WO2012153341A1 - Procédé pour la préparation d'iopéridone et sels pharmaceutiquement acceptables de celle-ci - Google Patents

Procédé pour la préparation d'iopéridone et sels pharmaceutiquement acceptables de celle-ci Download PDF

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Publication number
WO2012153341A1
WO2012153341A1 PCT/IN2011/000549 IN2011000549W WO2012153341A1 WO 2012153341 A1 WO2012153341 A1 WO 2012153341A1 IN 2011000549 W IN2011000549 W IN 2011000549W WO 2012153341 A1 WO2012153341 A1 WO 2012153341A1
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formula
iloperidone
impurity
base
alkali metal
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PCT/IN2011/000549
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English (en)
Inventor
Shailesh Shrikant ATHALYE
Kalpesh Dalpat PARGHI
Kamlesh Jayantilal Ranbhan
Pushpalata Balkrishna SARJEKAR
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Arch Pharmalabs Limited
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Publication of WO2012153341A1 publication Critical patent/WO2012153341A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • TITLE A novel process for the preparation of Iloperidone and pharmaceutically acceptable salts thereof.
  • the present invention relates to a novel process for the preparation of 1- [4-[3-[4-(6-fluoro- 1,2- benzisoxazol-3-yl)- l-piperidinyl]propoxy]-3-methoxyphenyl]- ethanone of formula I (Iloperidone).
  • the process comprises contacting 6-fluoro-3- (4-piperidinyl)-l,2-benzisoxazole of formula II as base itself rather than use of its hydrochloride salt as reported in the prior art (Drugs of Future 2000, 25(1): 29, EP 0402644) and l-[4-(3-chloropropoxy)-3- methoxyphenyl] ethanone of formula III.
  • This invention also relates to a process for the preparation of an unknown impurity of the formula IV herein referred as carbonated impurity formed during contact of compound of formula II and compound of formula III in presence of a base, method of its isolation and characterization thereof, as well as its use as a reference standard and reference marker in analytical department while evaluating the purity profile of iloperidone.
  • Iloperidone is an atypical antipsychotic. It is being investigated mainly for the treatment of schizophrenia. Hoechst Marion Roussel Inc. is the originator of this molecule; Vanda is currently developing this molecule for the treatment of schizophrenia. Iloperidone is 5-HT2 antagonist, which targets a selective set of dopamine, norepinephrine and serotonin receptor subtypes. The affinity for this particular set of receptors indicates that Iloperidone has the potential to be a broad spectrum antipsychotic, with efficacy against positive, negative, depressive and cognitive symptoms of schizophrenia, and a low propensity to induce side effects.
  • Iloperidone's IUPAC name is l-[4-[3-[4-(6-fluoro-l,2- benzisoxazol-3-yl)-l-piperidinyl]propoxy]-3-methoxyphenyl]ethanone.It is a non pharmacopeal product till date.
  • API active pharmaceutical ingredient product
  • the product mixture of a reaction is rarely a pure single compound complying to pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will in most cases be present.
  • an API such as Iloperidone
  • it must be analyzed for purity typically to determine the presence of any intermediates or by-products as impurities.
  • the API need not to be absolutely pure, as absolute purity is theoretically ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible and thus safe for human use.
  • impurities are identified spectroscopically and/or by other physical methods and then associated with a peak position, such as that in a chromatograph.
  • the relative position in the chromatogram is known as the "retention time.”
  • the retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors.
  • practitioners use the "relative retention time (RRT)" to identify impurities.
  • the RRT of an impurity is its retention time divided by retention time of "reference marker".
  • the reference marker can be the API itself, or it may be a compound other than API that is added to, or already present in the mixture, in an amount sufficiently large to be detectable and sufficiently low so as not to saturate the column and to use that compound as the reference marker for the determination of RRT.
  • a reference standard is similar to a "reference marker”, which is used for qualitative analysis only, but used to quantify the amount of compound of reference standard in an unknown mixture as well.
  • a reference standard is an "external standard", when a solution of a known concentration of reference standard and an unknown mixture are analyzed using the same technique.
