Deutetrabenazine analogues, their preparation and use

Abstract

To provide drug products containing an acceptable impurity profile.SOLUTION: The disclosure is directed to deutetrabenazine analogs, compositions comprising the same and methods of detecting the same in compositions comprising deutetrabenazine.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 471,484, filed March 15, 2017, which is incorporated by reference herein in its entirety. [Background technology]

[0002] Tetrabenazine (NITOMAN™, XENAZINE™, Ro 1-9569), i.e. 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinoline, is a vesicular monoamine transporter 2 (VMAT2) inhibitor. Tetrabenazine is commonly prescribed for the treatment of Huntington's disease (Savani et al., Neurology, 2007, 68(10), 797; and Kenney et al., Expert Review of Neurotherapeutics, 2006, 6(1), 7-17).

[0003] [ka]

[0004] d 6 - Tetrabenazine (USAN and INN: deutetrabenazine) is a deuterated analogue of tetrabenazine sold in the United States under the trade name AUSTEDO®. It has improved pharmacokinetic properties when compared to the non-deuterated drug. See, for example, US 8,524,733.

[0005] [ka]

[0006] A method for the synthesis of deutetrabenazine is disclosed in US Patent Application Publication No. 2015 / 0152099. A pharmaceutical composition comprising deutetrabenazine is disclosed in US Patent No. 9,233,959. US Patent Application Publication No. 2016 / 0287574 discloses deutetrabenazine for the treatment of abnormal involuntary movement disorders. Despite the desirable beneficial effects of deutetrabenazine, there is a continuing need for high quality compositions for treating the aforementioned disorders.

[0007] To provide assurance that the drug product will work as intended, applicants seeking marketing authorization are required to outline the impurities identified in the drug product both when produced using the proposed commercial manufacturing process and after storage. Applicants need to demonstrate that the impurities are biologically safe at the levels identified in the drug product after manufacture and storage. Drug products containing an acceptable impurity profile are required. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US No. 8,524,733 [Patent Document 2] US Patent Application Publication No. 2015 / 0152099 [Patent Document 3] U.S. Patent No. 9,233,959 [Patent Document 4] US Patent Application Publication No. 2016 / 0287574 [Non-patent literature]

[0009] [Non-Patent Document 1] Savani et al., Neurology, 2007, 68(10), 797 [Non-Patent Document 2] Kenney et al., Expert Review of Neurotherapeutics, 2006, 6(1), pp. 7-17 Summary of the Invention [Means for solving the problem]

[0010] The present disclosure is directed to a pharmaceutical composition comprising an admixture of a deutetrabenazine drug substance and a pharma- ceutically acceptable carrier, wherein the deutetrabenazine drug substance comprises deutetrabenazine, compound 1 at 0.5 area % or less relative to the concentration of deutetrabenazine as determined by HPLC methods, and compound 2 at 0.15 area % or less relative to the concentration of deutetrabenazine as determined by HPLC methods, and the pharmaceutical composition is stable when stored at room temperature for 1 to 24 months. Chemical structures of compound 1 and compound 2 are provided.

[0011] [ka]

[0012] The present disclosure is directed to isolated compounds having the structure of Compound 1 or Compound 2, as well as salts and stereoisomers thereof.

[0013] Compositions containing Compound 1 and / or Compound 2, as well as methods for using these compounds as reference standards, are also described.

[0014] The present disclosure is also directed to methods for testing whether a sample of a composition comprising deutetrabenazine contains undesirable impurities. Methods for producing deutetrabenazine formulations and distributing deutetrabenazine formulations containing deutetrabenazine drug substance are also described. Methods for validating for distribution a drug product containing deutetrabenazine and a pharma- ceutically acceptable carrier are described.

[0015] Methods of using the compounds and compositions described herein to treat a subject suffering from a hyperkinetic movement disorder are also described. [Brief description of the drawings]

[0016] [Figure 1] 1 is a graph of the FTIR spectrum of compound 1. [Diagram 2] 1 is a graph of 1H NMR of compound 1. [Diagram 3] 1 is a graph of 13C NMR of compound 1. [Figure 4] FIG. 1 is a representative chromatogram of compound 1. [Diagram 5] 1 is a graph of the FTIR spectrum of compound 2. [Figure 6] 1 is a graph of 1H NMR of compound 2. [Figure 7] 1 is a graph of 13C NMR of compound 2. [Figure 8] FIG. 1 is a representative chromatogram of compound 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] In this disclosure, unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include the plural and reference to a particular numerical value includes at least that particular value. Thus, for example, reference to "a material" is a reference to at least one of such material and equivalents thereof known to those skilled in the art, and so forth.

[0018] When a value is expressed as an approximation by use of the descriptor "about", it will be understood that the particular value forms another embodiment. In general, the use of the term "about" indicates an approximation that may vary depending on the desired properties sought to be obtained by the disclosed subject matter based on its function and should be interpreted in the specific context in which the term is used. In some aspects of the present disclosure, "about" refers to a range of values ​​±10% of the stated value. For example, "about 10" refers to "9 to 11" as well as "10". This can be interpreted as a routine by those skilled in the art. In some cases, the number of significant digits used for a particular value can be one non-limiting way of determining the range of the word "about". In other cases, the gradation used in a series of values ​​can be used to determine the intended range within which the term "about" is available for each value. When present, all ranges are inclusive and combinable. That is, reference to values ​​stated in a range includes every value within that range. When a parameter range is given, it is understood that all integers and decimal places within that range are also provided by the present invention. For example, "20 to 40 mg" includes 20.0 mg, 20.1 mg, 20.2 mg, 20.3 mg, etc., up to a maximum of 40.0 mg.

[0019] When lists are presented, unless otherwise stated, it is to be understood that each individual element of that list, and every combination of that list, is to be construed as a separate embodiment. For example, a list of embodiments presented as "A, B, or C" should be construed as including the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0020] For clarity of description, it should be understood that certain features of the invention that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless expressly incompatible or excluded, each individual embodiment is contemplated as combinable with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, for brevity of description, various features of the invention that are described in the context of a single embodiment may also be provided separately or in any subcombination. It is further noted that the claims may be drafted to the exclusion of any optional element. Thus, this statement is intended to serve as a predicate for the use of such exclusive language, such as "solely," "only," and the like, or the use of "negative" limitations in connection with the description of claim elements. Finally, while an embodiment may be described as part of a sequence of steps or part of a more general structure, each of said steps may be considered an independent embodiment in itself.

