, about 7.5 μm, about 7.6 μm, about 7.7 μm, about 7.8 μm, about 7.9 μm, about 8.0 μm, about 8.1 μm, about 8.2 μm, about 8.3 μm, about 8.4 μm, about 8.5 μm, about 8.6 μm, about 8.7 μm, about 8.8 μm, about 8.9 μm, about 9.0 μm about 9.1 μm, about 9.2 μm, about 9.3 μm, about 9.4 μm, about 9.5 μm, about 9.6 μm, about 9.7 μm, about 9.8 μm, about 9.9 μm, about 10.0 μm, about 10.1 μm, about 10.2 μm, about 10.3 μm, about 10.4 μm, about 10.5 μm, about 10.6 μm, about 10.7 μm, about 11.11.11.11.3 μm, about 11.4 μm, about 9.5 μm, about 9.6 μm, about 9.7 μm, about 9.8.8.8 μm, about 10.3 μm, about 10.3.3 μm, about 10.4.4 μm, about 10.4.4.4 μm, about 10.0 μm, about 10.5.1 μm, about 11.1 μm, about 11.11.3.3.3.3 μm, about 11.3.3.3.3 μm, the entire, about 11.4 μm, about 11.5 μm, about 11.6 μm, about 11.7 μm, about 11.8 μm, about 11.9 μm or about 12.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a D50 particle size with a digital length D50 of about 3.0 μm to about 12.0 μm, such as about 3.0 μm to about 3.5 μm, such as about 3.5 μm to about 4.0 μm, such as about 4.0 μm to about 4.5 μm, such as about 4.5 μm to about 5.0 μm, such as about 5.0 μm to about 5.5 μm, such as about 5.5 μm to about 6.0 μm, such as about 6.0 μm to about 6.5 μm, such as about 6.5 μm to about 7.0 μm, such as about 7.0 μm to about 7.5 μm, such as about 7.5 μm to about 8.0 μm, such as about 8.0 μm to about 8.5 μm, such as about 5.5 μm to about 9.5 μm to about 10.5 μm, such as about 10.10.5 μm to about 11.10.5 μm, such as about 10.5 μm to about 10.5 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-diimine yl chloride 1-oxide citrate forms particles having a D50 particle size with a digital length D50 of about 3.2 μm, about 3.6 μm, about 4.0 μm, about 4.1 μm, about 4.7 μm, about 6.2 μm, about 7.0 μm, about 7.4 μm or about 9.5 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a digital CE diameter D90 of about 5.0 μm to about 22.0 μm.

In some embodiments, the D50 particle size of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate particles is from about 5.0 μm to about 60.0 μm as determined using Malvern Mastersizer 3000.

In some embodiments, as measured using Malvern Mastersizer 3000, the D50 particle size of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate particles was about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm, about 12 μm, about 13 μm, about 14 μm, about 15 μm, about 16 μm, about 17 μm, about 18 μm, about 19 μm, about 20 μm, about 21 μm, about 22 μm, about 23 μm, about 24 μm, about 25 μm, about 26 μm, about 27 μm, about about 28 μm, about 29 μm, about 30 μm, about 31 μm, about 32 μm, about 33 μm, about 34 μm, about 35 μm, about 36 μm, about 37 μm, about 38 μm, about 39 μm, about 40 μm, about 41 μm, about 42 μm, about 43 μm, about 44 μm, about 45 μm, about 46 μm, about 47 μm, about 48 μm, about 49 μm, about 50 μm, about 51 μm, about 52 μm, about 53 μm, about 54 μm, about 55 μm, about 56 μm, about 57 μm, about 58 μm, about 59 μm or about 60 μm.

In some embodiments, the D50 particle size of N- { [ (2R) -2-hydroxy-3-piperidin-1-yl-propyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate particles is about 5.0 μm to about 60.0 μm, such as about 5.0 μm to about 6.0 μm, such as about 6.0 μm to about 7.0 μm, such as about 7.0 μm to about 8.0 μm, such as about 8.0 μm to about 9.0 μm, such as about 9.0 μm to about 10.0 μm, such as about 11.0 μm to about 12.0 μm, such as about 12.0 μm to about 13.0 μm, such as about 13.0 μm to about 14.0 μm, such as about 14.0 μm to about 15.0 μm, such as about 15.0 μm to about 16.0 μm, such as about 24.0 μm to about 36.0 μm, such as about 24.0.0 μm to about 24.0 μm, such as about 24.0 μm to about 35.0 μm, such as about 24.0.0 μm to about 35.0.0 μm to about 35.0.0.0 μm, such as about 24.30.0 μm to about 24.30.30.30.0 μm to about 35.30.0 μm, such as about 24.30.30.0 μm to about 35.30.0 μm, such as about 24.30.0 μm to about 35.0 μm, such as about 24.0.30.0 μm to about 35.0 μm, such as about 24.0 μm to about 35.0.0.0.0 μm to about 35.0 μm, such as about 35.0.0.0.0 μm to about 35.0.0 μm, such as from about 40.0 μm to about 41.0 μm, such as from about 41.0 μm to about 42.0 μm, such as from about 42.0 μm to about 43.0 μm, such as from about 43.0 μm to about 44.0 μm, such as from about 44.0 μm to about 45.0 μm, such as from about 45.0 μm to about 46.0 μm, such as from about 46.0 μm to about 47.0 μm, such as from about 47.0 μm to about 48.0 μm, such as from about 48.0 μm to about 49.0 μm, such as from about 49.0 μm to about 50.0 μm, such as from about 50.0 μm to about 51.0 μm, such as from about 51.0 μm to about 52.0 μm, such as from about 52.0 μm to about 53.0 μm, such as from about 53.0 μm to about 54.0 μm, such as from about 54.0 μm to about 55.0 μm, such as from about 55.0 μm to about 47.0 μm, such as from about 55.0 μm to about 49.0 μm, such as from about 49.0 μm to about 50.0 μm, such as from about 58.0 μm to about 58.0 μm, such as from about 58.0 μm to about 58.0.0 μm, such as from about 57.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a D90 particle size with a digital CE diameter D90 of about 5.0 μm, about 5.5 μm, about 6.0 μm, about 6.5 μm, about 7.0 μm, about 7.5 μm, about 8.0 μm, about 8.5 μm, about 9.0 μm, about 9.5 μm, about 10.0 μm, about 10.5 μm, about 11.0 μm, about 11.5 μm, about 12.0 μm, about 12.5 μm, about 13.0 μm, about 13.5 μm, about 14.0 μm, about 14.5 μm, about 15.5 μm, about 16.0 μm, about 16.5 μm, about 17.0 μm, about 17.5 μm, about 18.0 μm, about 18.20.5 μm, about 21.0 μm, about 21.5 μm or about 20.5 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-ylmethimidoyl chloride 1-oxide citrate forms particles having a D90 particle size with a digital CE diameter D90 of about 5.0 μm to about 22.0 μm, such as about 5.0 μm to about 6.0 μm, such as about 6.0 μm to about 7.0 μm, such as about 7.0 μm to about 8.0 μm, such as about 8.0 μm to about 9.0 μm, such as about 9.0 μm to about 10.0 μm, such as about 10.0 μm to about 11.0 μm, such as about 11.0 μm to about 12.0 μm, such as about 12.0 μm to about 13.0 μm, such as about 13.0 μm to about 14.0 μm, such as about 14.0 μm to about 15.0 μm, such as about 15.0 μm to about 16.0 μm, such as about 16.0 μm to about 17.0 μm, such as about 21.0.0 μm to about 18.0 μm, such as about 17.0 μm to about 20.0 μm, such as about 17.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-diimine yl chloride 1-oxide citrate forms particles having a D90 particle size with a digital CE diameter D90 of about 5.8 μm, about 7.4 μm, about 9.4 μm, about 10.1 μm, about 10.7 μm, about 13.3 μm, about 14.1 μm, about 15.0 μm or about 17.8 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminochloride 1-oxide citrate forms particles having a volume CE diameter D90 of about 10.0 μm to about 55.0 μm, for example, the digital CE diameter D90 of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-yiminochloride 1-oxide citrate particles is about 10.0 μm to about 55.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a volume CE diameter D90 of about 25.0 μm to about 55.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate forms particles having a D90 particle size that has a volume CE diameter D90 of about 25.0 μm, about 26.0 μm, about 27.0 μm, about 28.0 μm, about 29.0 μm, about 30.0 μm, about 31.0 μm, about 32.0 μm, about 33.0 μm, about 34.0 μm, about 35.0 μm, about 36.0 μm, about 37.0 μm, about 38.0 μm, about 39.0 μm, about 40.0 μm, about 41.0 μm, about 42.0 μm, about 43.0 μm, about 44.0 μm, about 45.0 μm, about 46.0 μm, about 47.0 μm, about 48.0 μm, about 49.0 μm, about 50.0 μm, about 51.0 μm, about 52.0 μm or about 55.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D90 particle size that has a volume CE diameter D90 of about 25.0 μm to about 55.0 μm, such as about 25.0 μm to about 30.0 μm, such as about 30.0 μm to about 35.0 μm, such as about 35.0 μm to about 40.0 μm, such as about 40.0 μm to about 45.0 μm, such as about 45.0 μm to about 50.0 μm, such as about 50.0 μm to about 55.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-diimine yl chloride 1-oxide citrate forms particles having a D90 particle size that has a volume CE diameter D90 of about 26.7 μm, about 34.5 μm, about 35.0 μm, about 36.0 μm, about 37.6 μm, about 43.5 μm, about 44.4 μm, about 47.1 μm, or about 52.2 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a volume CE diameter D [4,3] of about 8.0 μm to about 40.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a D90 particle size that is about 8.0 μm, about 9.0 μm, about 10.0 μm, about 11.0 μm, about 12.0 μm, about 13.0 μm, about 14.0 μm, about 15.0 μm, about 16.0 μm, about 17.0 μm, about 18.0 μm, about 19.0 μm, about 20.0 μm, about 21.0 μm, about 22.0 μm, about 23.0 μm, about 24.0 μm, about 25.0 μm, about 26.0 μm, about 27.0 μm, about 28.0 μm, about 29.0 μm, about 30.0 μm, about 31.0 μm, about 32.0 μm, about 33.0 μm, about 35.0 μm, about 34.0 μm, about 38.0 μm or about 0.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D90 particle size that has a volume CE diameter D [4,3] of about 8.0 μm to about 40.0 μm, such as about 8.0 μm to about 12.0 μm, such as about 12.0 μm to about 16.0 μm, such as about 16.0 μm to about 20.0 μm, such as about 20.0 μm to about 24.0 μm, such as about 24.0 μm to about 28.0 μm, such as about 28.0 μm to about 32.0 μm, such as about 32.0 μm to about 36.0 μm, such as about 36.0 μm to about 40.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-diimine yl chloride 1-oxide citrate forms particles having a D90 particle size with a volume CE diameter D [4,3] of about 13.7 μm, about 17.1 μm, about 22.1 μm, about 23.3 μm, about 25.4 μm, about 25.7 μm, about 27.1 μm, about 29.5 μm, about 38.8 μm or about 39.4 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a volume CE diameter D [3,2] of about 5.0 μm to about 30.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a D90 particle size that is about 5.0 μm, about 6.0 μm, about 7.0 μm, about 8.0 μm, about 9.0 μm, about 10.0 μm, about 11.0 μm, about 12.0 μm, about 13.0 μm, about 14.0 μm, about 15.0 μm, about 16.0 μm, about 17.0 μm, about 18.0 μm, about 19.0 μm, about 20.0 μm, about 21.0 μm, about 22.0 μm, about 23.0 μm, about 24.0 μm, about 25.0 μm, about 26.0 μm, about 27.0 μm, about 28.0 μm, about 29.0 μm, or about 30.0 μm in volume CE diameter D [3,2 ].

