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WO2023187762A1 - Co-cristaux de bromhydrate de vortioxétine - Google Patents

Co-cristaux de bromhydrate de vortioxétine Download PDF

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Publication number
WO2023187762A1
WO2023187762A1 PCT/IB2023/053299 IB2023053299W WO2023187762A1 WO 2023187762 A1 WO2023187762 A1 WO 2023187762A1 IB 2023053299 W IB2023053299 W IB 2023053299W WO 2023187762 A1 WO2023187762 A1 WO 2023187762A1
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Prior art keywords
vortioxetine hydrobromide
crystal form
resveratrol
powder
crystals
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Inventor
Venkateswara Rao Nandepu
Hardev Nandepu
Narender Rao SOMISETTI
Venkata krishna Reddy BIJJULA
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Metrochem Api Pvt Ltd
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Metrochem Api Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins

Definitions

  • the present invention relates to co-crystals of Vortioxetine hydrobromide, process for its preparation and pharmaceutical composition comprising the same.
  • Vortioxetine is a novel antidepressant jointly developed by Takeda Pharmaceuticals and H. Lundbeck A S, and used for the treatment of major depressive disorder.
  • the drug is approved in the form of hydrobromide salt and marketed under the trade name Brintellix and Trintellix.
  • Vortioxetine hydrobromide is chemically known as of l-[2-(2,4-dimethyl- phenylsulfanylj-phenyl] piperazine hydrobromide and represented by the following structural formula I.
  • Vortioxetine and process for its preparation of was first disclosed in W02003/029232A1.
  • the international publication W02007/144005 Al discloses crystalline Vortioxetine base and crystalline forms of Vortioxetine hydrobromide including a Form, 0 Form, y Form, a hemihydrate, and an ethyl acetate solvate.
  • the drug solubilizes in the gastrointestinal fluid but also that it remains solubilized until it gets absorbed into the bloodstream. If the drug precipitates before getting absorbed, it probably gets excreted unchanged and its effect is diminished.
  • Co-crystals are combinations of two or more distinct molecules arranged to create a unique crystal form. Co-crystals include two or more different components and often rely on hydrogen bonded assemblies between neutral molecules. Cocrystals with the same active pharmaceutical ingredient will have strikingly different pharmaceutical properties like melting point, solubility, dissolution, moisture uptake, chemical stability etc. depending on the nature of the second component.
  • Vortioxetine hydrobromide is one of the important pharmaceutical products available in the market useful for the treatment of major depressive disorder.
  • the discovery of new cocrystal form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product such as Vortioxetine hydrobromide.
  • the main object of the present invention is to provide novel cocrystals of Vortioxetine hydrobromide.
  • the present invention provides novel co-crystals of Vortioxetine hydrobromide with a suitable co-former, process for its preparation and pharmaceutical compositions comprising the same.
  • the novel co-crystals of Vortioxetine hydrobromide of the present invention may have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and a suitable co-former.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and a co-former; wherein the co-former is selected from resveratrol, piceatannol, quercetin, catechin, epicatechin, epigallocatechin gallate, epicatechin gallate, genistein, ferulic acid, caffeic acid, 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and salicylic acid.