[0021] The present disclosure is directed to deutetrabenazine pharmaceutical compositions that are stable when stored at room temperature. In some embodiments, the pharmaceutical compositions are stable when stored at room temperature for about 1 to about 24 months. In some embodiments, the pharmaceutical compositions are stable when stored at room temperature for about 1 to about 18 months. In some embodiments, the pharmaceutical compositions are stable when stored at room temperature for about 1 to about 12 months. In some embodiments, the pharmaceutical compositions are stable when stored at room temperature for about 1 to about 6 months. In some embodiments, the pharmaceutical compositions are stable when stored at room temperature for about 1 to about 3 months. In some embodiments, the pharmaceutical compositions are stable when stored at room temperature for about 1 month. For example, the pharmaceutical compositions of the present disclosure are stable when stored at room temperature for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or about 24 months.

[0022] The pharmaceutical compositions of the present disclosure include an admixture of a deutetrabenazine drug substance and a pharma- ceutically acceptable carrier. According to the present disclosure, the deutetrabenazine drug substance includes deutetrabenazine, compound 1, and compound 2. In a particularly preferred embodiment, the deutetrabenazine drug substance includes deutetrabenazine, compound 1 at 0.5 area % or less relative to the concentration of deutetrabenazine as determined by HPLC methods, and compound 2 at 0.15 area % or less relative to the concentration of deutetrabenazine as determined by HPLC methods.

[0023] In preferred embodiments, the deutetrabenazine drug substance comprises, in addition to deutetrabenazine, about 0.5 area % or less of compound 1 relative to the concentration of deutetrabenazine, as determined by an HPLC method. Exemplary HPLC methods are disclosed herein. In some embodiments, the deutetrabenazine drug substance comprises about 0.1 area % to about 0.5 area % of compound 1 relative to the concentration of deutetrabenazine, as determined by an HPLC method. In some embodiments, the deutetrabenazine drug substance comprises about 0.1 area % to about 0.4 area % of compound 1 relative to the concentration of deutetrabenazine, as determined by an HPLC method. In some embodiments, the deutetrabenazine drug substance comprises about 0.1 area % to about 0.3 area % of compound 1 relative to the concentration of deutetrabenazine, as determined by an HPLC method. In some embodiments, the deutetrabenazine drug substance comprises about 0.1 area % to about 0.2 area % of compound 1 relative to the concentration of deutetrabenazine, as determined by an HPLC method. In some embodiments, the deutetrabenazine drug substance comprises about 0.1 area % of compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the deutetrabenazine drug substance comprises about 0.15 area % of compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the deutetrabenazine drug substance comprises about 0.2 area % of compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the deutetrabenazine drug substance comprises about 0.25 area % of compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the deutetrabenazine drug substance comprises about 0.3 area % of compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the deutetrabenazine drug substance comprises about 0.35 area % of compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the deutetrabenazine drug substance contains about 0.4 area % Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods.In some embodiments, the deutetrabenazine drug substance contains about 0.45 area % of Compound 1 relative to the concentration of deutetrabenazine, as determined by HPLC methods. In some embodiments, the deutetrabenazine drug substance contains about 0.5 area % of Compound 1 relative to the concentration of deutetrabenazine, as determined by HPLC methods.

[0024] In preferred embodiments, the deutetrabenazine drug substance comprises, in addition to deutetrabenazine, about 0.15 area % or less of compound 2 relative to the concentration of deutetrabenazine, as determined by an HPLC method. Exemplary HPLC methods are disclosed herein. In some embodiments, the deutetrabenazine drug substance comprises about 0.05 area % to about 0.15 area % of compound 2 relative to the concentration of deutetrabenazine, as determined by an HPLC method. In some embodiments, the deutetrabenazine drug substance comprises about 0.05 area % to about 0.1 area % of compound 2 relative to the concentration of deutetrabenazine, as determined by an HPLC method. In some embodiments, the deutetrabenazine drug substance comprises about 0.15 area % of compound 2 relative to the concentration of deutetrabenazine, as determined by an HPLC method. In some embodiments, the deutetrabenazine drug substance comprises about 0.1 area % of compound 2 relative to the concentration of deutetrabenazine, as determined by an HPLC method. In some embodiments, the deutetrabenazine drug substance contains about 0.05 area % of Compound 2 relative to the concentration of deutetrabenazine as determined by HPLC methods.

[0025] In some embodiments, the pharmaceutical compositions of the present disclosure contain about 3 area % or less of compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In other embodiments, the pharmaceutical compositions of the present disclosure contain about 0.4 area % or less of compound 2 relative to the concentration of deutetrabenazine as determined by HPLC methods. In still other embodiments, the pharmaceutical compositions of the present disclosure contain about 3 area % or less of compound 1 and about 0.4 area % or less of compound 2, respectively, relative to the concentration of deutetrabenazine as determined by HPLC methods.

[0026] In some embodiments, the pharmaceutical compositions of the disclosure include 0.007% to 3% by area of ​​compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the pharmaceutical compositions of the disclosure include 0.01% to 3% by area of ​​compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the pharmaceutical compositions of the disclosure include 0.1% to 3% by area of ​​compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the pharmaceutical compositions of the disclosure include 1% to 3% by area of ​​compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods. For example, pharmaceutical compositions of the disclosure may contain 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 area % of Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods.

[0027] In some embodiments, the pharmaceutical compositions of the present disclosure comprise 0.007% to 0.4% by area of ​​compound 2 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the pharmaceutical compositions of the present disclosure comprise 0.03% to 0.4% by area of ​​compound 2 relative to the concentration of deutetrabenazine as determined by HPLC methods. In some embodiments, the pharmaceutical compositions of the present disclosure comprise 0.1% to 0.4% by area of ​​compound 2 relative to the concentration of deutetrabenazine as determined by HPLC methods. For example, the pharmaceutical compositions of the present disclosure comprise 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, or 0.4% by area of ​​compound 2 relative to the concentration of deutetrabenazine as determined by HPLC methods.

[0028] According to the present disclosure, the pharmaceutical composition of the present disclosure comprises a deutetrabenazine drug substance having a deuterium enrichment of about 50% or more. In some embodiments of the present disclosure, the pharmaceutical composition of the present disclosure comprises a deutetrabenazine drug substance having a deuterium enrichment of about 90% or more. In some embodiments, the pharmaceutical composition of the present disclosure comprises a deutetrabenazine drug substance having a deuterium enrichment of about 95% or more. In some embodiments, the pharmaceutical composition of the present disclosure comprises a deutetrabenazine drug substance having a deuterium enrichment of about 98% or more.

[0029] In some embodiments of the present disclosure, the deutetrabenazine in the deutetrabenazine drug substance of the present disclosure has a deuterium enrichment of about 50% or more at each of the methoxy moieties. In some embodiments of the present disclosure, the deutetrabenazine in the deutetrabenazine drug substance of the present disclosure has a deuterium enrichment of about 90% or more at each of the methoxy moieties. In some embodiments of the present disclosure, the deutetrabenazine in the deutetrabenazine drug substance of the present disclosure has a deuterium enrichment of about 95% or more at each of the methoxy moieties. In some embodiments of the present disclosure, the deutetrabenazine in the deutetrabenazine drug substance of the present disclosure has a deuterium enrichment of about 98% or more at each of the methoxy moieties.