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D90 particle size that has a volume CE diameter D [3,2] of about 5.0 μm to about 30.0 μm, such as about 5.0 μm to about 10.0 μm, such as about 10.0 μm to about 15.0 μm, such as about 15.0 μm to about 20.0 μm, such as about 20.0 μm to about 25.0 μm, such as about 25.0 μm to about 30.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-diimine yl chloride 1-oxide citrate forms particles having a D90 particle size that has a volume CE diameter D [3,2] of about 8.8 μm, about 11.4 μm, about 17.7 μm, about 17.5 μm, about 17.9 μm, about 19.5 μm, about 20.5 μm, about 21.8 μm, about 24.2 μm, or about 34.2 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D90 length of about 10.0 μm to about 20.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a numerical CE diameter average value of about 1.0 μm to about 12.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a mean numerical CE diameter of about 1.0 μm, about 1.5 μm, about 2.0 μm, about 2.5 μm, about 3.0 μm, about 3.5 μm, about 4.0 μm, about 4.5 μm, about 5.0 μm, about 5.5 μm, about 6.0 μm, about 6.5 μm, about 7.0 μm, about 7.5 μm, about 8.0 μm, about 8.5 μm, about 9.0 μm, about 9.5 μm, about 10.0 μm, about 10.5 μm, about 11.0 μm, about 11.5 μm, or about 12.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azoyl chloride 1-oxide citrate forms particles having a mean numerical CE diameter of about 1.0 μm to about 12.0 μm, such as about 1.0 μm to about 2.0 μm, such as about 2.0 μm to about 3.0 μm, such as about 3.0 μm to about 4.0 μm, such as about 4.0 μm to about 5.0 μm, such as about 5.0 μm to about 6.0 μm, such as about 6.0 μm to about 7.0 μm, such as about 7.0 μm to about 8.0 μm, such as about 8.0 μm to about 9.0 μm, such as about 9.0 μm to about 10.0 μm, such as about 10.0 μm to about 11.0 μm, such as about 11.0 μm to about 12.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide citrate forms particles having a mean numerical CE diameter of about 2.9 μm, about 3.4 μm, about 3.7 μm, about 4.2 μm, about 4.6 μm, about 5.3 μm, about 5.8 μm, about 6.7 μm, about 7.7 μm, or about 8.2 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate forms particles having a D90 particle size with a digital length D90 of about 10.0 μm, about 10.5 μm, about 11.0 μm, about 11.5 μm, about 12.0 μm, about 12.5 μm, about 13.0 μm, about 13.5 μm, about 14.0 μm, about 14.5 μm, about 15.0 μm, about 15.5 μm, about 16.0 μm, about 16.5 μm, about 17.0 μm, about 17.5 μm, about 18.0 μm, about 18.5 μm, about 19.0 μm, about 19.5 μm, or about 20.0 μm.

In some embodiments, the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate forms particles having a D90 particle size with a digital length D90 of about 10.0 μm to about 20.0 μm, such as about 10.0 μm to about 11.0 μm, such as about 11.0 μm to about 12.0 μm, such as about 12.0 μm to about 13.0 μm, such as about 13.0 μm to about 14.0 μm, such as about 14.0 μm to about 15.0 μm, such as about 15.0 μm to about 16.0 μm, such as about 16.0 μm to about 17.0 μm, such as about 17.0 μm to about 18.0 μm, such as about 18.0 μm to about 19.0 μm, such as about 19.0 μm to about 20.0 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-diimine yl chloride 1-oxide citrate forms particles having a D90 particle size with a digital length D90 of about 10.5 μm, about 13.9 μm, about 16.6 μm, about 16.8 μm, about 22.2 μm, about 24.8 μm, about 25.5 μm or about 26.7 μm.

In some embodiments, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate forms particles having a D90 particle size with a digital length D90 of from about 7.0 μm to about 35.0 μm.

In some embodiments, the D90 particle size of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate particles is from about 30.0 μm to about 130.0 μm as determined using Malvern Mastersizer 3000.

In some embodiments, the D90 particle size of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate particles is about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, about 100 μm, about 105 μm, about 110 μm, about 115 μm, about 120 μm, about 125 μm, or about 130 μm, as determined using Malvern Mastersizer 3000.

In some embodiments, the D90 particle size of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate particles is about 30.0 μm to about 130.0 μm, such as about 30.0 μm to about 35.0 μm, such as about 35.0 μm to about 40.0 μm, such as about 40.0 μm to about 45.0 μm, such as about 45.0 μm to about 50.0 μm, such as about 50.0 μm to about 55.0 μm, such as about 55.0 μm to about 60.0 μm, such as about 60.0 μm to about 65.0 μm, such as about 65.0 μm to about 70.0 μm, such as about 70.0 μm to about 75.0 μm, such as about 75.0 μm to about 80.0 μm, such as about 80.0 μm to about 85.0 μm, such as about 85.0 μm to about 45.0 μm, such as about 85.0 μm to about 120.0.100.100.0 μm, such as about 95.0 μm to about 120.0.100.100.0 μm, such as about 100.100.0 μm or about 95.0.100 μm, such as about 120.0 μm, as measured using Malvern Mastersizer.3000.

Project

1. A process for preparing ORZY-01,

wherein the method comprises:

step 1A) in a vessel a compound of formula (I)

With a compound of formula (II)

Step 1B), intermediate is reacted with NaNO ₂ Reacting in a second solvent at a second temperature to provide ORZY-01,

thereby providing an ORZY-01.

2. A process for preparing ORZY-01,

wherein the method comprises:

step 1A) in a vessel a compound of formula (I)

With a compound of formula (II)

Step 1B), intermediate is reacted with NaNO ₂ Reacting in a second solvent at a second temperature to extractFor the purpose of providing a medium such as ORZY-01,

thereby providing an ORZY-01.

3. The process according to any one of the preceding items, wherein the intermediate is isolated, optionally purified, prior to step 1B).

4. The method of any one of the preceding items, wherein the first solvent is a polar protic solvent or a mixture of polar protic solvents.

5. The method of any one of the preceding items, wherein the first solvent is selected from ethanol, water, methanol, 2-propanol, and any mixture thereof.

6. The method of any one of the preceding items, wherein the first solvent is a mixture of ethanol and water.

7. The method according to any of the preceding items, wherein step 1A is performed under alkaline conditions, e.g. by adding a hydroxide, e.g. NaOH or KOH.

8. The method of any one of the preceding items, wherein the second solvent is a chlorinated hydrocarbon or a mixture containing a chlorinated hydrocarbon.

9. The method of any one of the preceding items, wherein the second solvent is a mixture of dichloromethane and water.

10. The method of any one of the preceding items, wherein the first solvent is different from the second solvent.

11. The method of any one of the preceding items, wherein the first temperature is at the boiling point of the solvent.

12. The method of any one of the preceding items, wherein the first temperature is higher than the second temperature.

13. The method of any one of the preceding items, wherein the first temperature is from 70 ℃ to 90 ℃, such as from 72 ℃ to 88 ℃, such as from 74 ℃ to 86 ℃, such as from 76 ℃ to 84 ℃, such as from 78 ℃ to 82 ℃, such as 80 ℃.

14. The method of any one of the preceding items, wherein the second temperature is from 0 ℃ to 15 ℃, such as from 0 ℃ to 1 ℃, such as from 1 ℃ to 2 ℃, such as from 2 ℃ to 3 ℃, such as from 3 ℃ to 4 ℃, such as from 5 ℃ to 6 ℃, such as from 6 ℃ to 7 ℃, such as from 7 ℃ to 8 ℃, such as from 8 ℃ to 9 ℃, such as from 9 ℃ to 10 ℃, such as from 10 ℃ to 11 ℃, such as from 11 ℃ to 12 ℃, such as from 12 ℃ to 13 ℃, such as from 13 ℃ to 14 ℃, such as from 14 ℃ to 15 ℃.

15. The method of any one of the preceding items, wherein the second temperature is maintained for 1 hour.

16. The process of any one of the preceding items, wherein the compound of formula (II) is mixed with the compound of formula (I) in a molar ratio of 1.3:1.0.

17. The method of any one of the preceding items, wherein the method is carried out with NaNO ₂ The intermediate was not isolated prior to the reaction.

18. The process of any one of the preceding items, wherein the intermediate is reacted with at least 1.2 equivalents of NaNO ₂ And (3) reacting.

19. The process of any one of the preceding items, wherein the intermediate is reacted with 1.2 to 1.6 equivalents of NaNO ₂ And (3) reacting.

20. The method according to any of the preceding items, wherein the first solvent is heated to reflux for at least 2.5 hours, such as 3 hours or more, such as 4 hours or more, such as 5 hours or more, such as 6 hours or more.

21. The method according to any of the preceding items, wherein the first solvent is heated to a temperature of 75 ℃ to 85 ℃, e.g. 80 ℃ for a period of less than 3.5 hours.

22. The method of any one of the preceding items, wherein the first solvent is optionally denatured ethanol; and water, and maintaining the first solvent at 80 ℃ for at least 3 hours.

23. The method of any one of the preceding items, wherein the first solvent is optionally denatured ethanol; and water, and maintaining the first solvent at 80 ℃ for at least 3 hours; and wherein the second solvent is a mixture of dichloromethane and water.

24. A process for preparing ORZY-03,

wherein the method comprises the following successive steps:

a) ORZY-01 is carried out in a container

Mixing with dibenzoyl L-tartaric acid (L-DBTA) in a first step 2 solvent and heating the first step 2 solvent to a first step 2 temperature, optionally stirring the first step 2 solvent;

c) Separating the first step 2 solvent and the solid composition comprising ORZY-03, optionally by filtration,

thereby providing ORZY-03.

25. The method of item 24, further comprising the step of:

26. The method of any one of items 24-25, further comprising the step of:

e) The solid composition comprising ORZY-03 was dried under reduced pressure.

27. The method of any one of clauses 24-26, further comprising step a 1) prior to step b), wherein the first step 2 solvent is cooled to a third step 2 temperature; wherein the temperature of the third step 2 is higher than that of the second step 2.

28. The method of any one of clauses 24-27, wherein the cooling rate is selected from 15K/h;16K/h;17K/h;18K/h;19K/h;20K/h;21K/h;22K/h;23K/h;24K/h;25K/h;26K/h;27K/h;28K/h;29K/h;30K/h;31K/h;32K/h;33K/h;34K/h;35K/h;36K/h;37K/h;38K/h;39K/h;40K/h;41K/h;42K/h;43K/h;44K/h;45K/h;46K/h;47K/h;48K/h;49K/h; and 50K/h.

29. The method of any one of clauses 24-28, wherein the cooling rate is 15K/h to 50K/h, such as 15K/h to 16K/h; for example 16K/h to 17K/h; for example 17K/h to 18K/h; for example 18K/h to 19K/h; for example 19K/h to 20K/h; for example 20K/h to 21K/h; for example 21K/h to 22K/h; for example 22K/h to 23K/h; for example 23K/h to 24K/h; for example 24K/h to 25K/h; for example 25K/h to 26K/h; for example 26K/h to 27K/h; for example 27K/h to 28K/h; for example 28K/h to 29K/h; for example 29K/h to 30K/h; for example 30K/h to 31K/h; for example 31K/h to 32K/h; for example 32K/h to 33K/h; for example 33K/h to 34K/h; for example 34K/h to 35K/h; for example 35K/h to 36K/h; for example 36K/h to 37K/h; for example 37K/h to 38K/h; for example 38K/h to 39K/h; for example 39K/h to 40K/h; for example 40K/h to 41K/h; for example 41K/h to 42K/h; for example 42K/h to 43K/h; for example 43K/h to 44K/h; for example 44K/h to 45K/h; for example 45K/h to 46K/h; for example 46K/h to 47K/h; for example 47K/h to 48K/h; for example 48K/h to 49K/h; for example 49K/h to 50K/h.

30. The method of any one of clauses 24-29, wherein the cooling rate is 15K/h to 50K/h.

31. The method of any one of clauses 24-30, wherein the cooling rate is 15K/h to 40K/h.

32. The method of any one of clauses 24-31, wherein the cooling rate is 15K/h to 30K/h.

33. The method of any one of clauses 24-32, wherein the cooling rate is 17K/h to 30K/h.

34. The method of any one of clauses 24-33, wherein the first step 2 solvent is a polar protic solvent or a mixture of polar protic solvents.