  • the co-former is selected from resveratrol, piceatannol, quercetin, catechin, epicatechin, epigallocatechin gallate, epicatechin gallate, genistein, ferulic acid, caffeic acid, 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and salicylic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and a co-former in crystalline form.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and resveratrol.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and resveratrol characterized by powder X-ray diffractogram as shown in Figure 1, herein designated as Form M3.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and resveratrol characterized by powder X-ray diffractogram as shown in Figure 4, herein designated as Form M4.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and piceatannol.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and piceatannol characterized by powder X-ray diffractogram as shown in Figure 2; herein designated as Form Ml.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and piceatannol characterized by powder X-ray diffractogram as shown in Figure 3; herein designated as Form M2.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and 4-amino benzoic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and 4-amino benzoic acid characterized by powder X-ray diffractogram as shown in Figure 5, herein designated as Form M5.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and 4-hydroxy benzoic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and 4-hydroxy benzoic acid characterized by powder X-ray diffractogram as shown in Figure 6, herein designated as Form M6.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and gallic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and gallic acid characterized by powder X-ray diffractogram as shown in Figure 7, herein designated as Form M7.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and protocatechuic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and protocatechuic acid characterized by powder X-ray diffractogram as shown in Figure 8, herein designated as Form M8.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and salicylic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and salicylic acid characterized by powder X-ray diffractogram as shown in Figure 9, herein designated as Form M9.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide, which comprises dissolving or suspending a coformer in a suitable solvent; mixing Vortioxetine hydrobromide with the obtained solution or suspension; or vice versa; stirring the suspension or solution for sufficient period of time and isolating the co-crystals of Vortioxetine hydrobromide.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide, which comprises grinding a co-former and Vortioxetine hydrobromide with or without additional solvent; followed by dissolving the grinded material in a suitable solvent and kept for solvent evaporation to obtain the cocrystals of Vortioxetine hydrobromide.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M3, which comprises grinding resveratrol and Vortioxetine hydrobromide in the presence of a suitable solvent; dissolving the grinded material in a suitable solvent; and kept for solvent evaporation to obtain the Vortioxetine hydrobromide and resveratrol co-crystal Form M3.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M3, which comprises dissolving resveratrol in a suitable solvent; adding Vortioxetine hydrobromide to the obtained solution; optionally seeding with Form M3 material; filtering the solid obtained; and adding water to the obtained solid and isolating Vortioxetine hydrobromide and resveratrol co-crystal Form M3.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M4, which comprises dissolving Vortioxetine hydrobromide and resveratrol in a suitable solvent; and subjecting the obtained solution to slow solvent evaporation to obtain the Vortioxetine hydrobromide and resveratrol co-crystal Form M4.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and piceatannol co-crystal form Ml, which comprises dissolving piceatannol in a suitable solvent; adding Vortioxetine hydrobromide to the obtained solution; sonicating and stirring the obtained suspension for sufficient period of time to obtain Vortioxetine hydrobromide and piceatannol co-crystal form Ml.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and piceatannol co-crystal form M2, which comprises grinding piceatannol and Vortioxetine hydrobromide with or without additional solvent; dissolving the grinded material in a suitable solvent and kept for solvent evaporation to obtain Vortioxetine hydrobromide and piceatannol co-crystal form M2.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide, which comprises dissolving Vortioxetine hydrobromide and a co-former in a suitable solvent; cooling the obtained solution and isolating the corresponding co-crystals of Vortioxetine hydrobromide and a co-former; wherein the co-former is selected from 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and/or salicylic acid.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide, which comprises, a) dissolving Vortioxetine hydrobromide in a suitable solvent, b) mixing a co-former with the obtained solution; or vice versa, wherein the co-former is selected from 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and/or salicylic acid, c) adding water to the obtained suspension; and d) isolating the co-crystals of Vortioxetine hydrobromide.
  • the present invention provides a pharmaceutical composition comprising Vortioxetine hydrobromide co-crystals of the present invention and at least one pharmaceutically acceptable excipient.
  • Fig. 1 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and resveratrol co-crystal Form M3.
  • Fig. 2 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and piceatannol co-crystal Form Ml.
  • Fig. 3 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and piceatannol co-crystal Form M2.
  • Fig. 4 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and resveratrol co-crystal Form M4.
  • Fig. 5 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and 4- amino benzoic acid co-crystal Form M5.
  • Fig. 6 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and 4- hydroxy benzoic acid co-crystal Form M6.
  • Fig. 7 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and gallic acid co-crystal Form M7.
  • Fig. 8 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and protocatechuic acid co-crystal Form M8.
  • Fig. 9 illustrates an X-ray powder diffraction pattern of Vortioxetine hydrobromide and salicylic acid co-crystal Form M9.
  • PXRD Powder X-ray diffraction
  • DSC data in the present disclosure were recorded on a Perkin Elmer (Model-DSC 4000) at a heating rate of 20°C/min in the temperature range of from 25°C to 300°C.
  • Thermo gravimetric analysis (TGA) data in the present disclosure were recorded on a Perkin Elmer (TGA-4000) at a heating rate of 20°C/min in the temperature range of from 25°C to 300°C.
  • TGA-4000 Perkin Elmer
  • the present invention provides novel co-crystals of Vortioxetine hydrobromide with a suitable co-former, process for its preparation and pharmaceutical compositions comprising the same.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and a suitable co-former.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and a co-former; wherein the co-former is selected from resveratrol, piceatannol, quercetin, catechin, epicatechin, epigallocatechin gallate, epicatechin gallate, genistein, ferulic acid, caffeic acid, 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and salicylic acid.
