WO2017106641A1 - Formes à l'état solide de brexpiprazole - Google Patents

Formes à l'état solide de brexpiprazole Download PDF

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Publication number
WO2017106641A1
WO2017106641A1 PCT/US2016/067163 US2016067163W WO2017106641A1 WO 2017106641 A1 WO2017106641 A1 WO 2017106641A1 US 2016067163 W US2016067163 W US 2016067163W WO 2017106641 A1 WO2017106641 A1 WO 2017106641A1
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WO
WIPO (PCT)
Prior art keywords
brexpiprazole
degrees
theta
crystalline form
less
Prior art date
Application number
PCT/US2016/067163
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English (en)
Inventor
Ariel Mittelman
Sharona SHACHAN-TOV ALFSIE
Limor TESSLER-SHAMIS
Motti Erlich
Original Assignee
Assia Chemical Industries Ltd.
Teva Pharmaceutical Usa, Inc.
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Filing date
Publication date
Application filed by Assia Chemical Industries Ltd., Teva Pharmaceutical Usa, Inc. filed Critical Assia Chemical Industries Ltd.
Publication of WO2017106641A1 publication Critical patent/WO2017106641A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure encompasses solid state forms of Brexpiprazole and pharmaceutical compositions thereof.
  • Brexpiprazole is a novel D2 dopamine partial agonist called serotonin-dopamine activity modulator (SDAM) approved for the treatment of schizophrenia, and as an adjunctive treatment for depression. It is being developed by Otsuka.
  • SDAM serotonin-dopamine activity modulator
  • WO2013162046 describes anhydride, hydrate and dihydrate crystal forms of Brexpiprazole.
  • Polymorphism the occurrence of different crystalline forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state ( 1 C-) NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • X-ray diffraction pattern e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - "DSC”
  • X-ray diffraction pattern e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - "DSC”
  • X-ray diffraction pattern e.g. measured by thermogravimetric analysis - "T
  • Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
  • pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability).
  • a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability).
  • the present disclosure provides solid state forms of Brexpiprazole, and pharmaceutical compositions thereof.
  • the present disclosure also encompasses uses of the solid state forms of Brexpiprazole of the present disclosure for the preparation of pharmaceutical compositions and/or formulations of Brexpiprazole.
  • the present disclosure comprises processes for preparing the above mentioned pharmaceutical compositions and/or formulations.
  • the processes comprise combining the Brexpiprazole solid state form with at least one pharmaceutically acceptable excipient.
  • the solid state Forms of the present disclosure and the pharmaceutical compositions and/or formulations of Brexpiprazole of the present disclosure can be used as medicaments, particularly for the treatment of schizophrenia and/or depression.
  • Figure 1 shows an X-ray powder diffractogram of Form G of Brexpiprazole.
  • Figure 2 shows an X-ray powder diffractogram of Brexpiprazole obtained according to example lb.
  • Figure 3 shows an X-ray powder diffractogram of Brexpiprazole obtained according to example l a.
  • Figure 4 shows an X-ray powder diffractogram of Form J of Brexpiprazole.
  • Figure 5 shows the solid-state 1 C NMR spectrum of Brexpiprazole form G in the 0-180 ppm range.
  • Figure 6 shows the solid-state 1 C NMR spectrum of Brexpiprazole form G in the 90-170 ppm range.
  • the present disclosure encompasses solid state forms of Brexpiprazole.
  • Solid state properties of Brexpiprazole can be influenced by controlling the conditions under which the Brexpiprazole is obtained in solid form.
  • the crystalline form of Brexpiprazole of the disclosure is substantially free of any other forms of Brexpiprazole, or of specified polymorphic forms of Brexpiprazole, respectively.
  • Brexpiprazole refers to 7- ⁇ 4-[4-(l -benzothiophen-4- yl)piperazin-l -yl]butoxy ⁇ quinolin-2(lH)-one.
  • a solid state form may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms.
  • the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or about 0% of any other forms of the subject compound as measured, for example, by X-ray powder diffraction (XRPD).
  • solid state of Brexpiprazole described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject solid state form of Brexpiprazole. Accordingly, in some embodiments of the disclosure, the described solid state forms of Brexpiprazole may contain from about 1 % to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other solid state forms of Brexpiprazole.
  • the term “chemically pure” refers to a material which is substantially free of chemical impurities, such as reaction by-products, un-reacted intermediates or degradation product.
  • substantially free is meant that the chemically pure material of the present disclosure contains about 3% (w/w) or less of chemical impurities.