35. The method of any one of clauses 24-34, wherein the first step 2 solvent is selected from the group consisting of ethanol, water, methanol, 2-propanol, and any mixture thereof.

36. The method of any one of clauses 24-35, wherein the first step 2 solvent is a mixture of ethanol and water.

37. The method of any one of clauses 24-36, wherein the first step 2 solvent is 20.5 to 23.5kg of water per 55kg of ORZY-01; and 200 to 240kg EtOH per 55kg ORZY-01.

38. The method of any one of clauses 24-37, wherein the first step 2 solvent is 22kg of water per 55kg of ORZY-01; and 220kg EtOH per 55kg ORZY-01.

39. The method of any one of clauses 24-38, wherein the first step 2 temperature is 60 to 75 ℃, such as 61 to 74 ℃, such as 62 to 73 ℃, such as 63 to 72 ℃, such as 64 to 71 ℃, such as 65 to 70 ℃, such as 65 ℃.

40. The method of any one of clauses 24-39, wherein the second step 2 temperature is 10 to 30 ℃, such as 11 to 29 ℃, such as 12 to 28 ℃, such as 13 to 27 ℃, such as 14 to 26 ℃, such as 15 to 25 ℃, such as 20 ℃.

41. The method of any one of clauses 24-40, wherein the third step 2 temperature is 45 to 65 ℃, such as 46 to 64 ℃, such as 47 to 63 ℃, such as 48 to 62 ℃, such as 49 to 61 ℃, such as 50 to 60 ℃, such as 51 to 59 ℃, such as 52 to 58 ℃, such as 53 to 57 ℃, such as 54 to 56 ℃, such as 55 ℃.

42. The method of any one of clauses 24-41, wherein the third step 2 temperature is maintained for at least 30 minutes, such as at least 60 minutes.

43. The method of any one of clauses 24-42, wherein one or more ORZY-03 seeds are added to the container prior to step b.

44. The method of any one of clauses 24-43, wherein the one or more ORZY-03 seeds have a chiral purity of at least 95%.

45. The method of any one of clauses 24-44, wherein the mass of the one or more ORZY-03 seeds is 0.2 to 0.8kg per 55kg of ORZY-03, e.g., 0.55kg per 55kg of ORZY-03.

46. The method of any one of clauses 24-45, wherein the first predetermined volume of the solvent of the first step 2 is 35 to 55kg per 55kg of ORZY-03.

47. The method of any one of clauses 24-46, wherein the first predetermined volume of the first step 2 solvent is 41 to 45kg per 55kg of ORZY-03.

48. A process for preparing ORZY-05,

wherein the method comprises the steps of:

e) Purifying the ORZY-04 of step d) to obtain ORZY-05.

49. The method of item 48, wherein the method further comprises the step of:

i) Mixing the compound ORZY-03 with an aqueous solution of the base of the first step 3; and

ii) extracting the mixture obtained in step a) with a first step 3 solvent to obtain a solution of ORZY-03 in the first step 3 solvent;

a catalytic amount of citric acid according to step a) of item 48 is then added to the solution of ORZY-03 in the first step 3 solvent.

50. The method of any one of clauses 48 to 49, wherein said method further comprises washing the first step 3 solvent one or more times with water, thereby removing one or more byproducts from the first step 3 solvent.

51. The method of any one of clauses 48 to 50, wherein the method further comprises washing the first step 3 solvent one or more times with water after adding the first step 3 base, thereby removing one or more byproducts from the first step 3 solvent.

52. The method of any one of items 48 to 51, wherein the method comprises the steps of:

b) Solvent extracting the mixture obtained in step a) with a first step 3;

c) Adding a catalytic amount of citric acid to the organic phase of step b);

53. The method of any one of clauses 48 to 52, wherein the first step 3 solvent is a chlorinated hydrocarbon or a mixture containing a chlorinated hydrocarbon.

54. The method of any one of clauses 48 to 53, wherein the first step 3 solvent is methylene chloride or ethylene dichloride, preferably methylene chloride.

55. The method of any one of clauses 48 to 54, wherein the second step 3 solvent is a polar protic solvent or a mixture of polar protic solvents.

56. The method of any one of clauses 48 to 55, wherein the second step 3 solvent is selected from the group consisting of methanol, water, ethanol, 2-propanol, and any mixture thereof.

57. The method of any one of clauses 48 to 56, wherein the second step 3 solvent is methanol.

58. The method of any one of clauses 48 to 57, wherein the first step 3 base is a carbonate.

59. The method of any one of clauses 48 to 58, wherein the first step 3 base is selected from K ₂ CO ₃ And Cs ₂ CO ₃ Is a carbonate salt of (a).

60. The method of any one of clauses 48 to 59, wherein the first step 3 base is K ₂ CO ₃ 。

61. The method of any one of clauses 48 to 60, wherein K ₂ CO ₃ Comprises 16.8% K ₂ CO ₃ 。

62. The method of any one of clauses 48 to 61, wherein ORZY-03 and K ₂ CO ₃ For mixtures of (C) CH ₂ Cl ₂ Extraction is carried out three times.

63. The method of any one of clauses 48 to 62, wherein the solvent is removed from CH ₂ Cl ₂ Change to CH ₃ OH comprises the following steps:

a. partial distillation of CH ₂ Cl ₂ A solution;

b. adding CH to the distilled solution provided in step a) ₃ OH；

c. Partially distilling the solution provided in step b); and

d. adding CH to the solution provided in step c) ₃ OH。

64. The method of clause 63, wherein the amount distilled in steps a) and c) corresponds at least to the CH that dissolved ORZY-03 prior to the solvent change step ₂ Cl ₂ Is a combination of the amounts of (a) and (b).

65. The method of any one of clauses 63 to 64, wherein the method further comprises flowing the solvent from CH ₂ Cl ₂ Change to CH ₃ The solution obtained after OH was passed through an activated carbon filter.

66. The method of any one of clauses 48 to 65, further comprising the step of drying the ORZY-04.

67. The method of clause 66, wherein the drying step comprises drying the ORZY-04 at 45 ℃ under vacuum for at least 12 hours.

68. The method of item 48, wherein the method comprises the following sequential steps:

a) ORZY-03 was combined with 16.8% K ₂ CO ₃ Mixing the aqueous solution;

c) Adding a catalytic amount of citric acid to the organic phase of step b);

i. Partial distillation of CH from step c) ₂ Cl ₂ A solution;

adding CH to the distilled solution provided in step i) ₃ OH；

Partially distilling the solution provided in step ii); and

adding CH to the solution provided in step iii) ₃ OH；

e) Passing the solution obtained in step d) through an activated carbon filter;

g) Filtering the suspension provided in step e) to obtain ORZY-04;

h) Drying the ORZY-04 obtained in step g) at 45℃under vacuum for at least 12h, and

i) Purifying the ORZY-04 of step h) to obtain ORZY-05.

69. The method of any one of clauses 48 to 68, wherein the step of purifying ORZY-04 to obtain ORZY-05 comprises recrystallization of ORZY-04.

70. The method of clause 69, wherein the solvent used in the recrystallization is acetone.

71. The method of any one of clauses 69 to 70, wherein recrystallizing comprises the step of:

b. cooling the solution formed in step a) to 30±5 ℃;

c. Adding acetone to the solution of step b);

d. cooling the mixture of step c) to 0±5 ℃;

e. stirring the mixture of step d) at 0±10 ℃ for 12h to produce a suspension;

f. separating ORZY-05 from the suspension of step e) by filtering the suspension; and

the ORZY-05 obtained in step f) is dried under vacuum at 45℃for at least 12h.

72. A composition comprising ORZY-01

One or more impurities selected from the group consisting of:

73. the composition of item 72, wherein (a) is present in an amount of 0.1% to 0.5% by weight and/or (B) is present in an amount of 0.1% to 0.5% by weight.

74. The composition of any one of items 72 to 73, wherein (a) is present in an amount of 0.1% to 0.5%, such as 0.1% to 0.2%, such as 0.2% to 0.3%, such as 0.3% to 0.4%, such as 0.4% to 0.5% by weight.

75. The composition of any one of items 72 to 74, wherein (B) is present in an amount of 0.1% to 0.5%, such as 0.1% to 0.2%, such as 0.2% to 0.3%, such as 0.3% to 0.4%, such as 0.4% to 0.5% by weight.

76. A method for preparing apricots citrate (ORZY-05),

(apricots citrate),

comprising providing an ORZY-01 as defined in any one of the preceding items; ORZY-03; or OZY-04.

77. A method for preparing apricots citrate (ORZY-05),

(apricots citrate),

which comprises the following successive steps:

a. the method of providing an ORZY-01 as defined in any one of items 1 to 23,

b. precipitation of ORZY-01 with dibenzoyl L-tartaric acid to provide ORZY-03,

c. reacting ORZY-03 with a base followed by precipitation of the resulting ORZY-03 free base with citric acid to provide apricots citrate,

thereby providing apricots citrate.

78. A method for preparing apricots citrate,

(apricots citrate),

which comprises the following successive steps:

a. an ORZY-01 is provided which,

b. the method of providing an ORZY-03 as defined in any one of items 24 to 47,

thereby providing apricots citrate.

79. A method for preparing apricots citrate,

(apricots citrate),

which comprises the following successive steps:

a. an ORZY-01 is provided which,

b. precipitation of ORZY-01 with dibenzoyl L-tartaric acid to provide ORZY-03,

c. the method of providing an ORZY-05 as defined in any one of items 48 to 77,

thereby providing apricots citrate.

80. The method of any one of the preceding items, further comprising adding one or more ORZY-01 seeds to the vessel.

81. The method of any one of the preceding items, further comprising adding one or more ORZY-03 seeds to the vessel.

82. The method of any one of the preceding items, further comprising adding one or more ORZY-05 seeds to the vessel.

83. The method according to any one of the preceding items, as a first step, one or more ORZY-01 seeds are added to the vessel.

84. The method according to any one of the preceding items, as a first step, one or more ORZY-03 seeds are added to the vessel.

85. The method according to any one of the preceding items, as a first step, one or more ORZY-05 seeds are added to the vessel.

86. An oral formulation comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

87. The oral formulation of item 86, wherein the pharmaceutically acceptable salt is N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

88. The oral formulation of item 86 or item 87, wherein the oral formulation comprises a capsule.

89. The oral formulation of any one of items 86-88, wherein the formulation comprises a filler.

90. The oral formulation of any one of clauses 86-89, wherein the formulation comprises a lubricant.

91. The oral formulation of any one of clauses 86-90, wherein the capsule comprises hydroxypropyl methylcellulose (HPMC), titanium dioxide, and optionally one or more colorants.

92. The oral formulation of any one of clauses 86-91, wherein the filler is microcrystalline cellulose (MCC).

93. The oral formulation of any one of clauses 86-92, wherein the lubricant is magnesium stearate.

94. The oral formulation of any one of clauses 86-93, wherein the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is present at a dose of about 50mg to about 500 mg.

95. The oral formulation of any one of clauses 86-94, wherein the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is present at a dose of about 47mg, about 62mg, about 93mg, or about 124 mg.

96. The oral formulation of any one of clauses 86-94, wherein the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is present at a dose of about 75mg, about 100mg, about 150mg, about 200mg, or about 400 mg.

97. The oral formulation of any one of clauses 86-96, wherein the oral formulation comprises about 20 to about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

98. The oral formulation of any one of clauses 86-97, wherein the oral formulation comprises about 26.3% or about 52.6% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof.

99. The oral formulation of any one of clauses 86-98, wherein the oral formulation comprises about 40 to about 80% w/w microcrystalline cellulose.

100. The oral formulation of any one of clauses 86-99, wherein the oral formulation comprises about 73.2% or about 46.9% w/w microcrystalline cellulose.

101. The oral formulation of any one of clauses 86-100, wherein the oral formulation comprises about 0.0% to about 1.0% magnesium stearate.

102. The oral formulation of any one of clauses 86-101, wherein the oral formulation comprises about 0.5% magnesium stearate.