[0030] In some embodiments of the present disclosure, compound 1 in the deutetrabenazine drug substance of the present disclosure has a deuterium enrichment of about 50% or more at each of the methoxy moieties. In some embodiments of the present disclosure, compound 1 in the deutetrabenazine drug substance of the present disclosure has a deuterium enrichment of about 90% or more at each of the methoxy moieties. In some embodiments of the present disclosure, compound 1 in the deutetrabenazine drug substance of the present disclosure has a deuterium enrichment of about 95% or more at each of the methoxy moieties. In some embodiments of the present disclosure, compound 1 in the deutetrabenazine drug substance of the present disclosure has a deuterium enrichment of about 98% or more at each of the methoxy moieties.

[0031] In some embodiments of the present disclosure, compound 2 in the deutetrabenazine drug bulk of the present disclosure has a deuterium enrichment of about 50% or more at each of the methoxy moieties. In some embodiments of the present disclosure, compound 2 in the deutetrabenazine drug bulk of the present disclosure has a deuterium enrichment of about 90% or more at each of the methoxy moieties. In some embodiments of the present disclosure, compound 2 in the deutetrabenazine drug bulk of the present disclosure has a deuterium enrichment of about 95% or more at each of the methoxy moieties. In some embodiments of the present disclosure, compound 2 in the deutetrabenazine drug bulk of the present disclosure has a deuterium enrichment of about 98% or more at each of the methoxy moieties.

[0032] The present disclosure also provides a method for producing a method for the preparation of a compound having the structure:

[0033] [ka]

[0034] and salts and stereoisomers thereof.

[0035] In one embodiment of the invention, the isolated compound has the structure:

[0036] [ka]

[0037] has.

[0038] In one embodiment of the invention, the isolated compound has the structure:

[0039] [ka]

[0040] has.

[0041] The present invention further provides isolated compound 1 or 2, wherein each position designated as D has a deuterium enrichment of about 10% or more, preferably about 50% or more, more preferably about 90% or more, and most preferably about 98% or more.

[0042] The present invention also provides a compound comprising deutetrabenazine and a compound of the structure:

[0043] [ka]

[0044] and at least one compound having the formula:

[0045] In certain embodiments, the ratio of the weight of the compound to the weight of the deutetrabenazine in the composition is 90:10 to 10:90, or 85:15 to 15:85. For example, in some aspects, the ratio of the weight of the compound to the weight of the deutetrabenazine in the composition is 95:5, 90:10, 85:15, 80:20, 75:25, 70:30, 65:35, 60:40, 55:45, 50:50, 45:55, 40:60, 35:65, 30:70, 25:75, 20:80, 15:85, 10:90, or 5:95. In other embodiments, the ratio of the weight of compound to the weight of deutetrabenazine in the composition is 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5.

[0046] The present disclosure also provides a method for producing a method for the preparation of a compound having the structure:

[0047] [ka]

[0048] Also provided is a composition that is substantially free of deutetrabenazine, comprising at least one compound having the formula: embedded image As used herein, "substantially free of deutetrabenazine" refers to having less than 1 wt% deutetrabenazine, preferably less than 0.1 wt% deutetrabenazine. As used herein, "free of deutetrabenazine" refers to having no deutetrabenazine as determined by HPLC methods.

[0049] Compound 1 is a diastereomer of deutetrabenazine. It may appear in the drug substance as a by-product of the manufacturing process. The amount of compound 1 may increase over time when the drug substance or formulation (pharmaceutical composition) is stored. According to the present disclosure, to ensure stability over time in a pharmaceutical composition that does not contain more than 3 area % of compound 1 relative to the concentration of deutetrabenazine, as determined by HPLC method, it has been determined that the deutetrabenazine drug substance used to prepare the pharmaceutical composition should have 0.5 area % or less of compound 1 relative to the concentration of deutetrabenazine, as determined by HPLC method.

[0050] Compound 2 may be formed from the oxidation / dehydrogenation of deutetrabenazine. It may appear in the drug substance as a by-product of the manufacturing process. The amount of compound 2 may increase over time when the drug substance or formulation (pharmaceutical composition) is stored. According to the present disclosure, to ensure stability over time in a pharmaceutical composition that does not contain more than 0.4 area % of compound 2 relative to the concentration of deutetrabenazine as determined by HPLC method, it has been determined that the deutetrabenazine drug substance used to prepare the pharmaceutical composition should have no more than 0.15 area % of compound 2 relative to the concentration of deutetrabenazine as determined by HPLC method.

[0051] According to the present disclosure, to ensure stability over time in a pharmaceutical composition that does not contain more than 3 area % of compound 1 and more than 0.4 area % of compound 2, respectively, relative to the concentration of deutetrabenazine, as determined by HPLC methods, the deutetrabenazine drug substance used to prepare the pharmaceutical composition should have no more than 0.5 area % of compound 1 and no more than 0.15 area % of compound 2, respectively, relative to the concentration of deutetrabenazine, as determined by HPLC methods.

[0052] The present disclosure also provides a pharmaceutical composition comprising an amount of deutetrabenazine and at least one of Compound 1 and Compound 2, a) Compound 1 is present in the pharmaceutical composition in an amount of 10 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; or b) Compound 2 is present in the pharmaceutical composition in an amount of 10 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; Pharmaceutical compositions are also provided.

[0053] The present disclosure also provides a pharmaceutical composition comprising an amount of deutetrabenazine and at least one of Compound 1 and Compound 2, a) Compound 1 is present in the pharmaceutical composition in an amount of 3 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; or b) Compound 2 is present in the pharmaceutical composition in an amount of 0.4 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; Pharmaceutical compositions are also provided.

[0054] In one embodiment, at least one of Compound 1 and Compound 2 is present in the described pharmaceutical composition.

[0055] In one embodiment, the pharmaceutical composition is in the form of a capsule, tablet, or suspension, hi another embodiment, the pharmaceutical composition is in an oral unit dosage form.

[0056] In one embodiment, the pharmaceutical composition comprises between 5 and 30 mg of deutetrabenazine. In another embodiment, the pharmaceutical composition comprises between 6 and 24 mg of deutetrabenazine. In another embodiment, the pharmaceutical composition comprises about 6 mg of deutetrabenazine. In another embodiment, the pharmaceutical composition comprises about 9 mg of deutetrabenazine. In another embodiment, the pharmaceutical composition comprises about 12 mg of deutetrabenazine. In another embodiment, the pharmaceutical composition comprises about 15 mg of deutetrabenazine. In another embodiment, the pharmaceutical composition comprises about 18 mg of deutetrabenazine. In another embodiment, the pharmaceutical composition comprises about 21 mg of deutetrabenazine. In another embodiment, the pharmaceutical composition comprises about 24 mg of deutetrabenazine.

