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WO2020165807A1 - Formes solides de deutétrabénazine et leur procédé de préparation - Google Patents

Formes solides de deutétrabénazine et leur procédé de préparation Download PDF

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Publication number
WO2020165807A1
WO2020165807A1 PCT/IB2020/051164 IB2020051164W WO2020165807A1 WO 2020165807 A1 WO2020165807 A1 WO 2020165807A1 IB 2020051164 W IB2020051164 W IB 2020051164W WO 2020165807 A1 WO2020165807 A1 WO 2020165807A1
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WO
WIPO (PCT)
Prior art keywords
deutetrabenazine
vanillin
crystal
solvent
preparation
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/IB2020/051164
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English (en)
Inventor
Shanmukha Prasad Gopi
Jayprakash Amarpal YADAV
Satyanarayana THIRUNAHARI
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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 Dr Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Publication of WO2020165807A1 publication Critical patent/WO2020165807A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C07C47/58—Vanillin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

  • aspects of the present application provides co-crystals of Deutetrabenazine and Vanillin, process for the preparation of co-crystals and pharmaceutical composition comprising said co-crystals of Deutetrabenazine.
  • Deutetrabenazine or d 6 -tetrabenazine is a deuterated analog of tetrabenazine.
  • the drug compound having the adopted name “Deutetrabenazine” has chemical name: (RR, SS)-1, 3, 4, 6, 7, 1 lb-hexahydro- 9, 10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.
  • Deutetrabenazine is a racemic mixture containing the following structures:
  • AUSTEDOTM (Deutetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor for oral administration.
  • AUSTEDOTM was approved as oral tablets (6 mg, 9 mg, and 12 mg) by USFDA on 3 April 2017 for the treatment of chorea associated with Huntington’s disease. In August 2017 it was also approved for the treatment of tardive dyskinesia in adults.
  • US8524733B 1 discloses Deutetrabenazine or a pharmaceutically acceptable salt thereof, method for the treatment of chronic hyperkinetic movement disorders and pharmaceutical composition thereof.
  • US9550780B2 discloses crystalline Form I and crystalline Form II of Deutetrabenazine .
  • WO2017221169A1 discloses premixes of deutetrabenazine with polyvinylpyrrolidone K-30, copovidone, talc and magnesium stearate.
  • WO2019166962 A1 discloses crystalline Form Ml of Deutetrabenzine.
  • US 20190343815A1 disclose Deutetrabenazine Form APO-I, a co-crystal of Deutetrabenazine and quercetin, and Deutetrabenazine Form APO-II, a co crystal of Deutetrabenazine and luteolin.
  • polymorphism The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties, such as PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, and solubilities.
  • Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same structure.
  • the present application provides co-crystal of Deutetrabenazine and Vanillin, process of preparing said co-crystal and pharmaceutical composition comprising said co-crystal and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is in the form of a solid dosage form.
  • the pharmaceutical composition is a tablet.
  • Figure 1 illustrates a characteristic PXRD pattern of co-crystal of Deutetrabenazine and Vanillin obtained from example 1.
  • Figure 2 illustrates a comparative PXRD pattern of co-crystal of Deutetrabenazine and Vanillin and simulated PXRD pattern obtained from single crystal data.
  • Figure 3 illustrates a single Crystal structure of co-crystal of Deutetrabenazine and Vanillin.
  • Figure 4 illustrates a characteristic DSC thermogram of co-crystal of Deutetrabenazine and Vanillin.
  • Figure 5 illustrates a characteristic TGA thermogram of co-crystal of Deutetrabenazine and Vanillin.
  • Figure 6 illustrates a characteristic PXRD pattern of co-crystal of Deutetrabenazine and Vanillin obtained from example 2.
  • the co-crystal of Deutetrabenazine and Vanillin characterized by a PXRD pattern having X-ray powder diffraction peaks selected from the following at about 8.34°, 9.45°, 14.08° and 15.85° ⁇ 0.2°2Q is designated as Form DV 1.
  • the application provides co-crystal of Deutetrabenazine and Vanillin, characterized by an X-ray powder diffraction pattern as illustrated in Figure 1.