103. A pharmaceutical composition comprising N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, having a purity of greater than or equal to 98.0% as determined by HPLC.

104. The pharmaceutical composition of clause 103, wherein the composition contains less than 2 percent of an impurity selected from the group consisting of N- { [ (2S) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof, (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) pyridine methylimino acid methyl ester 1-oxide or a pharmaceutically acceptable salt thereof, or N-nitrosopiperidine, and combinations thereof.

105. A unit dosage form of the pharmaceutical composition of item 103 or item 104 and a pharmaceutically acceptable carrier or excipient.

106. The unit dosage form of clause 105, comprising the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof at a dosage of about 50mg to about 500 mg.

107. The unit dosage form of clause 105, or the oral formulation of clause 49, comprising an amount of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof of about 47mg, about 62mg, about 93mg, or about 124 mg.

108. A kit comprising the unit dosage form of any one of items 105-107 and instructions for administration.

109. The kit of item 108, wherein the kit further comprises prescription information and/or a plurality of unit doses.

110. A method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of the oral formulation, pharmaceutical composition, or unit dose of any one of items 86-107 is administered to the subject.

111. The oral formulation, pharmaceutical composition, or unit dose of any one of items 86-107 for use in treating or preventing niemann pick disease form C in a subject in need thereof.

112. Use of the oral formulation, pharmaceutical composition, or unit dose of any one of items 86-107 in the manufacture of a medicament for treating or preventing niemann pick disease type C in a subject in need thereof.

113. The oral formulation, pharmaceutical composition, or unit dose of any one of items 86-107 for use in treating or preventing niemann pick disease type C in a subject in need thereof.

114. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of any one of clauses 110-113, wherein the oral formulation, pharmaceutical composition or unit dose is administered three times per day.

115. The method, oral formulation, pharmaceutical composition or unit dose for use or use of an oral formulation, pharmaceutical composition or unit dose of any one of items 110-114, wherein the oral formulation, pharmaceutical composition or unit dose is administered to a pediatric subject having a weight of about 8kg to about 15 kg.

116. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of item 115, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 47 mg.

117. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of item 115, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 75 mg.

118. The method, oral formulation, pharmaceutical composition or unit dose for use or use of any one of items 110-114, wherein the oral formulation, pharmaceutical composition or unit dose is administered to a subject having a body weight of greater than about 15kg to about 30 kg.

119. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of item 118, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 62 mg.

120. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of item 118, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 100 mg.

121. The method, oral formulation, pharmaceutical composition or unit dose for use or use of any one of items 110-114, wherein the oral formulation, pharmaceutical composition or unit dose is administered to a subject having a body weight of greater than about 30kg to about 55 kg.

122. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of any one of clause 121, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 93 mg.

123. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of any one of clause 121, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 150 mg.

124. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of any one of items 110-114, wherein the oral formulation, pharmaceutical composition or unit dose is administered to a subject having a body weight of greater than about 55 kg.

125. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of item 124, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 124 mg.

126. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of item 124, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 200 mg.

127. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of any one of clauses 110-126, wherein not less than about 85 percent of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-carboimidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is dissolved into a solution in about 15 minutes.

128. The method, oral formulation for use, pharmaceutical composition or unit dose or use of an oral formulation, pharmaceutical composition or unit dose of any one of clauses 110-127, wherein the capsule ingredient is mixed as a liquid with a liquid for oral administration.

129. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-128, wherein after administration of a single dose, the geometric mean C of the composition _max At 1749 (CV 49%) ng/mL C _max Is within about 80.00% to about 125.00%.

130. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-128, wherein the AUC of the composition after administration of a single dose _{For 0 to 8 hours} AUC at 5317 (CV 17%) h.ng/mL _{For 0 to 8 hours} Is within about 80.00% to about 125.00%.

131. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-128, wherein the AUC of the composition after administration of a single dose _0-infinity AUC at 6331 (CV 17%) h.ng/mL _0-infinity Is within about 80.00% to about 125.00%.

132. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-128, wherein after administration the geometric mean C of the composition at steady state _{max, steady state} At C at 2090 (CV 23%) ng/mL _{max, steady state} Is within about 80.00% to about 125.00%.

133. The method, oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose for use of any one of clauses 110-128, wherein after administration, the AUC of the composition _{For 0-8 hours, steady state} AUC at 7207 (CV 19%) h.ng/mL _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

134. The method, oral formulation, pharmaceutical composition or unit dose for use or use of any one of items 129-133, wherein N- [ (2 r, z) -2-hydroxy-3- (1-piperidinyl) propoxy ] pyridine-3-azomethionyl chloride 1-oxide or a pharmaceutically acceptable salt thereof is measured in plasma.

135. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-114, wherein the geometric mean C of the composition at steady state after administration of the composition to a human weighing from about 8kg to about 15kg _{max, steady state} At 533ng/mL (368-770 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

136. The method, oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose for use of any one of clauses 110-114, wherein the AUC of the composition after administration of the composition to a human having a body weight of about 8kg to about 15kg _{For 0-8 hours, steady state} AUC at 2916 h.ng/mL (1924-4436 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

137. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-114, wherein upon administration of the composition to a human having a body weight of greater than about 15kg to about 30kg, the composition has a geometric average C at steady state _{max, steady state} At C of 593ng/mL (395-878 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

138. The method, oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose for use of any one of clauses 110-114, wherein the AUC of the composition after administration of the composition to a human having a body weight of greater than about 15kg to about 30kg _{For 0-8 hours, steady state} AUC at 3043 h.ng/mL _{For 0-8 hours, steady state} Within about 80.00% to about 125.00% (1938-4763 h.ng/mL, 5 th and 95 th percentiles).

139. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-114, wherein the geometric mean C of the composition at steady state after administration of the composition to a human having a body weight of greater than about 30 to about 55kg _{max, steady state} At C of 679ng/mL (450-1024 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

140. The method, oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose for use of any one of clauses 110-114, wherein the AUC of the composition after administration of the composition to a human having a body weight of greater than about 30kg to about 55kg _{For 0-8 hours, steady state} AUC at 3149 h.ng/mL (2010-4855 h.ng/mL, 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

141. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-114, wherein the geometric mean C of the composition at steady state after administration of the composition to a human having a body weight of greater than about 55kg _{max, steady state} At C of 743ng/mL (479-743 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

142. The method, oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose for use of any one of clauses 110-114, wherein the AUC of the composition after administration of the composition to a human having a body weight of greater than about 55kg _{For 0-8 hours, steady state} AUC at 3182 h.ng/mL (2057-4921 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

143. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-114, wherein the dose is between about 31mg and about 496m After a single oral dose of g, N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl]The exposure to oxy } pyridine-3-azomethionyl chloride 1-oxide citrate increases in proportion to the dose, with an estimate of the proportionality coefficient (90% CI) for C _max 1,149 (1,07-1, 20), for AUC _0-infinity 1,027 (0, 98-1,08).

144. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-114, wherein the overall median value t after administration _max From 0.25 to 3.0 hours.

145. The method, oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose for use of any one of clauses 110-114, wherein the median value t after administration _max About 0.5 hours.

146. The oral formulation, pharmaceutical composition, or unit dose of any one of clauses 86-107, wherein the oral formulation, pharmaceutical composition, or unit dose has a shelf life of at least 24 months at about 20 ℃ to about 25 ℃.

147. The oral formulation, pharmaceutical composition, or unit dose of any one of clauses 86-107, wherein the oral formulation, pharmaceutical composition, or unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide, or a pharmaceutically acceptable salt thereof, having a purity of greater than or equal to 98.0% as determined by HPLC.

148. A pharmaceutical composition comprising:

c) Less than about 2ppm of N-nitrosopiperidine.

149. A pharmaceutical composition comprising:

c) Less than about 2ppm of N-nitrosopiperidine.

150. A pharmaceutical composition comprising:

c) Up to about 0.1% of (Z) -N- (2-hydroxy-3- (piperidin-1-yl) propoxy) picolinic acid methyl ester 1-oxide or pharmaceutically acceptable salt thereof;

d) Up to about 2ppm of N-nitrosopiperidine.

151. A pharmaceutical composition comprising:

d) Up to about 2ppm of N-nitrosopiperidine.

152. The pharmaceutical composition of any of claims 148-151, wherein N-nitrosopiperidine is undetectable.

Examples

Example 1: preparation of ORZY-01

ORZY-01 can be prepared according to the optimized step 1 process described herein below, or can be prepared using the process described in WO 01/79174.

Material

Ethanol: SDA-3C was used. SDA (Special denatured ethanol) (200 proof, SDA 3C containing isopropanol), N-hydroxy-1-oxo-3-pyridinecarboxamidine "PCO-N-oxide" and 2-hydroxy-4-Azonia-spiro [3,5] nonane chloride "Azonia" are provided by Chiral Quest.

Method

One or more seeds of ORZY-01 may be added to the reaction vessel to completely remove the genotoxic compound N-nitrosopiperidine in the product of step 1, ORZY-01.

Sodium hydroxide (50% in water, 68.4g,855.0mmol,1.31 eq.) was mixed with water (215.8 mL) and then cooled to 10-20deg.C. 2-hydroxy-4-Azonia-spiro [3,5] nonane chloride "Azonia" (153.0 g,1.32 eq.) was added and the mixture cooled to 5-10℃and stirred for 40 min.

Ethanol (SDA-3 c,1000 ml) was added followed by N-hydroxy-1-oxo-pyridine formamidine "PCO-N-oxide" (112.0 g,653.0mmol, kf=11%). The mixture was heated to reflux (about 80 ℃) and held for 4 hours. The coupling reaction achieves about 95% conversion. After the reaction was complete, the batch was cooled to ambient temperature (about 25 ℃) and left overnight. The mixture was cooled to ambient temperature (about 25 ℃). Water (100 mL) and concentrated HCl (68.4 mL) were added to adjust the pH to 5 to 7 units (additional 6mL of 6N HCl was used for pH adjustment). During the neutralization, the internal temperature was kept below 30 ℃. The batch was distilled to about 5 volumes. Concentrated HCl (370 mL) was added. The batch was cooled to 0-5 ℃. A solution of sodium nitrite (55.4 g,803.0mmol,1.23 eq.) in water (75 mL) was slowly added, maintaining the internal temperature between 5-15 ℃. Almost complete conversion was observed. The mixture was left overnight at 5-15 ℃. DCM (600 mL) was added followed by 40% aqueous sodium hydroxide (491.6 g) maintaining the internal temperature below 15 ℃ (pH > 13.1). The DCM layer was separated and the aqueous layer was back-extracted with DCM (500 mL). The organic phase was distilled to about 5 volumes. MTBE (5 vol, 500 mL) was added. The mixture was distilled to about 5 volumes. MTBE (5 volumes, 500 mL) was added and the mixture was again distilled to 5 volumes. MTBE (5.5 volumes, mL) was added and the batch was cooled to 0-5 ℃ for 3 hours. The slurry was filtered. The wet cake was washed with MTBE (1.5 volumes, 150 mL) and then dried under vacuum overnight. 163.2g of isolated product ORZY-01 were obtained in 79.6% yield (99.7% purity).

Results

This optimized procedure provided an isolated ORZY-01 in 79.6% (99.7% purity).

By optimizing the reaction conditions, the optimal reactant ratios, reaction times and temperatures were established so that the product ORZY-01 was isolated in 79.6% yield without intermediate isolation or unnecessary steps. This yield is significantly higher than previously reported.

Example 2: step 1A optimization

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As summarized in table 1, studies were established to understand key reaction parameters that affected the overall outcome of the reaction. Three factors, namely, equivalent weight of "Azonia", reaction temperature and reaction time were studied for five responses, i.e., PCO-N-oxide (%), product (%), impurity a (%), impurity C (%), and reaction conversion (%).

Table 1: reaction conditions and results. Entries 3, 6, 7 and 8 produced high conversions and yields.