[0057] In another embodiment, the pharmaceutical composition is formulated for administration once per day. In another embodiment, the pharmaceutical composition is formulated for administration more than once per day, for example, twice per day, three times per day, four times per day, etc.

[0058] The disclosure also provides a method for isolating compound 1, comprising recrystallizing a mixture of deutetrabenazine and compound 1 from ethanol to produce compound 1.

[0059] The present disclosure also provides a method for preparing compound 2, comprising oxidizing deutetrabenazine to form compound 2.

[0060] The present disclosure also provides a method for testing whether a sample of a composition comprising deutetrabenazine contains an undesirable impurity, i.e., an undesirable amount of Compound 1 and / or Compound 2, comprising administering to the patient a composition comprising the structure:

[0061] [ka]

[0062] Also provided is a method comprising determining whether the sample contains a compound having the formula:

[0063] The present invention also provides a method for producing a deutetrabenazine formulation comprising the steps of obtaining a deutetrabenazine drug substance and mixing the deutetrabenazine drug substance with suitable excipients to produce a deutetrabenazine formulation, wherein the deutetrabenazine drug substance comprises: i) an amount of Compound 1 in the deutetrabenazine drug substance, which is equal to or less than 0.5 area % of Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods; or ii) a quantity of Compound 2 in the deutetrabenazine drug substance, the quantity being equal to or less than 0.15 area % of Compound 2 relative to the concentration of deutetrabenazine, as determined by HPLC methods; A method is also provided, including:

[0064] In one embodiment, the method further comprises determining the amount of at least one of Compound 1 and Compound 2 in the deutetrabenazine drug substance based on determination by HPLC method.

[0065] The present invention also provides a method for producing a deutetrabenazine formulation for commercial sale and / or human administration, comprising the steps of: i) an amount of Compound 1 in a batch of deutetrabenazine formulation, the amount being 3% or less by area of ​​Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods; or ii) in a batch of deutetrabenazine formulation, an amount of Compound 2, which is 0.4 area % or less of Compound 2 relative to the concentration of deutetrabenazine, as determined by HPLC method; obtaining a batch of a deutetrabenazine formulation comprising: Preparing Batches of Deutetrabenazine Formulations for Commercial Sale and / or Human Administration A method is also provided, including:

[0066] In one embodiment, the method further comprises determining the amount of at least one of compound 1 and compound 2 in the deutetrabenazine formulation.

[0067] The present invention also provides a method of distributing a deutetrabenazine formulation comprising a deutetrabenazine drug substance, the method comprising: a) The deutetrabenazine drug substance is i) an amount of Compound 1 in the deutetrabenazine drug substance, which is equal to or less than 0.5 area % of Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods; or ii) a quantity of Compound 2 in the deutetrabenazine drug substance, the quantity being equal to or less than 0.15 area % of Compound 2 relative to the concentration of deutetrabenazine, as determined by HPLC methods; obtaining a deutetrabenazine formulation, b) distributing deutetrabenazine preparations containing deutetrabenazine drug substance A method is also provided, including:

[0068] The present invention also provides a method of distributing a deutetrabenazine formulation, comprising the steps of: a) i) an amount of Compound 1 in a deutetrabenazine formulation, the amount being 3 area % or less of Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods; or ii) an amount of Compound 2 in a deutetrabenazine formulation, the amount being equal to or less than 0.4 area % of Compound 2 relative to the concentration of deutetrabenazine, as determined by HPLC methods; obtaining a deutetrabenazine formulation comprising b) Distributing deutetrabenazine preparations A method is also provided, including:

[0069] The present invention also provides an impurity for use as a reference standard for detecting trace amounts of an impurity in a pharmaceutical composition comprising deutetrabenazine, the impurity being Compound 1 or Compound 2.

[0070] The present invention also provides a method for determining the concentration of an impurity in a composition comprising deutetrabenazine, comprising the steps of: a) preparing a sample solution from a pharmaceutical composition; b) preparing a diluent containing acetonitrile; c) preparing a standard solution containing deutetrabenazine and a diluent; d) preparing a decomposition solution containing deutetrabenazine and impurities; e) preparing a buffer solution by dissolving 770 mg of ammonium acetate in 1000 mL of water; f) injecting the diluent, resolution solution, standard solution, and sample solution into the HPLC; g) running the HPLC using UV absorption between 190 and 400 nm (preferably 220 nm) and using buffer and diluent as mobile phases with a gradient program starting from 80% buffer / 20% diluent increasing to 100% buffer over 20 minutes; h) determining the retention time (RT) and peak area of ​​the impurities in the chromatogram of the sample solution; and i) performing quantification of the impurities with respect to the corresponding peaks in the chromatogram of the sample solution; and the impurity is Compound 1 or Compound 2.

[0071] The present invention also provides a method for determining the concentration of an impurity in a pharmaceutical composition comprising deutetrabenazine and a pharma- ceutically acceptable carrier, comprising the steps of: a) preparing a sample solution from a pharmaceutical composition; b) preparing a diluent comprising isopropyl alcohol and acetonitrile; c) preparing a standard solution containing deutetrabenazine and a diluent; d) preparing a decomposition solution containing deutetrabenazine and impurities; e) preparing a buffer solution by dissolving ammonium acetate in water; f) injecting the diluent, resolution solution, standard solution, and sample solution into the HPLC; g) performing HPLC using UV absorption at 190-400 nm or 220 nm and using a mixture of buffer and acetonitrile as the mobile phase; h) determining the retention time (RT) and peak area of ​​the impurities in the chromatogram of the sample solution; and i) performing quantification of the impurities with respect to the corresponding peaks in the chromatogram of the sample solution; and the impurity is Compound 1 or Compound 2.

[0072] The present invention also provides a method of treating a subject suffering from a hyperkinetic movement disorder, comprising the step of administering to the subject a pharmaceutical composition of the present invention.

[0073] The present invention also provides a method of treating a subject suffering from Huntington's disease, comprising the step of administering to the subject a pharmaceutical composition of the present invention.

[0074] The present invention also provides a method of treating a subject suffering from chorea associated with Huntington's disease, comprising the step of administering to the subject a pharmaceutical composition of the present invention.

[0075] The present invention also provides a method of treating a subject suffering from tardive dyskinesia, comprising the step of administering to the subject a pharmaceutical composition of the present invention.

[0076] The present invention also provides a method of treating a subject suffering from tics associated with Tourette's syndrome, the method comprising administering to the subject a pharmaceutical composition of the present invention.