  • the present application provides process for the preparation of co-crystal of Deutetrabenazine and Vanillin by dissolving Deutetrabenazine and Vanillin in a suitable solvent and cooling the obtained solution.
  • any suitable solvent can be used for preparing solution.
  • the suitable solvents can be selected from ketones, alcohols, esters, nitriles, or their mixtures.
  • the solution of Deutetrabenazine and Vanillin may be obtained by heating and stirring at suitable temperature. In embodiments the solution of Deutetrabenazine and Vanillin may be filtered to get particle free solution. In embodiments the seed of co-crystals of Deutetrabenazine and Vanillin may also be used for preparing product. The solution may be cooled to get precipitation at a temperature about -10 to 30°C, preferably about 0 to 25°C. The precipitated product may be isolated by filtration and dried at suitable temperature.
  • the present application provides process for the preparation of co-crystal of Deutetrabenazine and Vanillin, comprising the steps of; taking Deutetrabenazine and Vanillin into ball-milling capsule, adding acetonitrile in to it and grinding to obtain the Vanillin co-crystal of Deutetrabenazine .
  • the present application provides process for the preparation of co-crystal of Deutetrabenazine and Vanillin comprising;
  • step (a) adding the anti-solvent to the solution obtained in step (a);
  • any suitable solvent can be used for preparing solution.
  • the suitable solvents can be selected from ketones, alcohols, esters, nitriles, or their mixtures.
  • anti- solvent is added to solution obtained in step a).
  • the anti-solvent can be a solvent in which Deutetrabenazine is insoluble or having very poor solubility.
  • the anti-solvent can be selected from ethers, alkanes, cycloalkanes or mixtures thereof.
  • the anti- solvent can be a mixture of Methyl t-butyl ether and n- Heptane. In embodiments both anti- solvents can be added together or simultaneously.
  • Methyl t-butyl ether was added to the solution of step a) followed by addition of n-Heptane.
  • the ratio of solvent to anti-solvents can be in the range of 1:5 to 1:100 or preferably 1:5 to 1: 50 or any suitable combination.
  • the ratio of anti- solvents Methyl t-butyl ether and n-Heptane can be in the range of 1:1 to 1:10 or any suitable combination.
  • the seed of co-crystals of Deutetrabenazine and Vanillin may also be used for preparing product.
  • co-crystals of Deutetrabenazine and Vanillin according to the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce desired particle sizes and particle size distributions.
  • Single crystal X-ray structure of Deutetrabenazine and Vanillin reveals that the asymmetric unit consists of one molecule of Deutetrabenazine and one molecule of Vanillin. It is a 1:1 stoichiometric anhydrous co-crystal.
  • the single crystal structure of co-crystal of Deutetrabenazine and Vanillin is illustrated in Figure-3.
  • the co-crystals of Deutetrabenazine and Vanillin has a differential scanning calorimetric thermogram (DSC) substantially as shown in Figure. 4, which exhibits an endothermic peak at about 101.16°C.
  • DSC differential scanning calorimetric thermogram
  • the co-crystals of Deutetrabenazine and Vanillin has a thermal gravimetric analysis thermogram substantially as shown in Figure. 5.
  • the co-crystals of Deutetrabenazine and Vanillin is non-hygroscopic, chemically and physically stable and suitable for pharmaceutical formulation.
  • the following table provides the stability data of co-crystals of Deutetrabenazine and Vanillin.
  • Vanillin used in the present application is an organic compound with the molecular formula CsHsC and represented by the chemical structure;
  • Deutetrabenazine may be prepared by the processes described in US8524733B 1, US9550780B2, WO2015084622A1, WO2011153157A2 and WO2017182916A1.
  • the present application provides a pharmaceutical composition comprising the co-crystals of Deutetrabenazine and Vanillin as described in the present application together with at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is a solid dosage form suitable for oral administration, such as a capsule, tablet, pill, powder or granulate.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition provides a dose of Deutetrabenazine that is equivalent to the 6 mg, 9 mg or 12 mg of Deutetrabenazine found in AUSTEDO® drug products.