When other factors are considered (e.g., minimizing the formation of impurities), the conditions for optimization are: 1.32 equivalents of "Azonia" and a reaction time of 3.6 hours at 80 ℃. If the equivalent of "Azonia" is increased to about 2 equivalents, the reaction will complete within 2 hours. However, too much "Azonia" results in more impurity formation, thus making separation of ORZY-01 more difficult. If the equivalent of "Azonia" is reduced to less than 1.1 equivalent, the reaction does not reach 95% conversion after 6 hours.

The step 1A coupling reaction should preferably be carried out at about 78-82℃for more than 2 hours at the reflux temperature of the water/denatured ethanol (SDA-3C) mixture. According to this study, the lower temperature slowed the reaction significantly.

Example 3: step 1B optimization

And (3) performing step 1B optimization after the step 1A optimization is completed. After completion of step 1A, the mixture was subdivided into several equal fractions and these fractions were used for step 1B optimization to ensure that step 1B experiments began at the same point, which would provide comparable results for the study.

Two factors, namely, the equivalent weight of sodium nitrite and the reaction temperature, were studied for two responses, namely, the reaction conversion (%) and the product purity (%). In order to obtain a minimum of 95% conversion and a batch purity (before separation) of 80%, at least 1.2 sodium nitrite is required at a temperature of 5 to 15 ℃. If the reaction conversion is less than 95%, additional sodium nitrite may be added. The reaction temperature range of step 1B has been reported previously to be-5 ℃ with a target of 0 ℃. This temperature range of step 1B results in incomplete reaction at the beginning, requiring several supplements of sodium nitrite solution to drive the reaction to completion.

In addition to incomplete reactions, delayed exothermic reactions were also observed at 0 ℃, which is a potential safety issue for larger scale processes. Thus, increasing the target reaction temperature of step 1B to 5-15 ℃ successfully resulted in the reaction being completed with a single sodium nitrite addition. The diazonium salt generated in situ was rapidly converted to ORZY-01 by HCl without any delay in the exothermic reaction observed. The optimized reaction time of step 1B was about 1 hour.

The reaction temperature in step 1B was optimized to 10±5℃. When the reaction temperature is lower than 5 ℃, a delayed exothermic reaction may be observed. Temperatures above 15 ℃ will lead to very severe reactions and raise safety problems.

Example 4: step 2-chiral resolution

Overview of reaction steps

Material

Vendor/laboratory codes, lot numbers and assigned qualities are listed.

All treatments were performed under nitrogen atmosphere.

Method

Water (6 mL), etOH (95.06 mL), L-DBTA (15.83 g,0.88 eq.) and ORZY-01 (15.00 g,1.00 eq.) were added to the vessel at 20deg.C, followed by flushing the vessel with EtOH (19 mL). The mixture was then heated to 65-70 ℃ and stirred for 0.5 hours. Subsequently, the mixture was cooled to 55±5 ℃, and the mixture was stirred at 55±5 ℃ for 1 hour. ORZY-03 seed (0.15 g) was added; and the mixture was cooled to 20.+ -. 5 ℃ at a cooling rate of 30K/h. The mixture was then stirred at 20.+ -. 5 ℃ for 12h and the solid composition was triturated with EtOH (15.02 mL). The washed solid composition was re-added to the vessel, and EtOH (72.24 mL) and water (3.60 mL) were added to the vessel. Heating the mixture to 55 + -5 ℃; and stirred at 55.+ -. 5 ℃ for 1h. Subsequently, the mixture was cooled to 20 ℃ and stirring was continued at 20±5 ℃ for 2h, and the solid composition was triturated with EtOH (15.02 mL). The milled solid composition was then dried at 45 ℃ to provide ORZY-03.

Results

ORZY-03 was provided in 29% yield based on ORZY-01 with a chemical purity of 100% and a chiral purity of 98.1%.

Conclusion(s)

This example shows that surprisingly high chiral purity and chemical purity are obtained by chiral resolution using carefully selected amounts of L-DBTA and cooling rates of at least 15K/h. The chiral purity of the ORZY-03 obtained in step 2 is preserved in the final product ORZY-05 and can be further improved by recrystallization. An improved chiral resolution step, including a cooling rate of at least 15K/h, is capable of providing an ultrapure composition comprising apricots citrate (ORZY-05) that meets regulatory requirements of the pharmaceutical agency.

Example 5: step 2-correlation of Cooling Rate with chiral purity

Materials and methods

The materials and methods were essentially the same as in example 4. In this example, the cooling rate of the first cooling step to 20.+ -. 5 ℃ was varied and its effect on the chemical and chiral purity of ORZY-03 was determined.

Results

The results of this example are shown in table 2 below.

Table 2: cooling rate and chemical and chiral purity of the resulting ORZY-03.

A cooling rate of 15K/h or higher results in an increase in chiral purity. Chiral purity of 98.1% means that 98.1% of the composition corresponds to enantiomerically pure ORZY-03.

The cooling rate is a key process parameter for chiral resolution of ORZY-01 to provide an enantiomerically enriched salt ORZY-03. Surprisingly, by employing a cooling rate of 15K/h or higher, a significantly increased chiral purity of ORZY-03 is provided.

Example 6: step 3-salt exchange

Overview of reaction steps

Material

Vendor/laboratory codes, lot numbers and assigned qualities are listed.

Method

K was added to the vessel at 20℃ ₂ CO ₃ (16.8% aqueous solution, 140mL,2.4 eq.) and ORZY-03 (54.0 g,30 mL) and the mixture was stirred for 5 min. DCM (130 mL) was added to the vessel at 20deg.C and the mixture was stirred for 5 min. After each phase had stabilized, the phases were separated. DCM (120 mL) was added to the aqueous phase and the mixture was stirred for 5 min. After stabilization, the phases were separated. DCM (130 mL) was added to the aqueous phase and the mixture was stirred for 5 min. After stabilization, the phases were separated. H was added to the combined organic phases (370 mL) ₂ O (480 mL), and the mixture was stirred for 5 min. After stabilization, the phases are separated and the aqueous phase is discarded. The vessel was rinsed with DCM (32 mL).

The combined organic phases (400 mL) were added to the vessel at 20deg.C, and citric acid (anhydrous, 0.37g,1mL,0.02 eq.) was added. The solution was distilled to a target volume of 200mL at 40 ℃. MeOH (150 mL) was added to the solution and the solution was distilled to a target volume of 250mL at 40 ℃. MeOH (320 mL) was added and the solution was passed through an activated carbon filter (Carbofil CA) at 20 ℃ and the filter was rinsed with MeOH (10 mL). The color of the solution was then determined to be > B6 using IPC-1.

Citric acid solution was prepared by adding citric acid (15.01 g,130 mL) and MeOH (100 mL) to separate containers at 20 ℃ and stirring for 5 minutes. The citric acid solution was then added to the vessel containing the reaction solution, and the mixture was cooled to 0 ℃ and stirred at 0 ℃ for at least 12h. The resulting suspension was then filtered to isolate ORZY-04 and washed with MeOH (40 mL). Finally, the solid was dried in vacuo at 45 ℃.

Results

ORZY-04 was obtained in a solid form in 89% yield with a chiral purity of 99.10% based on ORZY-03.

This example describes the preparation of a composition by treatment with potassium carbonate (K ₂ CO ₃ ) Treatment removes dibenzoyl-L-tartaric acid and then treatment with citric acid gives ORZY-04, thereby converting ORZY-03 to ORZY-04.

This example demonstrates that the addition of a catalytic amount of citric acid inhibits the formation of "methoxylated ORZY-04" (also referred to as RRT 0.74) before changing the solvent from DCM to MeOH. This example further demonstrates that washing the combined DCM phases with water further reduces the level of impurities such as RRT 0.74.

Furthermore, this example demonstrates that, in the case of K ₂ CO ₃ The aqueous solution was neutralized to extract ORZY-03, and a by-product called "hydrolyzed ORZY-03" was effectively removed.

Methoxy ORZY-04 (RRT 0.74) hydrolyzed ORZY-03

Thus, high chiral purity and chemical purity are obtained.

Finally, this example demonstrates that ORZY-04 is stable after vacuum drying at 45℃for 168 hours.

Example 7: step 4-purification

Overview of reaction steps

Material

Vendor/laboratory codes, lot numbers and assigned qualities are listed.

Method

ORZY-04 (30.0 g,15 mL) and H ₂ O (58 mL) was added to the vessel andheat to 70±5 ℃ until a clear solution is observed. The solution was then cooled to 30.+ -. 5 ℃. Acetone (291 mL) was added and the mixture was cooled to 0±5 ℃. The mixture was stirred at 0.+ -. 10 ℃ for 12h. The suspension was filtered and the isolated solid was washed with acetone (38 mL) at 20 ℃. Finally, the solid was dried in vacuo at 45 ℃ for at least 12h.

Results

ORZY-05 was obtained in a solid form in a yield of 90% based on ORZY-04, with a chiral purity of 99.96%.

The impurity "hydrolyzed ORZY-04" may be formed during storage of ORZY-04 in water. However, after crystallization of the product was performed as outlined in this example, impurities remained in the mother liquor.

By-product "hydrolyzed ORZY-04"

This example demonstrates that recrystallization under given conditions results in high chiral and chemical purity. Example 8: step 4-correlation of cooling time and particle size of ORZY-05

Materials and methods

The materials and methods were essentially the same as in example 7. In this example, the cooling time of the cooling step from 30℃to 0℃after the addition of acetone was varied and its effect on the particle size of ORZY-05 was determined. The cooling time is a measure of the time required from 30℃to 0 ℃. Particle Size Distribution (PSD) data shown in table 3 were obtained using static auto-imaging (morphology 4).

Results

The results of this example are shown in table 3A below.

Table 3A: relationship between cooling time and Particle Size Distribution (PSD) for batches from activities "O502FP-17" and "O505 FP-18". CE as used herein refers to the circular equivalent diameter of the ORZY-05 particles. This example demonstrates the correlation between particle size as measured by PSD in the cooling step after addition of acetone and cooling time from 30℃to 0 ℃. Shorter cooling times result in smaller particle sizes. According to the data of this example, a cooling time of less than 5.5 hours results in smaller particles, as determined by their median diameter. The smaller size facilitates the preparation of dosage forms requiring a predetermined amount of substance, and increases the encapsulation efficiency when the dosage form is a capsule.

More batches of ORZY-05 were prepared essentially as in example 7 and checked for ORZY-05 particles as in example 11 using Malvern Mastersizer 3000. The PSD obtained is shown in Table 3B.

Table 3B. Overview of ORZY-05 batch and PSD measured using Malvern Mastersizer 3000.

Example 9 Capsule formation

Apricots citrate were formulated as bicolor HPMC hard capsules of size "0" for oral administration in sizes of 50mg, 75mg, 100mg, 150mg and 200mg (corresponding to 31, 47, 62, 93 and 124mg apricots free base). Capsules of 50mg, 75mg and 100mg gauge were made using a 100mg powder blend containing 26.2% apremilast citrate and filled with the capsule's allele (homothetic) (fill weight decreases proportionally with gauge). Accordingly, capsules of 150mg and 200mg gauge were made using 200mg powder blend containing 52.6% apremilast citrate and using allelic filling of the capsules. The capsules were packaged in High Density Polyethylene (HDPE) bottles (185 mL), induction heat sealed with foil liners at the neck openings, and closed with HDPE child resistant caps.

Manual wet granulation is replaced by dry granulation, using roller compaction to avoid contact with moisture and to eliminate the need for heating during the process.

The capsule may be swallowed whole or emptied for administration to patients with dysphagia (e.g. emptiedSprinkle capsules).

The capsule contents may be dispersed into 10-30mL of liquid (i.e., water or apple juice) that the patient or caregiver finds most convenient, or may be dispersed into a spoon of soft serve (i.e., yogurt, apple puree, or pudding) prior to administration. The dispersed contents may also be used for administration through a gastric feeding tube. Stability in dispersion has been demonstrated for up to two hours.

The qualitative composition and function of each excipient is provided in table 4.