  • the co-former is selected from resveratrol, piceatannol, quercetin, catechin, epicatechin, epigallocatechin gallate, epicatechin gallate, genistein, ferulic acid, caffeic acid, 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and salicylic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and a suitable co-former in crystalline form.
  • the co-crystals of Vortioxetine hydrobromide of the present invention are characterized by X-ray powder diffraction ("XRPD”) patterns, differential scanning calorimetry ("DSC”) curves, infrared (“IR”) absorption spectra, and H 1 NMR spectra.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • IR infrared
  • H 1 NMR spectra H 1 NMR spectra.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and resveratrol.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and resveratrol characterized by powder X-ray diffractogram as shown in Figure 1, herein designated as Form M3.
  • the present invention provides Vortioxetine hydrobromide and resveratrol co-crystal Form M3, characterized by its powder X-ray diffraction having one or more peaks at about 5.9, 8.2, 8.8, 11.3, 11.9, 14.2, 14.7, 14.9, 16.1, 16.6, 17.3, 17.7, 18.1, 19.0, 19.2, 21.4, 21.9, 23.3, 24.3, 24.6, 25.7, 26.3, 26.9, 29.1, 29.7, 32.8, 33.3 ⁇ 0.2° 20.
  • the co-crystal Form M3 of the present invention is characterized by DSC thermogram showing endothermic peak at about 217.9 ⁇ 3°C and/or by TGA showing weight loss of 0.767% from 30°C to 105°C.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and resveratrol characterized by powder X-ray diffractogram as shown in Figure 4, herein designated as Form M4.
  • the present invention provides Vortioxetine hydrobromide and resveratrol co-crystal Form M4, characterized by its powder X-ray diffraction having one or more peaks at about 4.3, 5.8, 11.9, 12.3, 13.2, 14.1, 15.3, 16.4, 16.8, 17.6, 18.8, 19.7,
  • the co-crystal Form M4 of the present invention is characterized by DSC thermogram showing endothermic peak at about 207.2 ⁇ 3°C and 214.3 ⁇ 3°C and/or by TGA showing weight loss of 2.013% from 25°C to 105°C.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and piceatannol.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and piceatannol characterized by powder X-ray diffractogram as shown in Figure 2; herein designated as Form Ml.
  • the present invention provides Vortioxetine hydrobromide and piceatannol co-crystal Form Ml characterized by its powder X-ray diffraction having one or more peaks at about 5.8, 8.3, 8.8, 11.3, 11.8, 14.2, 14.9, 16.2, 17.5, 17.7, 18.4, 19.0,
  • the present invention provides co-crystals of Vortioxetine hydrobromide and piceatannol characterized by powder X-ray diffractogram as shown in Figure 3; herein designated as Form M2.
  • the present invention provides Vortioxetine hydrobromide and piceatannol co-crystal Form M2 characterized by its powder X-ray diffraction having one or more peaks at about 4.3, 5.9, 8.6, 11.9, 12.3, 13.2, 14.2, 15.2, 16.4, 16.8, 17.7, 18.8, 19.7, 20.9, 21.5, 21.8, 22.2, 22.8, 23.0, 25.0, 26.7, 28.7, 29.5, 29.7 ⁇ 0.2° 20.
  • the co-crystal Form M2 of the present invention is characterized by DSC thermogram showing endothermic peak at about 158.2 ⁇ 3°C and 215.3 ⁇ 3°C and/or by TGA showing weight loss of 1.802% from 32°C to 105°C.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and 4-amino benzoic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and 4-amino benzoic acid characterized by powder X-ray diffractogram as shown in Figure 5, herein designated as Form M5.
  • the present invention provides Vortioxetine hydrobromide and 4-amino benzoic acid co-crystal Form M5 characterized by its powder X-ray diffraction having one or more peaks at about 5.9, 8.9, 11.9, 16.2, 17.6, 19.1, 21.2, 23.1, 23.8, 28.9 ⁇ 0.2° 26.
  • the co-crystal Form M5 of the present invention is further characterized by TGA showing weight loss of 1.054% from 30°C to 105°C.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and 4-hydroxy benzoic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and 4-hydroxy benzoic acid characterized by powder X-ray diffractogram as shown in Figure 6, herein designated as Form M6.