[0077] The present invention also provides a method for validating for distribution a batch of a pharmaceutical product containing deutetrabenazine and a pharma- ceutically acceptable carrier, comprising the steps of: a) determining the amount of at least one of Compound 1 and Compound 2 based on the determination by HPLC method; and b) i) the batch is determined to have a Compound 1 relative to the concentration of deutetrabenazine of 3% or less by area as determined by an HPLC Method; or ii) the batch is determined to have a compound 2 concentration of 0.4 area % or less relative to the deutetrabenazine concentration as determined by HPLC method; A process to validate a batch for distribution only if A method is also provided, including:

[0078] The present invention also provides a method for preparing a validated pharmaceutical composition comprising deutetrabenazine, comprising the steps of: a) obtaining a batch of deutetrabenazine drug substance; b) determining the amount of at least one of compound 1 and compound 2 based on the determination by HPLC method; and c) i) the batch is determined to have a Compound 1 relative to the concentration of deutetrabenazine of 0.5 area % or less, based on determination by HPLC Method; or ii) the batch is determined to have a compound 2 concentration of 0.15 area % or less relative to the deutetrabenazine concentration as determined by HPLC method; preparing the pharmaceutical composition from the batch only if A method is also provided, including:

[0079] Each embodiment disclosed herein is contemplated as being applicable to each of the other embodiments disclosed, and thus, any combination of the various elements described herein is within the scope of the invention.

[0080] For example, the elements listed in the packaging and pharmaceutical composition embodiments can be used in the method and use embodiments described herein.

[0081] term As used herein, and unless otherwise stated, each of the following terms shall have the definition set forth below.

[0082] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The present invention should be understood to encompass all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as D- and L-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing chiral centers, or by preparation and subsequent separation of a mixture of enantiomeric products, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic methods, direct separation of enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds of a particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. In addition, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof. In addition, compounds may exist as tautomers, and all tautomeric isomers are provided by the present invention. In addition, compounds disclosed herein may exist in unsolvated forms and in solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, and the like. In general, solvated forms are considered equivalent to unsolvated forms.

[0083] The term "3S,11bS enantiomer" or the term "3R,11bR enantiomer" refers to the compound of the structural formula shown below:

[0084] [ka]

[0085] It refers to any of the deutetrabenazine stereoisomers having the formula:

[0086] In certain embodiments, the chemical structure may be depicted as either the 3S,11bS enantiomer or the 3R,11bR enantiomer, although the text herein refers to the 3S,11bS enantiomer, the 3R,11bR enantiomer, and their racemic mixtures (which are (RR,SS)-d 6 -tetrabenazine), or it may be intended to describe all of the above.

[0087] As used herein, "drug substance" refers to the active ingredient of a formulation, or a composition containing the active ingredient prior to being formulated into a formulation, which provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or affects the structure or any function of the human or animal body.

[0088] As used herein, a "drug formulation" refers to a compounded or finished dosage form containing a drug substance and at least one pharma- ceutically acceptable carrier.

[0089] As used herein, an "isolated" compound is one that has been isolated from a crude reaction mixture by an affirmative act of isolation. The act of isolation involves separating the compound from other known components of the crude reaction mixture, although some impurities, unknown by-products, and residual amounts of other known components of the crude reaction mixture may remain. Purification is an example of an affirmative act of isolation.

[0090] As used herein, the term "stable", when referring to deutetrabenazine, means deutetrabenazine in which the levels of a specified impurity (e.g., compound 1, compound 2, or a combination thereof) do not increase beyond a specified limit when maintained at a specified temperature for a specified period of time. More specifically, the term "stable" means deutetrabenazine in which the level of compound 1 does not increase by more than 3% of the total area of ​​deutetrabenazine as measured by HPLC, or the level of compound 2 does not increase by more than 0.4% of the total area of ​​deutetrabenazine as measured by HPLC, when maintained at room temperature for about 1 to about 24 months.

[0091] As used herein, "room temperature" refers to a temperature in the range of about 20°C to about 30°C.

[0092] As used herein, "stability testing" refers to testing carried out at specific time intervals and under various environmental conditions (e.g., temperature and humidity) to determine whether and to what extent a drug product degrades over its indicated shelf life. The specific conditions and duration of testing are such as to promote the conditions that the drug product is expected to encounter over its shelf life. For example, detailed requirements for stability testing of finished pharmaceutical products are codified in 21 CFR Part 211, Section 166, the entire contents of which are incorporated herein by reference.

[0093] As used herein, "approximately" in the context of a numerical value or range means ±5% of the recited or claimed numerical value or range.

[0094] As used herein, the "amount" of compound measured in milligrams refers to the milligram of compound present in the preparation, regardless of the form of preparation.The "amount of compound that is 40 mg" means that the amount of compound in the preparation is 40 mg, regardless of the form of preparation.Therefore, in the case of a form with carrier, the mass of carrier required to produce a dose of 40 mg of compound is more than 40 mg due to the presence of carrier.

[0095] As used herein, "treating" and "treatment" include, for example, inducing the inhibition, regression, or cessation of a disease, disorder, or condition, or improving or alleviating the symptoms of a disease, disorder, or condition. "Ameliorating" or "alleviating" a state or condition, as used herein, is intended to mean alleviating or reducing the symptoms of the state or condition. "Inhibiting" the progression of a disease or a complication of a disease in a subject, as used herein, means preventing or reducing the progression of a disease and / or a complication of a disease in a subject.

[0096] "Administering to a subject" means giving, administering, or applying a medicine, drug, or remedy to a subject to relieve, cure, or reduce the symptoms associated with a condition, e.g., a disease state.

[0097] The drug substance of the invention, e.g., deutetrabenazine, may be administered in admixture with suitable pharmaceutical excipients, fillers, additives, or carriers (collectively referred to herein as pharma- ceutically acceptable carriers), suitably selected with respect to the intended mode of administration and consistent with conventional pharmaceutical practice. Capsules or tablets may contain suitable binders, lubricants, disintegrants, excipients, colorants, flow inducers, and melting agents.

[0098] Dosage units of the compounds used in the methods of the present invention may contain a single compound or a mixture thereof together with an additional therapeutic agent.

[0099] A "dose" or "dosage unit" or "unit dose" of deutetrabenazine measured in milligrams refers to the milligrams of deutetrabenazine present in a preparation, regardless of the form of the preparation. A dosage unit may contain a single compound or a mixture of compounds. Dosage units can be prepared for oral dosage forms such as tablets, capsules, pills, powders, suspensions, and granules. For example, a "dose" or "dosage unit" of deutetrabenazine can be 6, 9, 12, 15, 18, 21, or 24 mg.

[0100] As used herein, a "pharmaceutically acceptable" component is one that is suitable for use in humans and / or animals without undue adverse side effects (e.g., toxicity, irritation, and allergic response) and is commensurate with a reasonable benefit / risk ratio.