  • Iloperidone or pharmaceutically acceptable salt thereof can contain impurities that can come from many sources. They can be degradation products of Iloperidone, unreacted intermediate(s) used in the preparation of Iloperidone or by-products of reactions.
  • the present invention relates to an improved process for the preparation of iloperidone over the prior art by minimizing or eliminating the formation of unknown impurity and isolation and characterization of the said unknown of formula IV formed during the preparation of iloperidone of formula I, comprising contacting 6-fluoro-3-(4- piperidinyl)-l,2-benzisoxazole formula II with l-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone of formula III in presence of a base especially alkali metal carbonate.
  • the said impurity of formula IV is a potential reference marker in analytical methods for the analysis the quality of iloperidone.
  • Iloperidone compound of formula (I) was first disclosed in EP0402644 by Hoechst-Roussel Pharmaceutical Inc. Method for preparation of Iloperidone was first disclosed in EP0402644 (hereinafter referred as '644) , according to which, it was prepared by the condensation of the hydrochloride salt of formula (II) 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole and compound of formula (III) l-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone, in the presence of potassium carbonate as a base added in a single lot in dimethylformamide (DMF) followed by treating reaction mixture with water, extracting with organic solvent that is immiscible in water, washing, drying and concentrating the organic solvent to give the moist solid iloperidone, which was further recrystallized f om the ethyl alcohol to produce iloperidone as a beige (i.e. light brown)
  • Drugs of Future 2000, 25(1): 29 discloses the same process as disclosed in '644 for the preparation of iloperidone comprising the condensation of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride (II) with 1- [4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (III) in presence of K 2 C0 3 in hot DMF, there is no description of yield and iloperidone is obtained as a beige solid.
  • 1980/MUM/2007 discloses the preparation of iloperidone comprising the condensation of the HC1 salt of compound of formula (II) 6-fluoro-3-(4- piperidinyl)-l,2-benzisoxazole and compound of formula (III) l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone, in the presence of potassium carbonate as a preferable base in water as solvent.
  • the reaction for the preparation of iloperidone comprising contacting the compound of formula II with compound of formula III is a SN 2 type reaction for which bases like sodium methoxide, sodium hydroxide, sodium tert butylate are too strong since they do not function as only proper acid scavengers but also gets involved chemically inducing side reactions.
  • bases like sodium methoxide, sodium hydroxide, sodium tert butylate
  • the use of very strong base as acid scavengers is not advised.
  • the choice of a well balanced base to act as acid scavengers, which is neither too strong nor too weak is essential, therefore, generally carbonates are preferred.
  • the impurity of formula IV is found to be a carbonated impurity, it is assumed that metal bicarbonates particularly alkali metal bicarbonates being the source of carbon dioxide should also form the said impurity. But practically it has been observed by the inventors that use of bicarbonates and DMF do not result in the formation of the impurity of formula IV. This may be owing to the fact that for the formation of the impurity of formula IV a specific basicity of the base is necessary. This is met with minimum basic characteristic of potassium carbonate. Alkali metal bicarbonates do not meet such characteristic basicity; therefore, no impurity of formula IV is formed.
  • alkali metal hydroxides in combination with DMF does not form the said impurity of formula IV as there is no source of carbon dioxide but somehow alkali metal hydroxide is not an ideal base for the said reaction when DMF is used as a solvent at high temperature.
  • Inventors of the present invention have designed a reaction that is both efficient and tolerant to functional group of choice of a well balanced base, which is neither too strong nor too weak and compatible aprotic solvent like DMF.
  • the inventors of the present invention have also disclosed herein the compatible solvent and base combinations taking into consideration solubility and polarisability aspects.
  • Process for the preparation of Iloperidone disclosed herein comprises gradual/slow addition of selective alkali metal carbonate base to a reaction mixture comprising compounds of formulae II and III in an organic solvent preferably DMF which minimizes or eliminates the formation of an unknown impurity, use of compound of formula II as such (base) instead of acid addition salt with water as a solvent and isolation and characterization of said unknown impurity as compound of formula IV is not reported in the prior art.
  • Inventors of the present invention have replaced 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole hydrochloride by its base and then reacted with l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone in presence of a base and water as solvent avoiding extra consumption of base to neutralize the salt.
