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WO2016131431A1 - Formes solides d'empagliflozine - Google Patents

Formes solides d'empagliflozine Download PDF

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Publication number
WO2016131431A1
WO2016131431A1 PCT/CZ2016/000020 CZ2016000020W WO2016131431A1 WO 2016131431 A1 WO2016131431 A1 WO 2016131431A1 CZ 2016000020 W CZ2016000020 W CZ 2016000020W WO 2016131431 A1 WO2016131431 A1 WO 2016131431A1
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WO
WIPO (PCT)
Prior art keywords
empagliflozin
proline
complex
mixture
crystalline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CZ2016/000020
Other languages
English (en)
Inventor
Iva OBADALOVA
Lukas KREJCIK
Ondrej Dammer
Jaroslava SVOBODOVA
Marcela Tkadlecova
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of WO2016131431A1 publication Critical patent/WO2016131431A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to novel solid forms of empagliflozin of formula I, with the systematic name ( S ⁇ R ⁇ R ⁇ S ⁇ Ri-l- ⁇ -chloro-S-t ⁇ -tCSSi-oxolan-S-y ⁇ oxyphenyllmethyllphenyl] ⁇ - (hydroxy-methy oxane-S ⁇ -triol
  • Described is an amorphous or crystalline complex of empagliflozin with proline, a method of its preparation and use for the manufacture of a dosage form.
  • the crystalline complex of empagliflozin with proline can be advantageously used to increase the purity of empagliflozin and its stabilization in terms of chemical and polymorphic purity.
  • the invention further relates to an amorphous form of empagliflozin and a method of its preparation.
  • Empagliflozin is a new oral antidiabetic, designed for the treatment of type 2 diabetes mellitus.
  • the mechanism of its action consists in inhibition of the sodium glucose cotransporter (SGLT2), which results in glycosuria and decrease of glycaemia.
  • SGLT2 sodium glucose cotransporter
  • administration of empagliflozin led to a decrease of glycated haemoglobin both in monotherapy and in combination with metformin, sulfonylurea, pioglitazone and insulin, which means that empagliflozin represents an effective drug especially for combination treatment of diabetes.
  • empagliflozin is first mentioned in the patent application WO2005092877, which does not mention any details of the character of the solid form of the product.
  • a crystalline form of empagliflozin is first described in the patent application WO2006117359. This application also describes preparation methods of this crystalline form by crystallization from ethyl acetate, isopropanol or an ethanol-water mixture. Then, the same crystalline form of empagliilozin is prepared in the patent application WO2011039107 by crystallization from a mixture of at least two solvents. This only known crystalline form of empagliflozin so far is characterized by X-ray powder diffraction patterns and differential scanning calorimetry records.
  • the invention relates to an amorphous or crystalline complex of empagliflozin with proline, a method of its preparation and use for the manufacture of a dosage form.
  • the crystalline complex of empagliflozin with proline can be advantageously used to increase the purity of empagliflozin and its stabilization in terms of chemical and polymorphic purity.
  • the invention further relates to an amorphous form of empagliflozin and a method of its preparation. Detailed description of the invention
  • Empagliflozin very readily forms a complex with proline, which shows a high crystallization tendency and is stable. During its crystallization, the chemical purity of the product is considerably increased. Proline binds to empagliflozin in the molar ratio of proline to empagliflozin of 4:1 to 1:4, preferably 2:1 to 1:2, but ideally in the molar ratio of 1:1. The complex of empagliflozin with proline tends to be formed in many solvents.
  • the complex is formed both by a reaction in a solution and by stirring in a suspension.
  • CI to C8 hydrocarbons aliphatic and aromatic
  • CI to C4 alcohols CI to C8 ketones
  • CI to C4 nitriles CI to C8 esters
  • CI to C6 ethers acyclic or cyclic
  • Methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, butyl acetate, toluene or their mixtures can be advantageously used.
  • the benefit of using this complex consists in the possibility to increase the chemical purity during crystallization and possible re-crystallizations.
  • Preparation of the complex of empagliflozin with proline in accordance with variant A comprises the following steps: a/ dissolution and/or dispersion of a mixture of empagliflozin and proline in a solvent or mixture of solvents;
  • Preparation of the complex of empagliflozin with proline in accordance with variant B comprises the following steps: a/ dissolution and/or dispersion of empagliflozin in a solvent or a mixture of solvents; b/ addition of proline in the solid form or in the form of a solution;
  • the dissolution or dispersion according to the preparation variants A and B may be carried out in an organic solvent selected from CI to C8 hydrocarbons (aliphatic or aromatic), CI to C4 alcohols, CI to C8 esters, CI to C8 ketones, CI to C6 ethers (acyclic or cyclic), CI to C4 nitriles or their mixtures in the range from 20°C to the boiling point of the solvent or solvents.
  • an organic solvent selected from CI to C8 hydrocarbons (aliphatic or aromatic), CI to C4 alcohols, CI to C8 esters, CI to C8 ketones, CI to C6 ethers (acyclic or cyclic), CI to C4 nitriles or their mixtures in the range from 20°C to the boiling point of the solvent or solvents.
  • the mixture is usually cooled down, preferably to the range of -20°C to 30°C, and left to crystallize.