  • the present invention provides Vortioxetine hydrobromide and 4-hydroxy benzoic acid co-crystal Form M6 characterized by its powder X-ray diffraction having one or more peaks at about 4.3, 8.7, 13.1, 16.3, 17.6, 22.1, 26.6, 29.3 ⁇ 0.2° 26.
  • the co-crystal Form M6 of the present invention is characterized by DSC thermogram showing endothermic peak at about 81.25°C ⁇ 3°C and 222.21°C ⁇ 3°C and/or by TGA showing weight loss of 0.574% from 30°C to 105°C.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and gallic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and gallic acid characterized by powder X-ray diffractogram as shown in Figure 7, herein designated as Form M7.
  • the present invention provides Vortioxetine hydrobromide and gallic acid co-crystal Form M7 characterized by its powder X-ray diffraction having one or more peaks at about 4.5, 13.4, 16.5, 17.8, 22.3, 25.2, 26.8 ⁇ 0.2° 26.
  • the co-crystal Form M7 of the present invention is further characterized by TGA showing weight loss of 0.383% from 30°C to 105°C.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and protocatechuic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and protocatechuic acid characterized by powder X-ray diffractogram as shown in Figure 8, herein designated as Form M8.
  • the present invention provides Vortioxetine hydrobromide and protocatechuic acid co-crystal Form M8 characterized by its powder X-ray diffraction having one or more peaks at about 4.4, 13.2, 16.4, 17.7, 22.1, 25.0, 26.6, 29.4 ⁇ 0.2° 26.
  • the co-crystal Form M8 of the present invention is characterized by DSC thermogram showing endothermic peak at about 222.60°C ⁇ 3°C and/or by TGA showing weight loss of 3.350% from 30°C to 105°C.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and salicylic acid.
  • the present invention provides co-crystals of Vortioxetine hydrobromide and salicylic acid characterized by powder X-ray diffractogram as shown in Figure 9, herein designated as Form M9.
  • the present invention provides Vortioxetine hydrobromide and salicylic acid co-crystal Form M9 characterized by its powder X-ray diffraction having one or more peaks at about 4.4, 13.3, 16.3, 17.7, 22.2, 26.8, 29.4 ⁇ 0.2° 26.
  • the co-crystal Form M9 of the present invention is further characterized by TGA showing weight loss of 0.788% from 30°C to 105°C.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide, which comprises, a) dissolving or suspending a co-former in a suitable solvent; b) mixing Vortioxetine hydrobromide with the obtained solution or suspension; or vice versa; c) stirring the suspension or solution for sufficient period of time; and d) isolating the co-crystals of Vortioxetine hydrobromide.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide, which comprises, a) grinding a co-former and Vortioxetine hydrobromide with or without additional solvent; b) dissolving the grinded material in a suitable solvent; and c) subjecting the obtained solution to slow solvent evaporation to obtain the co-crystals of Vortioxetine hydrobromide.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M3, which comprises a) grinding resveratrol and Vortioxetine hydrobromide in the presence of a suitable solvent; b) dissolving the grinded material in a suitable solvent; and c) subjecting the obtained solution to slow solvent evaporation to obtain the Vortioxetine hydrobromide and resveratrol co-crystal Form M3.
  • a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M3 comprises grinding resveratrol and Vortioxetine hydrobromide in the presence of a suitable alcoholic solvent such as methanol; dissolving the grinded material in a suitable alcoholic solvent such as methanol; and subjecting the obtained solution to slow solvent evaporation to obtain Vortioxetine hydrobromide and resveratrol co-crystal Form M3.
  • the obtained co-crystals of Vortioxetine hydrobromide and resveratrol Form M3 is a methanol solvate.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M3, which comprises a) dissolving resveratrol in a suitable solvent; b) adding Vortioxetine hydrobromide to the step a) solution; c) optionally seeding with Form M3 material; d) filtering the solid obtained; e) adding water to the obtained solid; and f) isolating Vortioxetine hydrobromide and resveratrol co-crystal Form M3.
  • the obtained co-crystals of Vortioxetine hydrobromide and resveratrol Form M3 is a non solvated form.