[0101] The present invention is also intended to include all isotopes of atoms present in the compounds disclosed herein, including impurities.Isotopes include atoms having the same atomic number but different mass numbers.By way of general, non-limiting example, isotopes of hydrogen include tritium and deuterium.Isotopes of carbon include C-12, C-13, and C-14.

[0102] As used herein, the "detection limit" of an analytical method used in screening or testing for the presence of a compound in a sample is the threshold below which the analytical method used cannot detect the compound in the sample. The detection limit of a given HPLC method for detecting impurities in a sample containing deutetrabenazine can vary based on the method and the impurity or impurities detected. For example, the detection limit of a typical HPLC method for detecting compound 1 is 0.01 area %, and the detection limit for detecting compound 2 is 0.03 area %.

[0103] As used herein, the "quantitation limit" of an analytical method used in screening or testing for the presence of a compound in a sample is the threshold below which the analytical method used is unable to quantify the compound in the sample. The quantitation limit of a given HPLC method for detecting impurities in a sample containing deutetrabenazine may vary based on the impurity or impurities detected. For example, the quantitation limit of a typical HPLC method for quantifying compound 1 is 0.007 area %, and the quantitation limit of compound 2 is 0.007 area %.

[0104] The characteristics of the compound are: 1It refers to any quality that a compound exhibits, such as peak or retention time, as determined by H nuclear magnetic spectroscopy, mass spectroscopy, infrared, ultraviolet or fluorescence spectrophotometric colorimetry, gas chromatography, thin layer chromatography, high performance liquid chromatography, elemental analysis, Ames test, dissolution, stability, and any other quality that can be determined by an analytical method. Once a compound is characterized, the information can be used, for example, to screen or test for the presence of the compound in a sample.

[0105] As used herein, "NMT" means less than. As used herein, "LT" means less than.

[0106] The amounts of impurities are measured by reverse phase HPLC unless otherwise specified.

[0107] As used herein, the term "effective amount" refers to an amount of a component that is sufficient, when used in the manner of the present invention, to obtain a desired therapeutic response without undue adverse side effects (e.g., toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio, i.e., a therapeutically effective amount. The specific effective amount may vary depending on factors such as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of treatment, the nature of concurrent therapy (if any), and the specific formulation used, and the structure of the compound or its derivatives.

[0108] As used herein, "preparing a formulation for commercial sale" means activities that are performed in preparation for commercial sale. Examples include, but are not limited to, coloring, coding, marking, and packaging the formulation.

[0109] As used herein, "deuterium enrichment" refers to the percentage of a molecule that incorporates deuterium instead of hydrogen at a given position. For example, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the natural distribution of deuterium is about 0.0156%, the deuterium enrichment at any position of a compound synthesized using non-enriched starting materials is about 0.0156%. Deuterium enrichment can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0110] As used herein, "deuterated," when used to describe a given position in a molecule or the symbol "D," when used to represent a given position in a diagram of a molecular structure, means that the designated position is enriched with deuterium beyond the natural distribution of deuterium. In one embodiment, the deuterium enrichment is greater than or equal to about 1%, in another embodiment greater than or equal to about 5%, in another embodiment greater than or equal to about 10%, in another embodiment greater than or equal to about 20%, in another embodiment greater than or equal to about 50%, in another embodiment greater than or equal to about 70%, in another embodiment greater than or equal to about 80%, in another embodiment greater than or equal to about 90%, or in another embodiment greater than or equal to about 98% of deuterium at the designated position.

[0111] Pharmaceutical Compositions Although the compounds for use according to the present invention may be administered in the form of the raw compound, it is preferred to incorporate the active ingredient, optionally in the form of a physiologically acceptable salt, into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical auxiliary agents.

[0112] In one embodiment, the present invention provides pharmaceutical compositions comprising an active compound or a pharma- ceutically acceptable salt or derivative thereof, together with one or more pharma- ceutically acceptable carriers thereof, and optionally other therapeutic and / or prophylactic ingredients known and used in the art. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0113] Table 1 shows the structures of compounds 1-2.

[0114] [Table 1]

[0115] The present invention will be better understood by reference to the following Experimental Details, although those skilled in the art will readily appreciate that the specific experiments detailed are merely illustrative of the invention as more fully described in the claims which follow. EXAMPLES

[0116] Experimental details Example 1 Preparation of Compound 1

[0117] [ka]

[0118] The crude material (10 g) obtained from deutetrabenazine mother liquor was purified by recrystallization from EtOH (2×3V) to give 2.5 g of compound 1 as an off-white solid.

[0119] NMR identification analysis of compound 1 Compound 1: The following data in Table 2 was generated using a sample of compound 1 in CDCl 3 (99.9 atomic % D) as determined using a 300 MHz NMR instrument. See Figures 2 and 3.

[0120] [Table 2]

[0121] Example 2 Preparation of compound 2

[0122] [ka]

[0123] Toluene (300 mL) was added to deutetrabenazine (31.7 g, 10.0 mmol) and chloranil (26 g, 10.5 mmol) and the mixture was heated at reflux for 2.5 h. Toluene (500 mL) was added to the dark solution and the mixture was diluted with 300 mL of 2N NaOH and H 2 The toluene solution was washed with O. 2 SO 4 ), filtered and evaporated to dryness. The residue was crystallized from ethyl acetate to give 21 g (66%) of compound 2 as an off-white crystalline solid.

[0124] NMR identification analysis of compound 2 Compound 2: The following data in Table 3 were obtained using a sample of compound 2 in CDCl 3 (99.9 atomic % D) was determined using a 300 MHz NMR instrument.

[0125] [Table 3]

[0126] Example 3 Preparation of crude deutetrabenazine Step 1: 2-Acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide: 3-[(dimethylamino)methyl]-5-methyl-hexan-2-one (90 g, 0.526 mol, 1.00 equiv) was charged with methyl tert-butyl ether (1.35 L, 15.0 vol) and cooled to 0-10 °C. Methyl iodide (171 g, 1.209 mol, 2.3 equiv) was added slowly to the reaction mixture and stirred at 25-35 °C for 15 h. The reaction was warmed to 35-40 °C for 2 h. The precipitated solid was filtered under nitrogen and washed with methyl tert-butyl ether (900 mL, 10.0 vol). The crude product was further purified by slurrying in ethyl acetate (1.46 L, 10 vol) and filtering to give 2-acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide (146 g) as a white solid.

[0127] Step 2: 2-Acetyl-N,N,N,4-tetramethyl-1-pentanaminium iodide is reacted with d 6 (d) into a suspension containing -6,7-dimethoxy-3,4-dihydroisoquinoline (hydrochloride or free base, 1.00 equivalents) and a solvent. 6 When -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride is used, the base is added to the reaction mixture at room temperature. The reaction mixture is stirred at an appropriate temperature, cooled, and water is added. The reaction mass is filtered, the solid is washed with water, and dried to give the product.