  • the complex can be isolated either directly by filtration, or concentration of the mixture, or evaporation of the solvents may follow.
  • the result is an amorphous complex of empagliflozin with proline.
  • Preparation of the complex of empagliflozin with proline according to variant C is directly carried out during the formulation process, e.g. during wet granulation. Then, besides empagliflozin itself and excipients, proline is also placed into a homogenizer in the respective equivalent proportion. The complex of empagliflozin and proline is then formed directly during the wet granulation.
  • the complex of empagliflozin and proline is generally produced in an at least 80% yield, usually 90% yield, while the chemical purity, measured with HPLC, is not lower than that of the input empagliflozin. On the contrary, what often happens is that the chemical purity of the complex is considerably higher than the purity of the input empagliflozin.
  • the complex of empagliflozin with proline can be advantageously used to purify crude empagliflozin.
  • Empagliflozin forms the complex with proline in the molar ratios of proline to empagliflozin of 4: 1 to 1 :4, preferably 2: 1 to 1 :2, most preferably 1:1.
  • the invention further provides amorphous empagliflozin.
  • Figure 5 shows the XRPD pattern of the amorphous form of empagliflozin prepared by lyophilization. The lyophilization took 20 hours and it was carried out from a mixture of ter/-butanol and water. The glass transition temperature was determined to be 47 to 48 °C.
  • Amorphous empagliflozin can also be prepared by spray drying of a solution of empagliflozin, or by evaporation in a vacuum evaporator, e.g. from the solvent dichloromethane.
  • Fig.2 XRPD pattern of the complex of empagliflozin with proline
  • Fig. 3 DSC record of the complex of empagliflozin with proline
  • Fig. 4 TGA record of the complex of empagliflozin with proline
  • Fig. 5 XRPD pattern of amorphous empagliflozin
  • the following ingredients were charged into a homogenizer: crystalline empagliflozin, L- proline, lactose monohydrate, microcrystalHne cellulose, hydroxypropyl cellulose, sodium crosscarmellose and water. The mixture was homogenized at 20 rpm for 60 min. Finally, magnesium stearate and Si0 2 was added and the mixture was homogenized at 20 rpm for another 10 min.
  • the tabletting matter produced in the above mentioned way was compressed in a rotary tabletting machine and used for the production of cores with the approximate weight of 200 mg.
  • the obtained cores may possibly be coated (a mixture of hypromellose, titanium oxide, iron oxide) .
  • the following ingredients were charged into a homogenizer: the complex of empagliflozin with L-proline, lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium crosscarmellose and water. The mixture was homogenized at 20 rpm for 15 min. Finally, magnesium stearate and Si0 2 was added and the mixture was homogenized at 20 rpm for another 3 min.
  • the tabletting matter produced in the above mentioned way was compressed in a rotary tabletting machine and used for the production of cores with the approximate weight of 200 mg.
  • the obtained cores may possibly be coated (a mixture of hypromellose, titanium oxide, iron oxide).
  • the nuclear magnetic resonance (NMR) spectra were measured using a Bruker Avance 500 device.
  • the 1H spectra were measured at the frequency of 500.13 MHz, I3 C at the frequency of 125.8 MHz.
  • the sample was measured in a deuterated solvent specified for the particular analysis, normally at 25°C (unless specified otherwise for a particular analysis).
  • the chemical shift ⁇ is expressed as ppm, the interaction constants J are specified in Hz.
  • the spectra were normally referenced to the residual solvent content.
  • Carbon spectra of solid-state nuclear magnetic resonance (ssNMR) were measured with the use of an Avance 400 WB Bruker device, using the CP/MAS method in a 4mm rotor at the speed of 13 kHz, normally at 25°C.
  • the records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device made by the company Perkin Elmer.
  • the sample charge in a standard Al pot (40 ⁇ ,) was between 3-4 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of 1 min stabilization at the temperature of 20°C and then of heating up to 250°C at the heating rate of 10 °C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of 20 ml/min.
  • the records of the thermogravimetric analysis (TGA) were measured using a TGA 6 device made by the company Perkin Elmer.
  • the sample charge in a corundum pot was 14.5 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of 1 minute's stabilization at the temperature of 20°C and then of heating up to 250°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne de nouvelles formes solides d'empagliflozine de formule I, connue sous le nom systématique de (2S,3R54R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphényl]méthyl]phényl]-6-(hydroxyméthyl)oxane-3,4,5-triol. Elle concerne un complexe amorphe ou cristallin d'empagliflozine avec la proline, un procédé pour sa préparation et son utilisation pour la production d'une forme pharmaceutique. Le complexe cristallin d'empagliflozine avec la proline peut être avantageusement utilisé pour accroître la pureté de l'empagliflozine et sa stabilisation en termes de pureté chimique et polymorphe. Une forme amorphe d'empagliflozine et un procédé pour sa préparation sont en outre décrits.
PCT/CZ2016/000020 2015-02-18 2016-02-15 Formes solides d'empagliflozine Ceased WO2016131431A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2015-110 2015-02-18
CZ2015-110A CZ2015110A3 (cs) 2015-02-18 2015-02-18 Pevné formy empagliflozinu