  • a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M3 comprises dissolving resveratrol in a suitable alcoholic solvent; adding Vortioxetine hydrobromide to the obtained solution; stirring the obtained suspension for a sufficient period of time; preferably for 15-30 mins at room temperature; seeding with Form M3 material and stirring the obtained suspension for sufficient period of time, preferably for 12 hours at room temperature; filtering the solid obtained; adding water to the obtained solid and slurrying for 7 hrs at room temperature; and isolating the Vortioxetine hydrobromide and resveratrol co-crystal Form M3 by filtration.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M4, which comprises a) dissolving vortioxetine hydrobromide and resveratrol in a suitable solvent; b) subjecting the obtained solution to slow solvent evaporation to obtain the Vortioxetine hydrobromide and resveratrol co-crystal Form M4.
  • a process for the preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M4 comprises dissolving Vortioxetine hydrobromide and resveratrol in a suitable alcoholic solvent such as ethanol at room temperature; and subjecting the obtained solution to slow solvent evaporation at room temperature to obtain the Vortioxetine hydrobromide and resveratrol co-crystal Form M4.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and piceatannol co-crystal form Ml, which comprises, a) dissolving piceatannol in a suitable solvent; b) adding Vortioxetine hydrobromide to the obtained solution; c) sonicating and stirring the obtained suspension for a sufficient period of time; and d) isolating the Vortioxetine hydrobromide and piceatannol co-crystal form Ml .
  • a process for the preparation of Vortioxetine hydrobromide and piceatannol co-crystal form Ml comprises dissolving piceatannol in a suitable alcohol solvent such as methanol; adding Vortioxetine hydrobromide to the obtained solution; sonicating and stirring the obtained suspension for sufficient period of time, preferably for 12 hrs at room temperature; and isolating the Vortioxetine hydrobromide and piceatannol co-crystal form Ml by filtration.
  • a suitable alcohol solvent such as methanol
  • the obtained co-crystals of Vortioxetine hydrobromide and piceatannol Form Ml is a methanol solvate.
  • the present invention provides a process for the preparation of Vortioxetine hydrobromide and piceatannol co-crystal form M2, which comprises a) grinding piceatannol and Vortioxetine hydrobromide with or without additional solvent; b) dissolving the grinded material in a suitable solvent, and c) subjecting the obtained solution to slow solvent evaporation to obtain Vortioxetine hydrobromide and piceatannol co-crystal form M2.
  • a process for the preparation of Vortioxetine hydrobromide and piceatannol co-crystal form M2 comprises grinding piceatannol and Vortioxetine hydrobromide in the presence of a suitable alcoholic solvent such as methanol; dissolving the grinded material in a suitable alcoholic solvent such as methanol; and subjecting the obtained solution to slow solvent evaporation to obtain Vortioxetine hydrobromide and piceatannol co-crystal form M2.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide, which comprises dissolving Vortioxetine hydrobromide and a co-former in a suitable solvent such as alcohols; cooling the obtained solution and isolating the corresponding co-crystals of Vortioxetine hydrobromide and a co-former; wherein the co-former is selected from 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and/or salicylic acid.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide, which comprises, a) dissolving Vortioxetine hydrobromide in a suitable solvent, b) mixing a co-former with the obtained solution; or vice versa, wherein the coformer is selected from 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and/or salicylic acid, c) adding water to the obtained suspension; and d) isolating the co-crystals of Vortioxetine hydrobromide.
  • step a) dissolution of Vortioxetine hydrobromide in a suitable solvent; such as alcoholic solvent in step a) is carried out at a suitable temperature from about 10°C to about 40°C, preferably at room temperature; the mixing of a co-former selected from 4-amino benzoic acid, 4- hydroxy benzoic acid, gallic acid, protocatechuic acid and salicylic acid, in step b) with the obtained solution, or vice versa; is carried out at room temperature; followed by stirring the obtained suspension for a sufficient period of time, preferably for 10 to 30 mins at room temperature; the addition of water in step c) is carried out at room temperature; then the isolation of co-crystals of Vortioxetine hydrobromide in step d) is carried out by cooling the obtained solution in ice bath for sufficient period of time, preferably for 30 mins to 1 hour, stirring followed by filtration of the precipitated
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide and 4-amino benzoic acid, which comprises, a) dissolving Vortioxetine hydrobromide in a suitable alcoholic solvent, b) mixing a 4-amino benzoic acid with the obtained solution; or vice versa, c) adding water to the obtained suspension; and d) isolating the Vortioxetine hydrobromide and 4-amino benzoic acid co-crystals.