[0128] Example 4 Analysis of the amounts of compounds 1 and 2 in samples of deutetrabenazine drug substance. Compounds 1 and 2 are useful for determining the purity of deutetrabenazine-containing compositions. See Figures 4 and 8.

[0129] [Table 4]

[0130] [Table 5]

[0131] [Table 6]

[0132] Example 4 Fourier transform infrared spectroscopy (FTIR) analysis The FTIR spectra of compounds 1 and 2 are shown in FIG. 1 and FIG.

[0133] Example 4 Long-term stability of deutetrabenazine formulations.

[0134] [Table 7]

[0135] [Table 8]

[0136] Example 5 A 90-day GLP rat general toxicity study was conducted with Compound 1. In this study, the no observed adverse effect level (NOAEL) dose of deutetrabenazine was 10 mg / kg / day, which was shown to result in 0.346 mg / kg / day of Compound 1 in rats, approximating the human equivalent dose of 0.056 mg / kg.

[0137] Example 6 A 3-day GLP mouse micronucleus study was performed with Compound 1. The study included a GLP bacterial reverse mutation assay of deutetrabenazine with Compound 1. The study also included an in vitro chromosomal aberration study in cultured human peripheral blood lymphocytes. In this study, the highest level of deutetrabenazine, 80 mg / kg / day, was not genotoxic in males and females. That dose level was predicted to result in 2.77 mg / kg / day of Compound 1 in mice, approximating the human equivalent dose of 0.23 mg / kg.

[0138] Aspects Aspect 1. Structure:

[0139] [ka]

[0140] or a salt or stereoisomer thereof.

[0141] Aspect 2. Structure:

[0142] [ka]

[0143] 2. The isolated compound of embodiment 1, having the formula:

[0144] Aspect 3. Structure:

[0145] [ka]

[0146] 2. The isolated compound of embodiment 1, having the formula:

[0147] Aspect 4. Deutetrabenazine and the structure:

[0148] [ka]

[0149] and at least one compound having the formula:

[0150] Aspect 5. Structure:

[0151] [ka]

[0152] and being substantially free of deutetrabenazine.

[0153] Aspect 6. The compound has the structure:

[0154] [ka]

[0155] 6. The composition of claim 4 or 5, comprising:

[0156] Aspect 7. A compound having the structure:

[0157] [ka]

[0158] 6. The composition of claim 4 or 5, comprising:

[0159] Embodiment 8. A pharmaceutical composition comprising an amount of deutetrabenazine and at least one of compound 1 and compound 2, a) Compound 1 is present in the pharmaceutical composition in an amount of 10 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; or b) Compound 2 is present in the pharmaceutical composition in an amount of 10 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; Pharmaceutical compositions.

[0160] Aspect 9. a) Compound 1 is present in the pharmaceutical composition in an amount of 3 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; or b) Compound 2 is present in the pharmaceutical composition in an amount of 0.4 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; A pharmaceutical composition according to embodiment 8.

[0161] Aspect 10. a) Compound 1 is present in the pharmaceutical composition in an amount of 0.15 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; or b) Compound 2 is present in the pharmaceutical composition in an amount of 0.15 area % or less relative to the concentration of deutetrabenazine, as determined by HPLC methods; 10. A pharmaceutical composition according to embodiment 9.

[0162] Aspect 11. a) Compound 1 is present in the pharmaceutical composition in an amount greater than 0.01 area % and less than or equal to 3 area % relative to the concentration of deutetrabenazine, as determined by an HPLC method; or b) Compound 2 is present in the pharmaceutical composition in an amount of more than 0.01 area % to 0.4 area % relative to the concentration of deutetrabenazine, as determined by HPLC method; 10. A pharmaceutical composition according to embodiment 9.

[0163] Aspect 12. a) Compound 1 is present in the pharmaceutical composition in an amount greater than 0.01 area % and less than or equal to 0.15 area % relative to the concentration of deutetrabenazine, as determined by an HPLC method; or b) Compound 2 is present in the pharmaceutical composition in an amount of more than 0.01 area % to 0.15 area % relative to the concentration of deutetrabenazine, as determined by HPLC method; 10. A pharmaceutical composition according to embodiment 9.

[0164] Aspect 13. a) Compound 1 is present in the pharmaceutical composition in an amount of less than 0.04 area % relative to the concentration of deutetrabenazine, as determined by HPLC methods; or b) Compound 2 is present in the pharmaceutical composition in an amount of less than 0.04 area % relative to the concentration of deutetrabenazine, as determined by HPLC methods; 13. A pharmaceutical composition according to aspect 11 or 12.

[0165] Aspect 14. a) Compound 1 is present in the pharmaceutical composition in an amount of less than 0.01 area % relative to the concentration of deutetrabenazine, as determined by HPLC methods; or b) Compound 2 is present in the pharmaceutical composition in an amount of less than 0.01 area % relative to the concentration of deutetrabenazine, as determined by HPLC methods; 10. A pharmaceutical composition according to embodiment 9.

[0166] Aspect 15. The pharmaceutical composition according to any one of aspects 8 to 14, comprising compound 1 and compound 2.

[0167] Embodiment 16. The pharmaceutical composition according to any one of embodiments 8 to 14, comprising compound 1.

[0168] Embodiment 17. The pharmaceutical composition according to any one of embodiments 8 to 14, comprising compound 2.

[0169] Embodiment 18. The pharmaceutical composition of any one of embodiments 8 to 17, comprising deutetrabenazine.

[0170] Aspect 19. The pharmaceutical composition according to any one of aspects 8 to 18, which is in the form of a capsule, a tablet, or a suspension.

[0171] Aspect 20. The pharmaceutical composition of aspect 19, which is an oral unit dosage form.

[0172] Embodiment 21. The pharmaceutical composition according to embodiment 20, comprising between 5 and 30 mg of deutetrabenazine.

[0173] Embodiment 22. The pharmaceutical composition of embodiment 21, comprising between 6 and 24 mg of deutetrabenazine.

[0174] Embodiment 23. The pharmaceutical composition of embodiment 22, comprising about 6 mg of deutetrabenazine.

[0175] Embodiment 24. The pharmaceutical composition of embodiment 22, comprising about 9 mg of deutetrabenazine.

[0176] Embodiment 25. The pharmaceutical composition of embodiment 22, comprising about 12 mg of deutetrabenazine.

[0177] Embodiment 26. The pharmaceutical composition of embodiment 22, comprising about 15 mg of deutetrabenazine.

[0178] Embodiment 27. The pharmaceutical composition of embodiment 22, comprising about 18 mg of deutetrabenazine.

[0179] Embodiment 28. The pharmaceutical composition of embodiment 22, comprising about 21 mg of deutetrabenazine.