  • the base to be used for the said reaction may be any as long as it does not inhibit the reaction or does not impart / minimizes the impurity formation.
  • the proposed novel process of the present invention results into the formation of substantially pure iloperidone having the impurity of compound of formula IV up to about 1.5%.
  • Present invention does not use the acid addition salt of the compound of formula II, thereby avoiding an extra unit operation for its preparation and isolation and also use of extra mole of base.
  • First aspect of the invention is to provide a process for the preparation of iloperidone comprising contacting 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole the compound of formula (II) and l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone compound of formula (III) in DMF as a solvent and gradual/slow addition of selective alkali metal carbonate as a base to the reaction mixture minimizing or eliminating formation of said unknown impurity.
  • Second aspect of the invention is to provide a process for the preparation of iloperidone comprising contacting 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole the compound of formula (II) and l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone compound of formula (III) in DMF as solvent in presence of alkali metal bicarbonates or selective alkali metal carbonate optionally added in a single lot.
  • Third aspect of the invention is to provide a process for the preparation of iloperidone comprising contacting 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole the compound of formula (II) and l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone compound of formula (III), using water as a solvent in the presence of a base.
  • Fourth aspect of the invention is to provide a process for the preparation of said unknown impurity of formula IV comprising contacting of 6- fluoro-3-(4-piperidinyl)-l,2-benzisoxazole or its hydrochloride salt with 1- [4-(3 -chloropropoxy)-3 -methoxyphenyl]-ethanone.
  • Fifth aspect of the invention is to prepare, isolate and characterize the said carbonated impurity of formula IV that is formed during contacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole or its hydrochloride with 1- [4-(3-chloropropoxy)-3-methoxyphenyl]-ethanone by analytical techniques selected from Infrared spectroscopy, Mass spectroscopy, Differential scanning calorimetry, Proton magnetic resonance spectroscopy and the like.
  • Sixth aspect of the invention is to use the said carbonated impurity of formula IV that is formed during contacting 6-fluoro-3-(4-piperidinyl)- 1,2-benzisoxazole or its hydrochloride with l-[4-(3-chloropropoxy)-3- methoxyphenyl]-ethanone as a reference marker and reference standard while evaluating the quality of iloperidone.
  • iloperidone comprising optionally gradual/slow addition of selective alkali metal carbonate base to a reaction mixture of compounds of formulae II and III in an organic solvent preferably DMF which minimizes or eliminates the formation of an unknown impurity, use of base as such of compound of formula II instead of acid addition salt as reported in the prior art with water as a solvent and characterization of unknown impurity as compound of formula IV.
  • the base to be used for the said reaction may be any as long as it does not inhibit the reaction or which either does not impart the impurity formation or that forms the impurity that is manageable to be removed.
  • the solvent to be used for the said reaction may be any as long as it does take the reaction smoothly without any unwanted side products formation.
  • Contacting hereinabove and hereinbelow means reacting, mixing, condensing, stirring, heating or combination thereof and the like.
  • a process for the preparation of iloperidone of the formula I comprising contacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl]-ethanone of formula III in a solvent in the presence of a base
  • the stoichiometric ratio of the reactants viz. compounds of formulae II, III and the base may be any as long as it does not inhibit the reaction or does not impart the impurity formation that is not manageable.
  • the base to be used for the purpose may be any as long as it does not inhibit the reaction or does not impart the impurity formation. It could be selected from the group of hydroxides, carbonates, bicarbonates, alkyl amines and the like optionally to be added gradually/slowly in multiple lots.
  • the solvent used for the purpose of the reaction may be any as long as it does not inhibit the reaction or does not impart to impurity formation. It could be selected from the group of DMF, alcohol, ketones, nitriles, acetamides, water, pyrrolidinones, aromatic hydrocarbons with special preference to DMF.
  • the reaction temperature for the said reaction depends upon the reagent particularly solvent to be used and the like. The said reaction generally proceeds at temperature between about 50°C to about 90°C. The temperature of the reaction may be such; that takes reaction towards completion and does not cause formation of impurity.