Publications (1)

Publication Number Publication Date
WO2016131431A1 true WO2016131431A1 (fr) 2016-08-25

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WO (1) WO2016131431A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017141202A1 (fr) 2016-02-17 2017-08-24 Lupin Limited Complexe d'inhibiteur sglt2 et son procédé de préparation
US20190202814A1 (en) * 2015-11-09 2019-07-04 Cadila Healthcare Limited Processes for preparation of empagliflozin
RU2713428C1 (ru) * 2018-04-18 2020-02-05 Зентива, К.С. Частицы, содержащие аморфный эмпаглифлозин, способ их получения и содержащий их лекарственный препарат
CN112062757A (zh) * 2020-09-23 2020-12-11 天津大学 一种恩格列净-烟酰胺共晶及其制备方法
KR102218323B1 (ko) * 2020-09-09 2021-02-22 유니셀랩 주식회사 효율적이고 상전이가 되지 않는 엠파글리플로진 무정형의 제조방법
WO2022124749A1 (fr) * 2020-12-08 2022-06-16 Chong Kun Dang Pharmaceutical Corp. Composition pharmaceutique comprenant un co-cristal d'empagliflozine
WO2024062310A1 (fr) * 2022-09-22 2024-03-28 Savoi Guilherme Co-cristaux dérivés de l'empagliflozine et de la dapagliflozine avec de la l-proline
KR20250007816A (ko) 2023-07-06 2025-01-14 주식회사 경보제약 엠파글리플로진 ２ｌ­프롤린의 신규 결정형 및 이의 제조방법

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092877A1 (fr) 2004-03-16 2005-10-06 Boehringer Ingelheim International Gmbh Derives du benzol substitues par un glucopyranosyle,, medicaments renfermant ces composes, leur utilisation et leur procede de production
WO2006117359A1 (fr) 2005-05-03 2006-11-09 Boehringer Ingelheim International Gmbh FORME CRISTALLINE DE 1-CHLORO-4-(ß-D-GLUCOPYRANOS-1-YL)-2-[4-((S)-TETRAHYDROFURAN-3-YLOXY)-BENZYL]-BENZENE, SON PROCEDE DE PREPARATION ET SON UTILISATION DANS LA PREPARATION DE MEDICAMENTS
WO2008002824A1 (fr) * 2006-06-28 2008-01-03 Bristol-Myers Squibb Company Solvates cristallins et complexes de dérivés de (is)-1,5-anhydro-l-c-{3-[(phényl)méthyl]phényl}-d-glucitol avec des acides aminés en tant qu'inhibiteurs de sglt2 pour le traitement du diabète
WO2011039107A1 (fr) 2009-09-30 2011-04-07 Boehringer Ingelheim International Gmbh Procédé de préparation d'une forme cristalline de 1-chloro-4-(β-d-glucopyranos-1-yl)-2-[4-((s)-tétrahydrofuran-3-yloxy)-benzyl]-benzène
US20140031540A1 (en) * 2012-07-26 2014-01-30 Boehringer Ingelheim Vetmedica Gmbh Crystalline complex of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(ss- d-glucopyranos-1-yl)-benzene, methods for its preparation and the use thereof for preparing medicaments
WO2014101865A1 (fr) * 2012-12-31 2014-07-03 上海璎黎科技有限公司 Composition de dérivé de glucose et de proline, cristal, procédé de préparation et application