[0180] Embodiment 29. The pharmaceutical composition of embodiment 22, comprising about 24 mg of deutetrabenazine.

[0181]

[0041] Embodiment 30. The pharmaceutical composition according to embodiment 22, which is formulated for once-daily administration.

[0182] Embodiment 31. The pharmaceutical composition according to embodiment 22, which is formulated for administration more than once per day.

[0183] Embodiment 32. A method for testing whether a sample of a composition comprising deutetrabenazine contains an undesirable impurity, the method comprising the steps of:

[0184] [ka]

[0185] Based on the determination by HPLC method, the method includes a step of determining whether the composition contains at least one compound having the formula:

[0186] Aspect 33. A method for producing a deutetrabenazine formulation comprising obtaining a deutetrabenazine drug substance and mixing the deutetrabenazine drug substance with suitable excipients to produce a deutetrabenazine formulation, wherein the deutetrabenazine drug substance is i) an amount of Compound 1 in the deutetrabenazine drug substance, which is equal to or less than 0.5 area % of Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods; or ii) a quantity of Compound 2 in the deutetrabenazine drug substance, the quantity being equal to or less than 0.15 area % of Compound 2 relative to the concentration of deutetrabenazine, as determined by HPLC methods; A method comprising:

[0187] Embodiment 34. The method of embodiment 33, further comprising determining the amount of at least one of compound 1 and compound 2 in the deutetrabenazine drug substance.

[0188] Embodiment 35. A method for producing a deutetrabenazine formulation for commercial sale, comprising: i) an amount of Compound 1 in a batch of deutetrabenazine formulation, the amount being 3% or less by area of ​​Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods; or ii) in a batch of deutetrabenazine formulation, an amount of Compound 2, which is 0.4 area % or less of Compound 2 relative to the concentration of deutetrabenazine, as determined by HPLC method; obtaining a batch of a deutetrabenazine formulation comprising: Preparing batches of deutetrabenazine formulations for commercial sale A method comprising:

[0189] Embodiment 36. The method of embodiment 35, further comprising determining the amount of at least one of compound 1 and compound 2 in the batch of the deutetrabenazine formulation.

[0190] Embodiment 37. A method of distributing a deutetrabenazine formulation comprising a deutetrabenazine drug substance, comprising: a) The deutetrabenazine drug substance is i) an amount of Compound 1 in the deutetrabenazine drug substance, which is equal to or less than 0.5 area % of Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods; or ii) a quantity of Compound 2 in the deutetrabenazine drug substance, the quantity being equal to or less than 0.15 area % of Compound 2 relative to the concentration of deutetrabenazine, as determined by HPLC methods; obtaining a deutetrabenazine formulation, b) distributing deutetrabenazine preparations containing deutetrabenazine drug substance A method comprising:

[0191] Embodiment 38. A method of distributing a deutetrabenazine formulation, comprising: a) i) an amount of Compound 1 in a deutetrabenazine formulation, the amount being 3 area % or less of Compound 1 relative to the concentration of deutetrabenazine as determined by HPLC methods; or ii) a quantity of Compound 2 in a deutetrabenazine formulation, the amount being 0.4 area % or less of Compound 2 relative to the concentration of deutetrabenazine, as determined by HPLC methods; obtaining a deutetrabenazine formulation comprising b) Distributing deutetrabenazine preparations A method comprising:

[0192] Embodiment 39. An impurity for use as a reference standard to detect trace amounts of impurities in a pharmaceutical composition comprising deutetrabenazine.

[0193] [ka]

[0194] Embodiment 40. A method of treating a subject suffering from a hyperkinetic movement disorder, comprising administering to the subject a pharmaceutical composition according to any one of embodiments 8 to 31.

[0195] Embodiment 41. The method of embodiment 40, wherein the hyperkinetic movement disorder is Huntington's disease.

[0196] Embodiment 42. The method of embodiment 40, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

[0197] Embodiment 43. The method of embodiment 40, wherein the hyperkinetic movement disorder is tardive dyskinesia.

[0198] Embodiment 44. The method of embodiment 40, wherein the hyperkinetic movement disorder is the tics associated with Tourette's syndrome.

[0199] Embodiment 45. A method for validating for distribution a batch of a pharmaceutical product containing deutetrabenazine and a pharma- ceutically acceptable carrier, comprising: a) determining the amount of at least one of compound 1 and compound 2 in a batch; and b) i) the batch is determined to have Compound 1 equal to or less than 3 area % relative to the concentration of deutetrabenazine; or ii) The batch is determined to have Compound 2 at a concentration of deutetrabenazine of 0.4 area % or less. A process to validate a batch for distribution only if A method comprising:

[0200] Embodiment 46. A method for preparing a validated pharmaceutical composition comprising deutetrabenazine, comprising: a) obtaining a batch of deutetrabenazine drug substance; b) determining the amount of at least one of compound 1 and compound 2 in the batch; and c) i) the batch is determined to have Compound 1 relative to the concentration of deutetrabenazine of 0.5 area % or less; or ii) The batch is determined to have Compound 2 at or below 0.15 area % relative to the concentration of deutetrabenazine. preparing the pharmaceutical composition from the batch only if A method comprising:

Claims

1. 1. A process for preparing a deutetrabenazine formulation in the form of a tablet, comprising the steps of: The method further comprising: Compound 2, which is present in an amount of 0.05% to 0.15% by area relative to the concentration of deutetrabenazine in the deutetrabenazine drug substance. 【Chemistry 1】 obtaining a deutetrabenazine drug substance comprising mixing the deutetrabenazine drug substance with excipients to produce a deutetrabenazine formulation in the form of a tablet; and A step of adjusting the amount of compound 2 in the deutetrabenazine formulation stored at room temperature to 0.03 area % to 0.4 area % or less relative to the concentration of deutetrabenazine in the formulation. Including, The amount of compound 2 was determined by an HPLC method equipped with a C18, 150 x 4.6 mm, 3.5 μm column and a photodiode array / UV detector at 220 nm; a deutetrabenazine formulation having, after one month storage at room temperature, an amount of Compound 2 of 0.03 area % to 0.4 area % or less, based on the concentration of deutetrabenazine in the formulation, as determined by an HPLC method; A method for preparing a deutetrabenazine formulation in the form of a tablet.

2. 2. The method of claim 1, wherein the amount of compound 2 in the deutetrabenazine formulation is about 0.05 area % to 0.1 area % relative to the concentration of deutetrabenazine in the drug substance, as determined by HPLC methods.

3. 2. The method of claim 1, wherein the amount of compound 2 in the deutetrabenazine formulation is about 0.1 area % to 0.4 area % relative to the concentration of deutetrabenazine in the drug substance, as determined by HPLC method, after one month of storage at room temperature.

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