HPMC: hydroxypropyl methylcellulose; MCC: microcrystalline cellulose; NA: inapplicable; eur: european pharmacopoeia; USP: united states pharmacopoeia; NF: national prescription set

^a The 50mg, 75mg, 100mg, 150mg and 200mg of aprlomol citrate are equivalent to 31mg, 47mg, 62mg, 93mg and 124mg of aprlomol, respectively

^b HPMCSprinkle capsule (size No. 0)

Table 4.50 mg, 75mg, 100mg, 150mg and 200mg compositions of apricots citrate capsules

Dissolution out

The method used to evaluate the dissolution rate of the drug product was the ph.eur. Paddle method (instrument 2) using 1000mL of 0.1m NaCl/HCl buffer (USP no enzyme artificial gastric juice) at 75rpm, placing the sample in a standard ph.eur. Wire settler, taking 10mL of sample at 5, 10, 15, 30 and 60 minutes without supplementation, and filtering through a 10 μm full flow cannula filter, followed by final filtration through a 0.45 μm nylon filter. Samples were analyzed using UV method and detected at 260 nm. Quantification was performed using external standards.

Evaluation of the dissolution profiles for the five different specifications showed little difference between the average results for each specification.

The dissolution process was performed on all sizes of aprimor citrate capsules according to USP <711> and ph.eur.2.9.3 using instrument 2. After 30 minutes, the detection was performed at 260nm and the percentage of drug substance dissolved was measured by on-line or off-line UV readings.

Dissolution conditions

GF: glass fibers; rpm: a rotational speed per minute; UV: ultraviolet ray

HPLC verification

HPLC analysis procedures for identification, content uniformity and content determination were validated by testing specificity, range, linearity, accuracy, reproducibility, intermediate precision, robustness, solution stability and filter compatibility.

Stability study

Stability studies of 50mg, 75mg, 100mg, 150mg and 200mg apricots of capsules demonstrated good stability at 30%/75% RH.

Long-term 24-month storage of 100mg and 200mg specification capsules showed no significant change in any of the key quality attributes (e.g., appearance, content, impurities, moisture and dissolution) over time at 25 ℃/60% rh and 30 ℃/75% rh, and under accelerated conditions of 40 ℃/75% rh. Stability was tested under open storage and acceleration conditions (40 ℃/75% rh and 40 ℃/95% rh), indicating no significant change in any of the key mass properties.

EXAMPLE 10 pharmacokinetic Studies

The exposure variables were modeled using the population PK covariate model (popPK model; RUNU 030) according to the dose regimen in tables 5 and 6(AUC _0-8h,ss ，C _max,ss ). Steady state was ensured by calculating exposure variables after 7 days of administration at 8 hour intervals. For each weight range, 5000 groups of weights and ages were sampled from the NHANES III database using an age range of > 2 years to < 18 years. 5000 virtual subject PK profiles (per body weight range) were then generated using an updated popPK model including inter-individual differences.

Body weight of subject	Recommended dosage
		8kg to 15kg	31mg three times per day
>15kg to 22kg	47mg three times per day
		>22kg to 38kg	62mg three times per day
>38kg to 55kg	93mg three times per day
		>55kg	124mg three times per day

TABLE 5 dosage regimen 1

Body weight of subject	Recommended dosage
		8kg to 15kg	47mg three times per day
>15kg to 30kg	62mg three times per day
		>30kg to 60kg	93mg three times per day
>60kg	124mg three times per day

TABLE 6 dosing regimen 2

Compared to table 5, the dosing regimen in table 6 resulted in higher exposure in the lower body weight range, whereas the exposure levels in the higher body weight range were generally comparable between the two dosing regimens, see tables 7 and 8.

TABLE 7 AUC simulated from the dosing regimen of TABLE 5 _0-8,ss And C _max,ss

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TABLE 8 AUC simulated from the dosing regimen of TABLE 6 _0-8,ss And C _max,ss

Absorption and bioavailability

Single and multiple dose administration of apricots Mo Houa for the studyPK parameters of (a). Overall median t after single and multiple dose oral administration of apremilast _max From 0.25 to 3.00 hours.

After oral administration of apricots, absorption is rapid and extensive. In the human body test, 77.5% of the drug-related substances are recovered in urine, and 12% of the feces are recovered. The drug substance has demonstrated stability in both gastric and intestinal fluids. This stability allows for high permeability of apricots based on urine recovery in a human mass balance test.

After a single oral dose of 31mg to 496mg, apremilast exhibits linear and dose-proportional pharmacokinetics. Relative to the injection administration of apricots Mo Jingmai, the absolute bioavailability of apricots after oral administration was 85% (77% male, 90% female) in rats and 75% (based on AUC) in dogs _0-infinity )。

For C _max And AUC _0-infinity The estimated values of the proportionality coefficients (90% CI) are 1.14 (1.07-1.20) and 1.03 (0.98-1.08), respectively; all values fall within the range of 0.8 to 1.25, indicating a dose-proportional relationship. Thus, apremilast is considered to be dose proportional after a single administration in the dose range of 31mg to 496mg (free base).

After administration of 62-372mg of apremilast (free base) three times daily in multiple doses, apremilast PK parameters (C _max And AUC _0-8 ) Increasing in proportion to the dose. After single dose administration of 31-496mg of apremilast (free base), apremilast PK parameters (C _max And AUC _0-8 ) Increasing in proportion to the dose.

Example 11: determination of Particle Size Distribution (PSD)

Malvern Mastersizer 3000: the particle size distribution of apricots citrate (ORZY-05) was determined by light scattering using a Malvern Mastersizer 3000 particle size analyzer (Malvern Instruments Ltd, grovwood Road, malvern, worcestershire WR, 1XZ, uk) with a Hydro MV wet dispersion unit. 2-propanol with 1.8g/L SPAN-85 additive was used as the dispersion medium ("dispersant") and added to the dispersion unit. By measuring before adding the sampleThe background count of the system was determined by circulating the dispersant through the measuring cell under conditions (2500 rpm stirrer speed). Samples for analysis were prepared by adding the appropriate amount of apricots citrate to a 10mL vial and pre-dispersing it with dispersant for a few seconds with gentle agitation. The pre-dispersed samples were then pipetted into a Hydro MV dispersion unit with dispersant to meet the 10-15% laser shielding rate range. For this purpose, a disposable PE pipette was used and sampling from a 10mL vial was ensured by continuous stirring to be representative. No sonication was applied to the added sample as it was found to damage the apricots citrate particles. Volume distributions are obtained and D10, D50 and D90 are calculated and reported from these distributions. For each sample, only a single sample preparation was analyzed using red light measurement. After the measurement is completed, the sample cell is emptied and cleaned.

Morphology 4: the particle size distribution of apricots citrate (ORZY-05) was also measured using a Malvern Morphologi apparatus.

For needle-shaped particles, a wet measurement was used. Different solvents were tested and 2-propanol was found to provide the best results in terms of API non-solubilisation. Measurements were performed using a fine path wet cell (thin path wet cell) (75 x 75 mm). Samples were prepared by adding 20mL of dispersant to 10mg API followed by stirring for 30s and sonicating for 2 minutes to break agglomeration. The microscope magnification of X10 or X20 is used, and the split sharpened edge and/or thresholding is used to improve the focus of the focusing microscope.

Equivalents (Eq.)

The details of one or more embodiments of the invention are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise.

Claims

1. A pharmaceutical composition comprising at least 94% enantiomeric excess (ee) of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

2. The pharmaceutical composition of claim 1, wherein the ee of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is at least 95%.

3. The pharmaceutical composition according to any of the preceding claims, wherein the ee of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate is at least 96%.

4. The pharmaceutical composition according to any of the preceding claims, wherein the ee of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is at least 97%.

5. The pharmaceutical composition according to any of the preceding claims, wherein the ee of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide citrate is at least 98%.

6. The pharmaceutical composition according to any of the preceding claims, wherein the composition comprises:

a) At least 94% ee of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate, e.g. at least 95% ee, e.g. at least 96% ee, e.g. at least 97% ee, e.g. at least 98% ee; and

7. The pharmaceutical composition according to any of the preceding claims, wherein the composition comprises:

a) At least 94% ee of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridine-3-azomethionyl chloride 1-oxide citrate, e.g. at least 95% ee, e.g. at least 96% ee, e.g. at least 97% ee, e.g. at least 98% ee;

c) Less than 2ppm of N-nitrosopiperidine.

8. The pharmaceutical composition of any one of the preceding claims, wherein the composition has a purity of greater than or equal to 99.0% n- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate as determined by HPLC.

9. The pharmaceutical composition of any one of the preceding claims comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a D10 particle size of from about 2.0 μιη to about 20.0 μιη, the D10 particle size determined using Malvern Mastersizer 3000.

10. The pharmaceutical composition of any one of the preceding claims comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a D50 particle size of from about 5.0 μιη to about 60.0 μιη, the D50 particle size determined using Malvern Mastersizer 3000.

11. The pharmaceutical composition of any one of the preceding claims comprising particles of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a D90 particle size of from about 30.0 μιη to about 130.0 μιη, the D90 particle size determined using Malvern Mastersizer 3000.

12. The pharmaceutical composition according to any of the preceding claims, wherein the composition comprises:

13. The pharmaceutical composition according to any of the preceding claims, wherein the composition comprises:

d) Less than 2ppm of N-nitrosopiperidine.

14. An oral formulation comprising a pharmaceutical composition as defined in any one of the preceding claims 1-13, and at least one pharmaceutically acceptable excipient.

15. The oral formulation of claim 14, wherein the oral formulation comprises a capsule.

16. The oral formulation of any one of claims 14-15, wherein the oral formulation comprises a filler.

17. The oral formulation of any one of claims 14-16, wherein the oral formulation comprises a lubricant.

18. The oral formulation of any one of claims 15-17, wherein the capsule comprises hydroxypropyl methylcellulose (HPMC), titanium dioxide, and optionally one or more colorants.

19. The oral formulation of any one of claims 16-18, wherein the filler is microcrystalline cellulose (MCC).

20. The oral formulation of any one of claims 17-19, wherein the lubricant is magnesium stearate.

21. The oral formulation of any one of claims 14-20, wherein the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate is present at a dose of about 50mg to about 500 mg.

22. The oral formulation of any one of claims 14-21, wherein the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-methyliminochloride 1-oxide citrate is present at a dose of about 75mg, about 100mg, about 150mg, about 200mg, or about 400 mg.

23. The oral formulation of any one of claims 14-22, wherein the oral formulation comprises about 20% to about 60% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

24. The oral formulation of any one of claims 14-23, wherein the oral formulation comprises about 26.3% or about 52.6% w/w of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

25. The oral formulation of any one of claims 14-24, wherein the oral formulation comprises about 40% to about 80% w/w microcrystalline cellulose.

26. The oral formulation of any one of claims 14-25, wherein the oral formulation comprises about 73.2% or about 46.9% w/w microcrystalline cellulose.

27. The oral formulation of any one of claims 14-26, wherein the oral formulation comprises about 0.0% to about 1.0% magnesium stearate.

28. The oral formulation of any one of claims 14-27, wherein the oral formulation comprises about 0.5% magnesium stearate.

29. A unit dosage form of a pharmaceutical composition as defined in any one of the preceding claims 1 to 13 and a pharmaceutically acceptable carrier or excipient.

30. The unit dosage form of claim 29, comprising the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-imidoyl chloride 1-oxide or a pharmaceutically acceptable salt thereof in a dosage of about 50mg to about 500 mg.

31. The unit dosage form of any one of claims 29-30, or the oral formulation of any one of claims 14-28, comprising a dose of about 47mg, about 62mg, about 93mg, or about 124mg of N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate.

32. A kit comprising a unit dosage form according to any one of claims 29-31 and instructions for administration.

33. The kit of claim 32, wherein the kit further comprises prescription information and/or a plurality of unit doses.

34. A method of treating or preventing niemann pick disease form C in a subject in need thereof, wherein a therapeutically effective amount of a pharmaceutical composition, oral formulation or unit dose as defined in any one of claims 1 to 31 is administered to the subject.

35. A pharmaceutical composition, oral preparation or unit dose as defined in any one of claims 1 to 31 for use in the treatment or prophylaxis of niemann pick disease type C in a subject in need thereof.