  • the chemically pure material of the present disclosure contains about 3% (w/w) or less, about 2% (w/w) or less, about 1 % (w/w) or less, about 0.5% (w/w) or less, or about 0.2% (w/w) or less, or about 0% of chemical impurities.
  • chemically pure material of the present disclosure contains from about 0.01% to about 3% (w/w), of chemical impurities.
  • the solid state form of Brexpiprazole of the present disclosure has advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability- such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.
  • a solid state form such as a crystal form or amorphous form, may be referred to herein as being characterized by graphical data "as depicted in” or “as substantially depicted in” a Figure.
  • Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
  • the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called "fingerprint") which cannot necessarily be described by reference to numerical values or peak positions alone.
  • the modifier "about” should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4" also discloses the range “from 2 to 4. " When used to modify a single number, the term “about” may refer to plus or minus 10% of the indicated number and includes the indicated number. For example, “about 10%” may indicate a range of 9% to 1 1%, and “about 1 " means from 0.9-1.1.
  • Brexpiprazole of the present disclosure corresponds to a solid state form of Brexpiprazole that is physically separated from the reaction mixture in which it is formed. [0030] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength of 1.5418 A.
  • a thing e.g., a reaction mixture
  • room temperature or “ambient temperature,” often abbreviated as "RT.”
  • RT room temperature
  • room temperature is from about 20°C to about 30°C, about 22°C to about 27°C, or about 25°C.
  • the amount of solvent employed in a chemical process may be referred to herein as a number of "volumes” or “vol” or “V.”
  • a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
  • this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent.
  • v/v may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.
  • a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10 to about 18 hours, typically about 16 hours.
  • reduced pressure refers to a pressure that is less than atmospheric pressure.
  • reduced pressure is about 10 mbar to about 50 mbar.
  • anhydrous in relation to crystalline Brexpiprazole relates to a crystalline Brexpiprazole which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form does not contain more than about 1% (w/w) of either water or organic solvents as measured for example by TGA.
  • the present disclosure comprises crystalline form of Brexpiprazole, designated form G, characterized by data selected from one or more of the following: an X-ray powder diffraction pattern having peaks at 9.8, 10.9, 17.3, 19.9 and 24.0 degrees two theta ⁇ 0.1 degrees two theta; an X-ray powder diffraction pattern as depicted in Figure 1 ; an X-ray powder diffraction pattern having peaks at: 9.8, 10.9, 17.3, 19.9 and 24.0 degrees two theta ⁇ 0.2 degrees two theta and also by absence of XRPD peak at 6.8 degrees two theta ⁇ 0.2 degrees two theta; or combinations of these data.
  • crystalline Form G of Brexpiprazole may be further characterized by X-ray powder diffraction pattern having peaks at: 9.8, 10.9, 17.3, 19.9 and 24.0 degrees two theta ⁇ 0.1 degrees two theta and also having one, two, three, four or five peaks selected from: 14.0, 16.4, 15.8, 21.2 and 23.2 degrees two theta ⁇ 0.1 degrees two theta.
  • crystalline form G of Brexpiprazole may be further characterized by one or more of the following: a solid-state 1 C NMR spectrum with signals at about 101.4, 107.0 and 109.0 ⁇ 0.2 ppm; a solid-state 1 C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 90 to 170 ppm of about 0.0, 5.6, 7.6 and 21.6 ⁇ 0.2 ppm; a signal exhibiting the lowest chemical shift in the chemical shift area of 90 to 170 ppm at about 101.4 ⁇ 1 ppm; a solid- state 1 C NMR spectrum substantially as depicted in Figure 5 or Figure 6.
  • Crystalline Form G of Brexpiprazole may be characterized by each of the above characteristics alone and/or by all possible combinations.
  • the present disclosure comprises a crystalline form of Brexpiprazole, designated form J, characterized by data selected from one or more of the following: an X-ray powder diffraction pattern having peaks at 4.2, 8.5, 12.7, 17.7 and 21.0 degrees two theta ⁇ 0.2 degrees two theta; an X-ray powder diffraction pattern as depicted in Figure 4; or combinations of these data.
  • crystalline form J of Brexpiprazole may be further characterized by X-ray powder diffraction pattern having peaks at 4.2, 8.5, 12.7, 17.7 and 21.0 degrees two theta ⁇ 0.2 degrees two theta and also having one, two, three, four or five peaks selected from: 16.0, 17.0, 18.2, 19.9 and 21.5 degrees two theta ⁇ 0.2 degrees two theta.
  • Crystalline Form J of Brexpiprazole may be characterized by each of the above characteristics alone and/or by all possible combinations.