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092877A1 (fr) 2004-03-16 2005-10-06 Boehringer Ingelheim International Gmbh Derives du benzol substitues par un glucopyranosyle,, medicaments renfermant ces composes, leur utilisation et leur procede de production
WO2006117359A1 (fr) 2005-05-03 2006-11-09 Boehringer Ingelheim International Gmbh FORME CRISTALLINE DE 1-CHLORO-4-(ß-D-GLUCOPYRANOS-1-YL)-2-[4-((S)-TETRAHYDROFURAN-3-YLOXY)-BENZYL]-BENZENE, SON PROCEDE DE PREPARATION ET SON UTILISATION DANS LA PREPARATION DE MEDICAMENTS
WO2008002824A1 (fr) * 2006-06-28 2008-01-03 Bristol-Myers Squibb Company Solvates cristallins et complexes de dérivés de (is)-1,5-anhydro-l-c-{3-[(phényl)méthyl]phényl}-d-glucitol avec des acides aminés en tant qu'inhibiteurs de sglt2 pour le traitement du diabète
WO2011039107A1 (fr) 2009-09-30 2011-04-07 Boehringer Ingelheim International Gmbh Procédé de préparation d'une forme cristalline de 1-chloro-4-(β-d-glucopyranos-1-yl)-2-[4-((s)-tétrahydrofuran-3-yloxy)-benzyl]-benzène
US20140031540A1 (en) * 2012-07-26 2014-01-30 Boehringer Ingelheim Vetmedica Gmbh Crystalline complex of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(ss- d-glucopyranos-1-yl)-benzene, methods for its preparation and the use thereof for preparing medicaments
WO2014101865A1 (fr) * 2012-12-31 2014-07-03 上海璎黎科技有限公司 Composition de dérivé de glucose et de proline, cristal, procédé de préparation et application
EP2940026A1 (fr) * 2012-12-31 2015-11-04 China Gateway Pharmaceuticals Development Co., Ltd Composition de dérivé de glucose et de proline, cristal, procédé de préparation et application

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190202814A1 (en) * 2015-11-09 2019-07-04 Cadila Healthcare Limited Processes for preparation of empagliflozin
WO2017141202A1 (fr) 2016-02-17 2017-08-24 Lupin Limited Complexe d'inhibiteur sglt2 et son procédé de préparation
RU2713428C1 (ru) * 2018-04-18 2020-02-05 Зентива, К.С. Частицы, содержащие аморфный эмпаглифлозин, способ их получения и содержащий их лекарственный препарат
KR102218323B1 (ko) * 2020-09-09 2021-02-22 유니셀랩 주식회사 효율적이고 상전이가 되지 않는 엠파글리플로진 무정형의 제조방법
CN112062757A (zh) * 2020-09-23 2020-12-11 天津大学 一种恩格列净-烟酰胺共晶及其制备方法
WO2022124749A1 (fr) * 2020-12-08 2022-06-16 Chong Kun Dang Pharmaceutical Corp. Composition pharmaceutique comprenant un co-cristal d'empagliflozine
CN116648263A (zh) * 2020-12-08 2023-08-25 株式会社钟根堂 包含恩格列净共晶的药物组合物
JP2023552817A (ja) * 2020-12-08 2023-12-19 チョン クン ダン ファーマシューティカル コーポレーション エンパグリフロジン共結晶を含有する医薬組成物
JP7614354B2 (ja) 2020-12-08 2025-01-15 チョン クン ダン ファーマシューティカル コーポレーション エンパグリフロジン共結晶を含有する医薬組成物
WO2024062310A1 (fr) * 2022-09-22 2024-03-28 Savoi Guilherme Co-cristaux dérivés de l'empagliflozine et de la dapagliflozine avec de la l-proline
KR20250007816A (ko) 2023-07-06 2025-01-14 주식회사 경보제약 엠파글리플로진 ２ｌ­프롤린의 신규 결정형 및 이의 제조방법

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