  • the schematic representation for the above can be represented as follows:
  • Formula I Referring to first aspect of the invention, disclosed herein is a process for the preparation of iloperidone of the formula I comprising contacting 6- fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II with l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone of formula III using DMF as a solvent in the presence of alkali metal carbonate to be added slowly in multiple lots while heating devoiding or minimizing the formation of impurity of formula IV.
  • DMF alkali metal carbonate
  • the base to be used in the first aspect for the said reaction may be any as long as it does not inhibit the reaction or does not impart the impurity formation when added slowly in multiple lots and reaction mass is heated.
  • Preferable base is alkali metal carbonate selected from the group of lithium, sodium, potassium, cesium carbonates and the like.
  • iloperidone is prepared by contacting 6- fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula U with l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone of formula III using DMF as a solvent in presence of base selected from the group comprising potassium carbonate and cesium carbonate added slowly in multiple lots while heating, devoiding or minimizing the formation impurity of formula IV.
  • base selected from the group comprising potassium carbonate and cesium carbonate added slowly in multiple lots while heating, devoiding or minimizing the formation impurity of formula IV.
  • iloperidone of the formula I comprising contacting 6- fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II with l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone of formula III using DMF as solvent in presence of alkali metal bicarbonate or selective alkali metal carbonates optionally added slowly in multiple lots while heating.
  • the base is selected from the alkali metal carbonate, like sodium carbonate, lithium carbonate or mixture thereof.
  • Alkali metal bicarbonate is selected from lithium, sodium, potassium, cesium bicarbonate or mixture thereof.
  • the reaction temperature for the said reaction depends upon the reagent particularly solvent to be used and the like.
  • a process for the preparation of iloperidone of the formula I comprising contacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II with l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone of formula III in DMF as solvent using a base selected from the group comprising sodium bicarbonate, sodium carbonate, lithium carbonate optionally added slowly in multiple lots while heating .
  • a base selected from the group comprising sodium bicarbonate, sodium carbonate, lithium carbonate optionally added slowly in multiple lots while heating .
  • iloperidone of the formula I comprising contacting 6- fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II with l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone of formula III using water as solvent in the presence of a base.
  • the base to be used in the third aspect for the said reaction may be any as long as it does not inhibit the reaction or does not impart the impurity formation. It could be selected from the group comprising hydroxides, carbonates, bicarbonates, alkyl amines and the like optionally to be added slowly in multiple lots.
  • the reaction temperature for the said reaction depends upon the reagent particularly solvent to be used and the like.
  • a process for the preparation of Iloperidone of the formula I comprising contacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II with l-[4-(3- chloropropoxy)-3-methoxyphenyl]-ethanone of formula III using water as solvent in presence of a base selected from the group of alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate and like.
  • base is alkali metal carbonate. More preferably base is potassium carbonate.
  • a process for the preparation of carbonated Iloperidone impurity of formula IV comprising contacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl]-ethanone of formula III in DMF using potassium carbonate added in a single lot.
  • Reaction mass is heated at about 70-90 °C, till the formation of impurity to a reasonable extent.
  • Reaction mass is quenched over water and then extracted with ethyl acetate.
  • the fifth, sixth aspect of the invention disclosed herein is a process for the isolation of the said impurity using column chromatography and to characterize the impurity using analytical techniques such as Infrared spectroscopy, Mass spectroscopy, Proton magnetic resonance spectroscopy and the like.
  • the impurity if formula IV is identified as 3-(4-acetyl-2- methoxyphenoxy)propyl 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine- 1 - carboxylate, which in short is referred herein below and herein above as carbonated impurity of formula IV.
  • Figure III is Proton Magnetic Resonance spectra for impurity of formula
  • Example-1 is for illustrative purposes only and are not intended, or should they be interpreted to limit the scope of the invention.