36. Use of a pharmaceutical composition, oral formulation or unit dose as defined in any one of claims 1 to 31 in the manufacture of a medicament for the treatment or prophylaxis of niemann-pick disease type C in a subject in need thereof.

37. Use of a pharmaceutical composition, oral formulation or unit dose as defined in any one of claims 1 to 31 for the treatment or prophylaxis of niemann pick disease type C in a subject in need thereof.

38. The method of any one of claims 34-37, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein the oral formulation, pharmaceutical composition, or unit dose is administered 3 times per day.

39. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein the oral formulation, pharmaceutical composition, or unit dose is administered to a pediatric subject having a weight of about 8kg to about 15 kg.

40. The method of claim 39, the oral formulation, pharmaceutical composition or unit dose for use, or the use of an oral formulation, pharmaceutical composition or unit dose, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 47 mg.

41. The method of claim 39, the oral formulation, pharmaceutical composition or unit dose for use, or the use of an oral formulation, pharmaceutical composition or unit dose, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 75 mg.

42. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein the oral formulation, pharmaceutical composition, or unit dose is administered to a subject having a body weight of greater than about 15kg to about 30 kg.

43. The method of claim 42, the oral formulation, pharmaceutical composition or unit dose for use, or the use of an oral formulation, pharmaceutical composition or unit dose, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 62 mg.

44. The method of claim 42, the oral formulation, pharmaceutical composition or unit dose for use, or the use of an oral formulation, pharmaceutical composition or unit dose, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 100 mg.

45. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein the oral formulation, pharmaceutical composition, or unit dose is administered to a subject having a body weight of greater than about 30kg to about 55 kg.

46. The method of claim 45, the oral formulation, pharmaceutical composition or unit dose for use, or the use of an oral formulation, pharmaceutical composition or unit dose, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 93 mg.

47. The method of claim 45, the oral formulation, pharmaceutical composition or unit dose for use, or the use of an oral formulation, pharmaceutical composition or unit dose, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 150 mg.

48. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein the oral formulation, pharmaceutical composition, or unit dose is administered to a subject having a body weight of greater than about 55 kg.

49. The method of claim 48, the oral formulation, pharmaceutical composition or unit dose for use, or the use of an oral formulation, pharmaceutical composition or unit dose, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 124 mg.

50. The method of claim 48, the oral formulation, pharmaceutical composition or unit dose for use, or the use of an oral formulation, pharmaceutical composition or unit dose, wherein the oral formulation, pharmaceutical composition or unit dose is administered at a dose of 200 mg.

51. The method of any one of claims 34-50, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein not less than about 85% of the N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide, or a pharmaceutically acceptable salt thereof, dissolves into solution within about 15 minutes.

52. The method of any one of claims 34-51, an oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose, wherein the capsule component is mixed with a liquid for oral administration as a liquid.

53. The method of any one of claims 34-52, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein geometric mean C of the composition after administration of a single dose _max At 1749 (CV 49%) ng/mL C _max Is within about 80.00% to about 125.00%.

54. The method of any one of claims 34-52, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein after administration of a single dose the AUC of the composition _{For 0 to 8 hours} AUC at 5317 (CV 17%) h.ng/mL _{For 0 to 8 hours} Is within about 80.00% to about 125.00%.

55. The method of any one of claims 34-52, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein after administration of a single dose the AUC of the composition _0-infinity AUC at 6331 (CV 17%) h.ng/mL _0-infinity Is within about 80.00% to about 125.00%.

56. The method of any one of claims 34-52, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein following administration, the composition has a geometric mean C at steady state _{max, steady state} At C at 2090 (CV 23%) ng/mL _{max, steady state} Is within about 80.00% to about 125.00%.

57. The method of any one of claims 34-52, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein after administration the AUC of the composition _{For 0-8 hours, steady state} AUC at 7207 (CV 19%) h.ng/mL _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

58. The method of any one of claims 54-57, an oral formulation, a pharmaceutical composition or a unit dose for use, or a use of an oral formulation, a pharmaceutical composition or a unit dose, wherein N- [ (2 r, z) -2-hydroxy-3- (1-piperidinyl) propoxy ] pyridine-3-azomethionyl chloride 1-oxide citrate is measured in plasma.

59. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein upon administration of the composition to a human weighing from about 8kg to about 15kg, the composition has a geometric mean C at steady state _{max, steady state} At 533ng/mL (368-770 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

60. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein the AUC of the composition after administration of the composition to a human weighing from about 8kg to about 15kg _{For 0-8 hours, steady state} AUC at 2916 h.ng/mL (1924-4436 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

61. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein upon administration of the composition to a human having a body weight of from greater than about 15kg to about 30kg, the composition has a geometric mean C at steady state _{max, steady state} At C of 593ng/mL (395-878 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

62. The method of any one of claims 34-38, theAn oral formulation, pharmaceutical composition or unit dose for such use, or use of an oral formulation, pharmaceutical composition or unit dose, wherein upon administration of the composition to a human having a body weight of from greater than about 15kg to about 30kg, the AUC of the composition _{For 0-8 hours, steady state} AUC at 3043 h.ng/mL (1938-4763 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

63. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein upon administration of the composition to a human having a body weight of greater than about 30 to about 55kg, the composition has a geometric mean C at steady state _{max, steady state} At C of 679ng/mL (450-1024 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

64. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein the AUC of the composition after administration of the composition to a human having a body weight of greater than about 30 to about 55kg _{For 0-8 hours, steady state} AUC at 3149 h.ng/mL (2010-4855 h.ng/mL, 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

65. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition, or unit dose for use, or use of an oral formulation, pharmaceutical composition, or unit dose, wherein upon administration of the composition to a human having a body weight of greater than about 55kg, the composition has a geometric mean C at steady state _{max, steady state} At C of 743ng/mL (479-743 ng/mL, 5 th and 95 th percentiles) _{max, steady state} Is within about 80.00% to about 125.00%.

66. The method according to any one of claims 34-38, the useOr a unit dose thereof, or the use of an oral formulation, pharmaceutical composition or unit dose thereof, wherein the AUC of the composition after administration of the composition to a human having a body weight of greater than about 55kg _{For 0-8 hours, steady state} AUC at 3182 h.ng/mL (2057-4921 h.ng/mL 5 th and 95 th percentiles) _{For 0-8 hours, steady state} Is within about 80.00% to about 125.00%.

67. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose, wherein N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl following a single oral dose of about 31mg to about 496mg]The exposure to oxy } pyridine-3-azomethionyl chloride 1-oxide citrate increases in proportion to the dose, with an estimate of the proportionality coefficient (90% CI) for C _max 1,149 (1,07-1, 20), for AUC _0-infinity 1,027 (0, 98-1,08).

68. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose, wherein the overall median t after administration _max From 0.25 to 3.0 hours.

69. The method of any one of claims 34-38, an oral formulation, pharmaceutical composition or unit dose for use, or use of an oral formulation, pharmaceutical composition or unit dose, wherein the median t after administration _max About 0.5 hours.

70. The oral formulation, pharmaceutical composition, or unit dose of any one of claims 1-31, wherein the oral formulation, pharmaceutical composition, or unit dose has a shelf life of at least 24 months at about 20 ℃ to about 25 ℃.

71. The oral formulation, pharmaceutical composition, or unit dose of any one of claims 1-31, wherein the oral formulation, pharmaceutical composition, or unit dose comprises N- { [ (2R) -2-hydroxy-3-piperidin-1-ylpropyl ] oxy } pyridin-3-azomethionyl chloride 1-oxide citrate having a purity of greater than or equal to 98.0% as determined by HPLC.

72. A process for preparing ORZY-01,

wherein the method comprises:

step 1A), the compound of formula (I) is placed in a vessel

With a compound of formula (II)

thereby providing an ORZY-01.

73. A process for preparing ORZY-01,

wherein the method comprises:

step 1A), the compound of formula (I) is placed in a vessel

With a compound of formula (II)

thereby providing an ORZY-01.

74. The process of any one of claims 72-73, wherein the intermediate is isolated, optionally purified, prior to step 1B).

75. The method of any of claims 72-74, wherein the first solvent is a polar protic solvent or a mixture of polar protic solvents.

76. The method of any one of claims 72-75, wherein the first solvent is selected from the group consisting of ethanol, water, methanol, 2-propanol, and any mixture thereof.

77. The method of any of claims 72-76, wherein the first solvent is a mixture of ethanol and water.

78. The method of any one of claims 72-77, wherein step 1A is performed under alkaline conditions, such as by adding a hydroxide, such as NaOH or KOH.

79. The method of any of claims 72-78, wherein the second solvent is a chlorinated hydrocarbon or a mixture containing a chlorinated hydrocarbon.

80. The method of any of claims 72-79, wherein the second solvent is a mixture of dichloromethane and water.

81. The method of any one of claims 72-80, wherein the first solvent is different from the second solvent.

82. The method of any one of claims 72-81, wherein the first temperature is at the boiling point of the solvent.

83. The method of any of claims 72-82, wherein the first temperature is higher than the second temperature.

84. The method of any one of claims 72-83, wherein the first temperature is 70 ℃ to 90 ℃, such as 72 ℃ to 88 ℃, such as 74 ℃ to 86 ℃, such as 76 ℃ to 84 ℃, such as 78 ℃ to 82 ℃, such as 80 ℃.

85. The method of any one of claims 72-84, wherein the second temperature is 0 ℃ to 15 ℃, such as 0 ℃ to 1 ℃, such as 1 ℃ to 2 ℃, such as 2 ℃ to 3 ℃, such as 3 ℃ to 4 ℃, such as 5 ℃ to 6 ℃, such as 6 ℃ to 7 ℃, such as 7 ℃ to 8 ℃, such as 8 ℃ to 9 ℃, such as 9 ℃ to 10 ℃, such as 10 ℃ to 11 ℃, such as 11 ℃ to 12 ℃, such as 12 ℃ to 13 ℃, such as 13 ℃ to 14 ℃, such as 14 ℃ to 15 ℃.

86. The method of any one of claims 72-85, wherein the second temperature is maintained for 1 hour.

87. The process of any of claims 72-86, wherein the compound of formula (II) is mixed with the compound of formula (I) in a molar ratio of 1.3:1.0.

88. The method of any one of claims 72-87, wherein the polypeptide is purified from NaNO ₂ The intermediate was not isolated prior to the reaction.

89. The process of any one of claims 72-88, wherein the intermediate is reacted with at least 1.2 equivalents of NaNO ₂ And (3) reacting.

90. The process of any of claims 72-89 wherein the intermediate is reacted with 1.2 to 1.6 equivalents of NaNO ₂ And (3) reacting.

91. The method of any one of claims 72-90, wherein the first solvent is heated to reflux for at least 2.5 hours, such as 3 hours or more, such as 4 hours or more, such as 5 hours or more, such as 6 hours or more.

92. The method of any one of claims 72-91, wherein the first solvent is heated to a temperature of 75 ℃ to 85 ℃, such as 80 ℃ for a period of less than 3.5 hours.

93. The method of any one of claims 72-92, wherein the first solvent is optionally denatured ethanol; and water, and maintaining the first solvent at 80 ℃ for at least 3 hours.

94. The method of any one of claims 72-93, wherein the first solvent is optionally denatured ethanol; and water, and maintaining the first solvent at 80 ℃ for at least 3 hours; and wherein the second solvent is a mixture of dichloromethane and water.

95. A process for preparing ORZY-03,

Wherein the method comprises the following successive steps:

a) ORZY-01 is carried out in a container

thereby providing ORZY-03.

96. The method of claim 95, further comprising the step of:

97. The method of any one of claims 95-96, further comprising the step of:

e) The solid composition comprising ORZY-03 was dried under reduced pressure.

98. The method of any one of claims 95-97, further comprising step a 1) prior to step b), wherein the first step 2 solvent is cooled to a third step 2 temperature; wherein the temperature of the third step 2 is higher than that of the second step 2.