  • the obtained co-crystals of Vortioxetine hydrobromide and a 4-amino benzoic acid is a methanol solvate.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide and 4-hydroxy benzoic acid, which comprises, a) dissolving Vortioxetine hydrobromide in a suitable solvent, b) mixing a 4-hydroxy benzoic acid with the obtained solution; or vice versa, c) adding water to the obtained suspension; and d) isolating the Vortioxetine hydrobromide and 4-hydroxy benzoic acid co-crystals.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide and gallic acid, which comprises, a) dissolving Vortioxetine hydrobromide in a suitable solvent, b) mixing a gallic acid with the obtained solution; or vice versa, c) adding water to the obtained suspension; and d) isolating the Vortioxetine hydrobromide and gallic acid co-crystals.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide and protocatechuic acid, which comprises, a) dissolving Vortioxetine hydrobromide in a suitable solvent, b) mixing a protocatechuic acid with the obtained solution; or vice versa, c) adding water to the obtained suspension; and d) isolating the Vortioxetine hydrobromide and protocatechuic acid co-crystals.
  • the present invention provides a process for the preparation of cocrystals of Vortioxetine hydrobromide and salicylic acid, which comprises, a) dissolving Vortioxetine hydrobromide in a suitable solvent, b) mixing a salicylic acid with the obtained solution; or vice versa, c) adding water to the obtained suspension; and d) isolating the Vortioxetine hydrobromide and salicylic acid co-crystals.
  • Vortioxetine co-crystal formation with co-former is carried out at room temperature and maintain for a sufficient period of time i.e., till complete formation of cocrystal. Further the isolation of vortioxetine co-crystals with 4-amino benzoic acid, 4-hydroxy benzoic acid, gallic acid, protocatechuic acid and/or salicylic acid is carried out by cooling the solution obtained in previous step in ice bath, stirring the obtained suspension followed by filtration of the precipitated solid.
  • Vortioxetine hydrobromide is known in the art and commercially available. The same can be procured from commercial sources or can be prepared by the methods known in the art. Further, the staring vortioxetine hydrobromide may be in any form such as amorphous or any other crystalline or solvated forms known in the art.
  • the co-crystals of Vortioxetine hydrobromide of the present invention may readily be incorporate into pharmaceutical compositions for immediate or delayed or modified release for the treatment of major depressive disorder.
  • the present invention provides a pharmaceutical composition comprising Vortioxetine hydrobromide co-crystals and at least one pharmaceutically acceptable excipient.
  • the stoichiometry of each component in the co-crystal can vary.
  • the stoichiometry of the complex is 1 :1, i.e., one molecule of Vortioxetine hydrobromide co-crystallized with one molecule of coformer.
  • one molecule of Vortioxetine hydrobromide co-crystallizes with more than one molecule of coformer, such that the stoichiometry between the two molecules is, e.g., 1:2, 1 :3, 1:4 etc.
  • Vortioxetine hydrobromide co-former.
  • one molecule of Vortioxetine hydrobromide co-crystallizes with less than one molecule of conformer, such that the stoichiometry between the two molecules is, e.g., 4:1, 3:1, 2:1, etc.
  • Vortioxetine hydrobromide co-former.
  • the solvates and hydrates (e.g., monohydrate, dihydrate etc.) as well as anhydrous forms of Vortioxetine hydrobromide co-crystals also included in the scope of the present invention.
  • suitable solvents used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n- pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride,
  • Example 1 Preparation of Vortioxetine hydrobromide and resveratrol co-crystal Form M3:
  • Vortioxetine hydrobromide (166.04 mg) and Resveratrol (50 mg) was taken into a mortar pestle and grind by adding methanol drops for 20 min. The grinded material was dissolved in methanol (4 ml), filtered the obtained solution and the filtrate kept for slow solvent evaporation to get the titled compound.
  • Resveratrol (1 g) was dissolved in methanol (4 ml) at room temperature. To this solution, Vortioxetine hydrobromide (300.8 mg) was added. The obtained suspension was stirred for 15 mins, 50 mg of seed material was added to the suspension and stirred overnight and filtered the material and dried. Water (5 ml) was added to the obtained material and stirred for 7 hours at room temperature, filtered the material to get the title compound.