  • the above described solid state form of Brexpiprazole can be used to prepare chemically pure Brexpiprazole.
  • the present disclosure encompasses the above described solid state form of Brexpiprazole for use in the chemical purification of Brexpiprazole.
  • Brexpiprazole according to any aspect or embodiment of the disclosure for the preparation of other solid state forms of Brexpiprazole.
  • the solid state form of Brexpiprazole may be converted to other solid state forms by, e.g., recrystallization.
  • the above described solid state form of Brexpiprazole can be used to prepare pharmaceutical compositions and/or formulations.
  • the present disclosure encompasses the above described solid state forms of Brexpiprazole for uses in the preparation of pharmaceutical compositions and/or formulations.
  • the present disclosure also comprises pharmaceutical compositions and formulations comprising the above described solid state forms of Brexpiprazole.
  • the pharmaceutical composition is a solid composition and the Brexpiprazole retains its solid state form.
  • compositions and/or formulations can be prepared by processes comprising combining any one or a combination of the above described solid state forms of Brexpiprazole with at least one pharmaceutically acceptable excipient.
  • the present disclosure further encompasses 1) uses of the above- solid state form of Brexpiprazole in the manufacture of pharmaceutical compositions, and 2) methods of treating a subject suffering from schizophrenia and/or depression, or otherwise in need of the treatment, comprising administration of an effective amount of a pharmaceutical composition comprising any one or a combination of the above described solid state form of Brexpiprazole described herein.
  • Brexpiprazole can be prepared according to any method known in the art.
  • a 3L reactor was loaded with Brexpiprazole (123.59 g, 0.28 mol), ethanol (1230 mL) and water (300 mL). The reaction mixture was stirred at reflux for 0.5 hours followed by drop-wise addition of 32% HCl (26.1 mL) over a period of 20 minutes. The reaction mixture was stirred for an additional 1 h under reflux to give a white slurry, which was cooled gradually to 25 °C (Tj) during lh and then to 10 °C (Tj) during 6 h. After stirring at 10 °C for overnight, ethanol (300 mL) was added to the obtained white slurry. The precipitation was collected by vacuum filtration followed by washings with ethanol (2x100 mL) to give Brexpiprazole hydrochloride (294.2 g).
  • the isolated Brexpiprazole hydrochloride (294.2 g) was loaded into a 3L reactor followed by addition of ethanol (1330 mL) and water (1064 ml). The reaction mixture was stirred at 80 °C (Tj) for 1 h and then at 83 °C (Tj) for additional lh to give clear yellow solution.
  • An aqueous solution of Na 2 HCC>3 (26 g were dissolved in 365 mL of water) was added drop- wise over a period of 2 h to the stirred reaction mixture at 80 °C (Tj) followed by cooling gradually to 25 °C (Tj) during lh and then to 10 °C (Tj) during 6h.
  • Brexpiprazole prepared according to example la (5.42 g) and a mixture of THF/water (1 : 1 v/v; 40 Vol.; 110 ml each) to obtain a reaction mixture.
  • the mixture was slurried at 70°C for one hour.
  • the slurry was cooled to ambient temperature and stirred overnight.
  • the slurry was filtered.
  • the obtained solid was characterized by a X-ray powder diffractogram to obtain the crystalline form as depicted in Figure 2.
  • the crystalline form of Brexpiprazole is prepared according to the following procedure: A 250 ml flask with magnetic stirrer was charged with the crystalline Brexpiprazole prepared according to example la (5.42 g) and a mixture of THF/water (1 : 1 v/v) (40 ml) to obtain a reaction mixture. The mixture was slurried at 70°C for one hour. The slurry was cooled to ambient temperature and stirred overnight. The slurry was filtered. The obtained solid was characterized by X-ray powder diffractogram to obtain the crystalline form having the same diffractogram as shown in Figure 2.
  • the crystalline Brexpiprazole obtained according to example lb was dried in desiccator for 6 days. A sample of 118 mg was charged in DVS and initially dried under a continuous flow of dried nitrogen for 300 min. The DVS (dynamic vapor sorption) atmosphere was then changed to 70% ethanol vapors (in nitrogen) for additional 60 minutes to give a solid. The obtained solid was characterized by X-ray powder diffractogram to obtain the crystalline form G as depicted in Figure 1.
  • the crystalline Brexpiprazole obtained according to example lb was dried in a desiccator for 30 days.
  • the obtained solid was characterized by X-ray powder diffractogram to obtain the crystalline form G, having the same diffractogram as shown in Figure 1.
  • the crystalline Brexpiprazole obtained according to example lb was stored under an NMP (N-methyl2-pyrrolidone) vapor saturated atmosphere for 1W (1 week) at ambient temperature to give a solid, which was characterized by an X-ray powder diffractogram to obtain the crystalline form G having the same diffractogram as shown in Figure 1.
  • NMP N-methyl2-pyrrolidone