99. The method of any one of claims 95-98, wherein the cooling rate is selected from the group consisting of: 15K/h;16K/h;17K/h;18K/h;19K/h;20K/h;21K/h;22K/h;23K/h;24K/h;25K/h;26K/h;27K/h;28K/h;29K/h;30K/h;31K/h;32K/h;33K/h;34K/h;35K/h;36K/h;37K/h;38K/h;39K/h;40K/h;41K/h;42K/h;43K/h;44K/h;45K/h;46K/h;47K/h;48K/h;49K/h and 50K/h.

100. The method of any one of claims 95-99, wherein the cooling rate is 15K/h to 50K/h, such as 15K/h to 16K/h; for example 16K/h to 17K/h; for example 17K/h to 18K/h; for example 18K/h to 19K/h; for example 19K/h to 20K/h; for example 20K/h to 21K/h; for example 21K/h to 22K/h; for example 22K/h to 23K/h; for example 23K/h to 24K/h; for example 24K/h to 25K/h; for example 25K/h to 26K/h; for example 26K/h to 27K/h; for example 27K/h to 28K/h; for example 28K/h to 29K/h; for example 29K/h to 30K/h; for example 30K/h to 31K/h; for example 31K/h to 32K/h; for example 32K/h to 33K/h; for example 33K/h to 34K/h; for example 34K/h to 35K/h; for example 35K/h to 36K/h; for example 36K/h to 37K/h; for example 37K/h to 38K/h; for example 38K/h to 39K/h; for example 39K/h to 40K/h; for example 40K/h to 41K/h; for example 41K/h to 42K/h; for example 42K/h to 43K/h; for example 43K/h to 44K/h; for example 44K/h to 45K/h; for example 45K/h to 46K/h; for example 46K/h to 47K/h; for example 47K/h to 48K/h; for example 48K/h to 49K/h; for example 49K/h to 50K/h.

101. The method of any one of claims 95-100, wherein the cooling rate is 15K/h to 50K/h.

102. The method of any one of claims 95-101, wherein the cooling rate is 15K/h to 40K/h.

103. The method of any one of claims 95-102, wherein the cooling rate is 15K/h to 30K/h.

104. The method of any one of claims 95-103, wherein the cooling rate is 17K/h to 30K/h.

105. The method of any one of claims 95-104, wherein the first step 2 solvent is a polar protic solvent or a mixture of polar protic solvents.

106. The method of any of claims 95-105, wherein the first step 2 solvent is selected from the group consisting of ethanol, water, methanol, 2-propanol, and any mixture thereof.

107. The method of any one of claims 95-106, wherein the first step 2 solvent is a mixture of ethanol and water.

108. The method of any one of claims 95-107, wherein the first step 2 solvent is 20.5 to 23.5kg of water per 55kg of ORZY-01; and 200 to 240kg EtOH per 55kg ORZY-01.

109. The process of any one of claims 95-108, wherein the first step 2 solvent is about every 55kg of ORZY-01 22kg of water; and 220kg EtOH per 55kg ORZY-01.

110. The method of any one of claims 95-109, wherein the first step 2 temperature is 60 to 75 ℃, such as 61 to 74 ℃, such as 62 to 73 ℃, such as 63 to 72 ℃, such as 64 to 71 ℃, such as 65 to 70 ℃, such as 65 ℃.

111. The method of any one of claims 95-110, wherein the second step 2 temperature is 10 to 30 ℃, such as 11 to 29 ℃, such as 12 to 28 ℃, such as 13 to 27 ℃, such as 14 to 26 ℃, such as 15 to 25 ℃, such as 20 ℃.

112. The method of any one of claims 95-111, wherein the third step 2 temperature is 45 to 65 ℃, such as 46 to 64 ℃, such as 47 to 63 ℃, such as 48 to 62 ℃, such as 49 to 61 ℃, such as 50 to 60 ℃, such as 51 to 59 ℃, such as 52 to 58 ℃, such as 53 to 57 ℃, such as 54 to 56 ℃, such as 55 ℃.

113. The method of any one of claims 95-112, wherein the third step 2 temperature is maintained for at least 30 minutes, such as at least 60 minutes.

114. The method of any one of claims 95-113, wherein one or more ORZY-03 seeds are added to the vessel prior to step b.

115. The method of any one of claims 95-114, wherein the chiral purity of one or more ORZY-03 seeds is at least 95%.

116. The method of any one of claims 95-115, wherein the mass of one or more ORZY-03 seeds is 0.2 to 0.8kg per 55kg of ORZY-03, e.g., 0.55kg per 55kg of ORZY-03.

117. The method of any one of claims 95-116, wherein the first predetermined volume of solvent of the first step 2 is between 35 and 55kg per 55kg of ORZY-03.

118. The method of any of claims 95-117, wherein the first predetermined volume of solvent of the first step 2 is 41 to 45kg per 55kg of ORZY-03.

119. A process for preparing ORZY-05,

wherein the method comprises the steps of:

e) Purifying the ORZY-04 of step d) to obtain ORZY-05.

120. The method of claim 119, wherein the method further comprises the steps of:

a catalytic amount of citric acid is then added to a solution of ORZY-03 in the first step 3 solvent according to step a) of claim 119.

121. The method of any one of claims 119 to 120, wherein the method further comprises washing the first step 3 solvent one or more times with water, thereby removing one or more byproducts from the first step 3 solvent.

122. The method of any one of claims 119-121, wherein the method further comprises washing the first step 3 solvent with water one or more times after adding the first step 3 base, thereby removing one or more byproducts from the first step 3 solvent.

123. The method of any one of claims 119 to 122, wherein the method comprises the steps of:

b) Solvent extracting the mixture obtained in step a) with a first step 3;

c) Adding a catalytic amount of citric acid to the organic phase of step b);

124. The method of any one of claims 119-123, wherein the first step 3 solvent is a chlorinated hydrocarbon or a mixture containing a chlorinated hydrocarbon.

125. The process of any one of claims 119 to 124, wherein the first step 3 solvent is dichloromethane or dichloroethane, preferably dichloromethane.

126. The method of any one of claims 119 to 125, wherein the second step 3 solvent is a polar protic solvent or a mixture of polar protic solvents.

127. The process of any one of claims 119 to 126, wherein the second step 3 solvent is selected from the group consisting of methanol, water, ethanol, 2-propanol, and any mixtures thereof.

128. The process of any one of claims 119 to 127, wherein the second step 3 solvent is methanol.

129. The process of any one of claims 119 to 128, wherein the first step 3 base is a carbonate.

130. The process of any one of claims 119 to 129, wherein the first step 3 base is selected from K ₂ CO ₃ And Cs ₂ CO ₃ Is a carbonate salt of (a).

131. The process of any one of claims 119 to 130, wherein the first step 3 base is K ₂ CO ₃ 。

132. The method of any one of claims 119-131, wherein K ₂ CO ₃ Comprises 16.8% K ₂ CO ₃ 。

133. The method of any one of claims 119-132, wherein ORZY-03 and K are combined ₂ CO ₃ For mixtures of (C) CH ₂ Cl ₂ Extraction is carried out three times.

134. The process of any one of claims 119 to 133, wherein the solvent is removed from CH ₂ Cl ₂ Change to CH ₃ OH comprises the following steps:

a. partial distillation of CH ₂ Cl ₂ A solution;

b. adding CH to the distilled solution provided in step a) ₃ OH；

c. Partially distilling the solution provided in step b); and

d. adding CH to the solution provided in step c) ₃ OH。

135. The method according to claim 134, wherein the amount distilled in steps a) and c) corresponds at least to the CH that dissolves ORZY-03 prior to the solvent replacing step ₂ Cl ₂ Is a combination of the amounts of (a) and (b).

136. The method of any one of claims 134 to 135, wherein the method further comprises, in moving the solvent from CH ₂ Cl ₂ Change to CH ₃ The solution obtained after OH was passed through an activated carbon filter.

137. The method of any one of claims 119-136, further comprising the step of drying ORZY-04.

138. The method of claim 137, wherein the drying step comprises drying the ORZY-04 under vacuum at 45 ℃ for at least 12 hours.

139. The method of claim 119, wherein the method comprises the sequential steps of:

a) ORZY-03 was combined with 16.8% K ₂ CO ₃ Mixing the aqueous solution;

c) Adding a catalytic amount of citric acid to the organic phase of step b);

e) Partial distillation of CH from step c) ₂ Cl ₂ A solution;

f) Adding CH to the distilled solution provided in step i) ₃ OH；

g) Partially distilling the solution provided in step ii); and

h) Adding CH to the solution provided in step iii) ₃ OH；

i) Passing the solution obtained in step d) through an activated carbon filter;

j) Adding about a stoichiometric amount of citric acid to the mixture obtained in step e) to form a suspension;

k) Filtering the suspension provided in step e) to obtain ORZY-04;

l) drying the ORZY-04 obtained in step g) at 45℃under vacuum for at least 12h, and

m) purifying the ORZY-04 of step h) to obtain ORZY-05.

140. The method of any one of claims 119-139, wherein the step of purifying ORZY-04 to obtain ORZY-05 comprises recrystallization of ORZY-04.

141. The method of claim 140, wherein the solvent used in the recrystallization is acetone.

142. The method of any one of claims 140 to 141, wherein recrystallising comprises the steps of:

b. cooling the solution formed in step a) to 30±5 ℃;

c. adding acetone to the solution of step b);

d. cooling the mixture of step c) to 0±5 ℃;

f. separating ORZY-05 from the suspension by filtering the suspension of step e); and drying the ORZY-05 obtained in step e) at 45℃under vacuum for at least 12h.

143. A composition comprising ORZY-01,

and

one or more impurities selected from the group consisting of:

144. the composition of claim 143, wherein (a) is present in an amount of 0.1% to 0.5% by weight and/or (B) is present in an amount of 0.1% to 0.5% by weight.

145. The composition of any one of claims 143 to 144, wherein (a) is present in an amount of 0.1% to 0.5%, such as 0.1% to 0.2%, such as 0.2% to 0.3%, such as 0.3% to 0.4%, such as 0.4% to 0.5% by weight.

146. The composition of any one of claims 143 to 145, wherein (B) is present in an amount of 0.1% to 0.5%, such as 0.1% to 0.2%, such as 0.2% to 0.3%, such as 0.3% to 0.4%, such as 0.4% to 0.5% by weight.

147. A method for preparing apricots citrate (ORZY-05),

comprising providing an ORZY-01 as defined in any one of claims 72-142; ORZY-03; or OZY-04.

148. A method for preparing apricots citrate (ORZY-05),

which comprises the following successive steps:

a. the method of providing ORZY-01 as defined in any one of claims 72 to 94,

b. precipitation of ORZY-01 with dibenzoyl L-tartaric acid to provide ORZY-03,

and

thereby providing apricots citrate.

149. A method for preparing apricots citrate,

Which comprises the following successive steps:

a. an ORZY-01 is provided which,

b. the method of providing ORZY-03 as defined in any one of claim 95 to 118,

and

thereby providing apricots citrate.

150. A method for preparing apricots citrate,

which comprises the following successive steps:

a. an ORZY-01 is provided which,

b. precipitation of ORZY-01 with dibenzoyl L-tartaric acid to provide ORZY-03,

and

c. the method of providing ORZY-05 as defined in any one of claim 119 to 142,

thereby providing apricots citrate.

151. The method of any one of claims 72-142, further comprising adding one or more ORZY-01 seeds to the vessel.

152. The method of any one of claims 72-142, further comprising adding one or more ORZY-03 seeds to the vessel.

153. The method of any one of claims 72-142, further comprising adding one or more ORZY-05 seeds to the vessel.

154. The method of any one of claims 72-142, wherein as a first step, one or more ORZY-01 seeds are added to the vessel.

155. The method of any one of claims 72-142, wherein as a first step, one or more ORZY-03 seeds are added to the vessel.

156. The method of any one of claims 72-142, wherein as a first step, one or more ORZY-05 seeds are added to the vessel.

157. A pharmaceutical composition comprising ORZY-05 obtainable by a method as defined in any one of claims 119-142.