  • IR Shiadzu, KBr: 470.6, 569.0, 642.3, 804.3, 956.7, 1031.9, 1099.5, 1122.6, 1220.9, 1263.4, 1350.2, 1415.8, 1512.2, 1591.3, 1612.5, 1680.1, 1695.5, 2852.8, 2924.2, 2960.8 and 3076.6 cm-1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé pour la préparation de 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pipéridinyl]propoxy]-3- méthoxyphényl]-éthanone (Ilopéridone) et des sels de celle-ci. Le procédé de synthèse comprend la réaction du 6-fluoro-3-(4-pipéridinyl)-1,2-benzisoxazole de formule II lui-même sous forme de base plutôt que l'utilisation de son chlorhydrate comme il est principalement rapporté dans l'art antérieur et de 1-[4-(3- chloropropoxy)-3-méthoxyphényl]éthanone de formule III. Cette invention concerne en outre un procédé pour la préparation d'ilopéridone carbonatée ; une impureté de formule IV formée pendant la condensation du composé de formule II et du composé de formule III en présence d'une base, un procédé pour son isolement et la caractérisation de celui-ci, ainsi que son utilisation en tant que standard de référence et marqueur de référence dans un département analytique pour évaluer le profil de pureté de l'ilopéridone. Formule (I) (II) (III)
PCT/IN2011/000549 2011-05-12 2011-08-17 Procédé pour la préparation d'iopéridone et sels pharmaceutiquement acceptables de celle-ci WO2012153341A1 (fr)

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IN1458/MUM/2011 2011-05-12

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103130785A (zh) * 2012-12-20 2013-06-05 安徽悦康凯悦制药有限公司 伊潘立酮的制备方法
CN106831742A (zh) * 2016-12-28 2017-06-13 北京医药集团有限责任公司 一种伊潘立酮中间体的制备方法
CN111548303A (zh) * 2020-06-28 2020-08-18 山东美泰医药有限公司 一种盐酸左布比卡因的杂质及其制备和分析方法
US11311532B2 (en) 2017-09-21 2022-04-26 Neurocrine Biosciences, Inc. High dosage valbenazine formulation and compositions, methods, and kits related thereto
US11439629B2 (en) 2017-01-27 2022-09-13 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
US11654142B2 (en) 2017-10-10 2023-05-23 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0402644A1 (fr) 1989-05-19 1990-12-19 Hoechst-Roussel Pharmaceuticals Incorporated N-(aryloxyalkyl)hétéroarylpipéridines et -hétéroarylpipérazines, leur procédé de préparation et leur application comme médicaments
US20100076196A1 (en) * 2008-09-19 2010-03-25 Vertessy Miklos Process for the preparation of iloperidone

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0402644A1 (fr) 1989-05-19 1990-12-19 Hoechst-Roussel Pharmaceuticals Incorporated N-(aryloxyalkyl)hétéroarylpipéridines et -hétéroarylpipérazines, leur procédé de préparation et leur application comme médicaments
US20100076196A1 (en) * 2008-09-19 2010-03-25 Vertessy Miklos Process for the preparation of iloperidone

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JOSEPH T. STRUPCZEWSKI ET AL: "3-[[(Aryloxy)alkyl]piperidinyl]-1,2-Benzisoxazoles as D2/5-HT2 Antagonists with Potential Atypical Antipsychotic Activity: Antipsychotic Profile of Iloperidone", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, 1995, pages 1119 - 1131, XP002665423 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103130785A (zh) * 2012-12-20 2013-06-05 安徽悦康凯悦制药有限公司 伊潘立酮的制备方法
CN106831742A (zh) * 2016-12-28 2017-06-13 北京医药集团有限责任公司 一种伊潘立酮中间体的制备方法
CN106831742B (zh) * 2016-12-28 2019-08-23 北京医药集团有限责任公司 一种伊潘立酮中间体的制备方法
US11439629B2 (en) 2017-01-27 2022-09-13 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
US11311532B2 (en) 2017-09-21 2022-04-26 Neurocrine Biosciences, Inc. High dosage valbenazine formulation and compositions, methods, and kits related thereto
US11654142B2 (en) 2017-10-10 2023-05-23 Neurocrine Biosciences, Inc. Methods for the administration of certain VMAT2 inhibitors
CN111548303A (zh) * 2020-06-28 2020-08-18 山东美泰医药有限公司 一种盐酸左布比卡因的杂质及其制备和分析方法

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