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes solides de brexpiprazole, ainsi que des utilisations et des compositions comprenant les formes à l'état solide.
PCT/US2016/067163 2015-12-17 2016-12-16 Formes à l'état solide de brexpiprazole WO2017106641A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562268836P 2015-12-17 2015-12-17
US62/268,836 2015-12-17
US201662280390P 2016-01-19 2016-01-19
US62/280,390 2016-01-19

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017208251A1 (fr) * 2016-05-31 2017-12-07 Cipla Limited Nouvelle forme polymorphe stable de brexpiprazole et son procédé de préparation
CN107674067A (zh) * 2017-10-19 2018-02-09 上海博志研新药物技术有限公司 一种伊匹哌唑的纯化方法
US20190010145A1 (en) * 2015-12-28 2019-01-10 Honour (R&D) Process for the preparation of quinolin-2(ih)-one derivatives
CN111440158A (zh) * 2020-03-24 2020-07-24 石药集团中奇制药技术（石家庄）有限公司 一种盐酸依匹哌唑新晶型及其制备方法
US11229644B1 (en) * 2020-12-31 2022-01-25 Lake O'hara Llc Methods of treating psychiatric disorders in obese patients with brexpiprazole

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112464A1 (fr) 2005-04-14 2006-10-26 Otsuka Pharmaceutical Co., Ltd. Benzothiophenes a substituant piperazine pour le traitement de troubles mentaux
WO2013015456A1 (fr) * 2011-07-28 2013-01-31 Otsuka Pharmaceutical Co., Ltd. Procédé de production d'un composé benzo[b]thiophène
WO2013162046A1 (fr) 2012-04-23 2013-10-31 Otsuka Pharmaceutical Co., Ltd. Dihydrate de composé de benzothiophène ou de sel de celui-ci, et son procédé de production
EP2868318A1 (fr) * 2012-04-23 2015-05-06 Otsuka Pharmaceutical Co., Limited Formulation injectable

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112464A1 (fr) 2005-04-14 2006-10-26 Otsuka Pharmaceutical Co., Ltd. Benzothiophenes a substituant piperazine pour le traitement de troubles mentaux
WO2013015456A1 (fr) * 2011-07-28 2013-01-31 Otsuka Pharmaceutical Co., Ltd. Procédé de production d'un composé benzo[b]thiophène
WO2013162046A1 (fr) 2012-04-23 2013-10-31 Otsuka Pharmaceutical Co., Ltd. Dihydrate de composé de benzothiophène ou de sel de celui-ci, et son procédé de production
EP2868318A1 (fr) * 2012-04-23 2015-05-06 Otsuka Pharmaceutical Co., Limited Formulation injectable

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190010145A1 (en) * 2015-12-28 2019-01-10 Honour (R&D) Process for the preparation of quinolin-2(ih)-one derivatives
US10464931B2 (en) * 2015-12-28 2019-11-05 Honour (R&D) Process for the preparation of Quinolin-2(1H)-one derivatives
WO2017208251A1 (fr) * 2016-05-31 2017-12-07 Cipla Limited Nouvelle forme polymorphe stable de brexpiprazole et son procédé de préparation
CN107674067A (zh) * 2017-10-19 2018-02-09 上海博志研新药物技术有限公司 一种伊匹哌唑的纯化方法
CN111440158A (zh) * 2020-03-24 2020-07-24 石药集团中奇制药技术（石家庄）有限公司 一种盐酸依匹哌唑新晶型及其制备方法
US11229644B1 (en) * 2020-12-31 2022-01-25 Lake O'hara Llc Methods of treating psychiatric disorders in obese patients with brexpiprazole
US11951105B2 (en) 2020-12-31 2024-04-09 Lake O'hara Llc Methods of treating psychiatric disorders in obese patients with brexpiprazole

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