  • Vortioxetine hydrobromide (400 mg) and Resveratrol (30 mg) were added in ethanol (18 ml) at room temperature. Filtered the obtained solution and kept for slow solvent evaporation to get the title compound.
  • Vortioxetine hydrobromide (93.1 mg) and Piceatannol (30 mg) was taken into a mortar pestle and grind by adding methanol drops for 20 min. The grinded material was dissolved in methanol (4 ml), filtered the obtained solution and kept for slow solvent evaporation to get the title compound.
  • Vortioxetine hydrobromide (1 g) was dissolved in methanol (20 ml) at room temperature and filtered the solution. To this solution, 4-amino benzoic acid (182 mg) was added and stirred for 10 minutes. Water (20 ml) was added to the above suspension at room temperature. Then, the obtained solution was kept in ice bath for 30 minutes, stirred and filtered the precipitated solid to get the title compound.
  • Vortioxetine hydrobromide 80 mg was dissolved in methanol (2 ml) at room temperature and filtered the solution. To this solution, 4-hydroxy benzoic acid (18.2 mg) was added and stirred for 10 mins. Water (2 ml) was added to the above suspension at room temperature. Then, the obtained solution was kept in ice bath for 30 minutes, stirred and filtered the precipitated solid to get the title compound.
  • Vortioxetine hydrobromide (1 g) was dissolved in methanol (20 ml) at room temperature and filtered the solution. To this solution, gallic acid (220 mg) was added and stirred for 10 minutes. Water (20 ml) was added to the above suspension at room temperature. Then, the obtained solution was kept in ice bath for 30 minutes, stirred and filtered the precipitated solid to get the title compound.
  • Vortioxetine hydrobromide (3 g) was dissolved in methanol (60 ml) at room temperature and filtered the solution. To this solution, protocatechuic acid (1.22 g) was added and stirred for 10 minutes. Water (120 ml) was added to the above suspension at room temperature. Then, the obtained solution was kept in ice bath for 30 minutes, stirred and filtered the precipitated solid to get the title compound.
  • Vortioxetine hydrobromide 100 mg was dissolved in methanol (2 ml) at room temperature and filtered the solution. To this solution, salicylic acid (18.2 mg) was added and stirred for 10 mins. Water (2 ml) was added to the above suspension at room temperature. Then, the obtained solution was kept in ice bath for 30 minutes, stirred and filtered the precipitated solid to get the title compound.

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Abstract

La présente invention concerne des co-cristaux de bromhydrate de vortioxétine, un procédé pour sa préparation et une composition pharmaceutique les comprenant.
PCT/IB2023/053299 2022-04-01 2023-04-01 Co-cristaux de bromhydrate de vortioxétine Ceased WO2023187762A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2885266A1 (fr) * 2012-09-19 2014-03-27 Sandoz Ag Nouvelle forme cristalline de bromhydrate de vortioxetine
WO2018224594A1 (fr) * 2017-06-08 2018-12-13 Enantia, S.L. Co-cristaux de bromhydrate de vortioxétine et de résorcinol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2885266A1 (fr) * 2012-09-19 2014-03-27 Sandoz Ag Nouvelle forme cristalline de bromhydrate de vortioxetine
WO2018224594A1 (fr) * 2017-06-08 2018-12-13 Enantia, S.L. Co-cristaux de bromhydrate de vortioxétine et de résorcinol

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAIRA M R, CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS, TOPICS IN CURRENT CHEMISTRY, DESIGN OF ORGANIC SOLIDS, vol. 198, 1 January 1998 (1998-01-01), BERLIN, pages 163 - 208, XP001156954, ISSN: 0340-1022, DOI: 10.1007/3-540-69178-2-5 *
VEMURI VENKATA DEEPTHI, LANKALAPALLI SRINIVAS: "Insight into Concept and Progress on Pharmaceutical Co-Crystals: An overview", INDIAN JOURNAL OF PHARMACEUTICAL EDUCATION AND RESEARCH, vol. 53, no. 4s, 11 November 2019 (2019-11-11), pages s522 - s538, XP093098367, DOI: 10.5530/ijper.53.4s.147 *

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