  • Suitable pharmaceutically acceptable excipients are preferably inert with respect to the co-crystal of Deutetrabenazine and Vanillin of the present invention, and may include, for example, one or more excipients selected from binders such as lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydro xypropyl methylcellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatine, polyvinylpyrollidone (PVP) and sodium alginate; fillers or diluents such as lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose), calcium sulphate, xylitol and lacti
  • excipients including preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherents or glidants may be added as required.
  • suitable excipients and the preparation of solid oral dosage forms is well known to person of skill in the art, and is described generally, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 45).
  • the solid dosage forms may be prepared with coatings, such as enteric coatings and extended release coatings, using standard pharmaceutical coatings.
  • coatings such as enteric coatings and extended release coatings, using standard pharmaceutical coatings.
  • Such coatings, and their application are well known to persons skilled in the art, and are described, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 47).
  • Heating rate 10° C per minute.
  • Heating rate 10° C. per minute.
  • Purge gas nitrogen.
  • Example-1 Preparation of co-crystal of Deutetrabenazine and Vanillin
  • Deutetrabenazine (1.616 g), Vanillin (0.760) and ethylformate (8 mL) were taken into taken into EasyMax reactor and stirred at 50°C to get clear solution.
  • the clear solution was cooled to 35°C and seed material (100 mg) was added.
  • the obtained suspension was stirred for 2 h at 25°C.
  • the precipitated product was filtered to obtain the co-crystal of Deutetrabenazine and Vanillin.
  • Deutetrabenazine (300 mg) and Vanillin (141 mg) were taken into ball- milling capsule and added 1 ml of Acetonitrile and kept for grinding with 25 RPM for 1 h to obtain the co-crystal of Deutetrabenazine and Vanillin.
  • the PXRD pattern of the isolated material is represented as Figure-6.
  • Deutetrabenazine (970 mg), Vanillin (456 mg) and acetonitrile (6 mL) were taken into EasyMax reactor and stirred for 1 h at 50°C to clear get solution. The temperature was reduced to 40°C and seed material was added to the solution. The solution was gradually cooled to 25°C. The precipitated product was filtered to obtain the co-crystal of Deutetrabenazine and Vanillin.
  • Deutetrabenazine (323 mg), Vanillin (152 mg) and acetonitrile (3 mL) were taken into EasyMax reactor and stirred for 20 min at 45°C to get clear solution. The solution was filtered to get particle free solution. Methyl t-butyl ether (10 mL) and n-Heptane (15 mL) were added to the clear solution under stirring. The solution was kept overnight for evaporation of solvent. The title product was obtained by filtration.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des co-cristaux de deutétrabénazine et de vanilline, un procédé de préparation de co-cristaux et une composition pharmaceutique comprenant lesdits co-cristaux de deutétrabénazine. Les co-cristaux de deutétrabénazine et de vanilline sont non hygroscopiques, chimiquement et physiquement stables et appropriés pour une formulation pharmaceutique et leur utilisation dans le traitement de la dyskinésie tardive et de la chorée associée à la maladie de Huntington.
PCT/IB2020/051164 2019-02-14 2020-02-13 Formes solides de deutétrabénazine et leur procédé de préparation Ceased WO2020165807A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN201941005900 2019-02-14
IN201941005900 2019-02-14
IN201941011996 2019-03-27
IN201941011996 2019-03-27

Publications (1)

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WO2020165807A1 true WO2020165807A1 (fr) 2020-08-20

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180263972A1 (en) * 2017-03-15 2018-09-20 Auspex Pharmaceuticals, Inc. Analogs of deutetrabenazine, their preparation and use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180263972A1 (en) * 2017-03-15 2018-09-20 Auspex Pharmaceuticals, Inc. Analogs of deutetrabenazine, their preparation and use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FRANCOISE M. AMOMBO NOA ET AL.: "Co-crystals and salts of vanillic acid and vanillin with amines", CRYSTENGCOMM, vol. 20, no. 7, 8 January 2018 (2018-01-08), pages 896 - 905, XP055732880 *
LINDA LANGE ET AL.: "Predicting the Solubility of Pharmaceutical Cocrystals in Solvent/Anti-Solvent Mixtures", MOLECULES, vol. 21, no. 5, 7 May 2016 (2016-05-07), pages 1 - 18, XP055732884 *

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