WO2017154016A1 - Novel crystalline polymorphs of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for preparation thereof - Google Patents

Novel crystalline polymorphs of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for preparation thereof Download PDF

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WO2017154016A1
WO2017154016A1 PCT/IN2017/000055 IN2017000055W WO2017154016A1 WO 2017154016 A1 WO2017154016 A1 WO 2017154016A1 IN 2017000055 W IN2017000055 W IN 2017000055W WO 2017154016 A1 WO2017154016 A1 WO 2017154016A1
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formula
compound
dimethyl
phenylsulfanyl
phenyl
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PCT/IN2017/000055
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French (fr)
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Ghojala Venkat Reddy
Sagyam RAJESHWAR REDDY
Bekkam MARKONDAIAH
Boge RAJESHAM
Rangineni Srinivasulu
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Msn Laboratories Private Limited
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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
    • A61K31/33—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention provides novel crystalline polymorphs of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide represented by the following structural formula- l a and processes for their preparation.
  • l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide is an atypical antidepressant made by Lundbeck and Takeda. It was approved by USFDA on September 30, 2013 and by European Medicines Agency on December 18, 2013 for the treatment of major depressive disorder (MDD) in adults. l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and its pharmaceutically acceptable salts were first described in US7144884B2 (herein after referred as US'884 patent).
  • US8722684B2 discloses various crystalline polymorphic forms of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide and processes for their preparation. Those polymorphs include alpha form, beta form, gamma form, hemihydrate form, mixture of ethyl acetate solvate and alpha form.
  • US8598348B2 patent discloses crystalline isopropanol solvate form of l-[2-(2,4- dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for its preparation.
  • WO2014044721A1 discloses delta crystalline form and crystalline hydrate (monoclinic) form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
  • the first aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-Mi.
  • the second aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-M 2 .
  • the third aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-M 3 .
  • the fourth aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-M ⁇
  • the fifth aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-Ms.
  • the sixth aspect of the present invention is to provide crystalline polymorph of l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, characterized by its PXRD pattern as illustrated in figure-7.
  • the seventh aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, which is herein designated as form-E.
  • the eighth aspect of the present invention is to provide a process for the preparation of novel crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the ninth aspect of the present invention is to provide novel crystalline form of l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein designated as form-F.
  • the tenth aspect of the present invention is to provide a process for the preparation of crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the eleventh aspect of the present invention is to provide novel crystalline form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein designated as form-G.
  • the twelfth aspect of the present invention is to provide a process for the preparation of crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • Figure-1 Illustrates the PXRD pattern of crystalline form-Mi of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide.
  • Figure-2 Illustrates the PXRD pattern of crystalline form-M 2 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide.
  • Figure-3 Illustrates the PXRD pattern of crystalline form-M 3 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide .
  • Figure-4 Illustrates the PXRD pattern of crystalline form-M 4 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide.
  • Figure-5 Illustrates the PXRD pattern of crystalline form-M 5 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide .
  • Figure-6 Illustrates the PXRD pattern of crystalline isopropyl alcohol solvate form of l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
  • Figure-7 Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide obtained according to example-7.
  • Figure-8 Illustrates the PXRD pattern of crystalline form-E of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la.
  • Figure-9 Illustrates the PXRD pattern of crystalline form-F of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la.
  • Figure-10 Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained according to example- 10.
  • Figure-11 Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la obtained according to example- 11.
  • Figure-12 Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained according to example- 12.
  • Figure-13 Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained according to example-13.
  • Figure-14 Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained by drying the compound obtained according to example-13 for 10 hrs at 60°C.
  • Figure-15 Illustrates the DSC thermogram of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained by drying the compound obtained according to example-13 for 10 hrs at 60°C.
  • Figure-16 Illustrates the PXRD pattern of crystalline l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide compound of formula- la obtained by drying the compound obtained according to example-13 for 15 hrs at 100°C.
  • suitable solvent used in the present invention can be selected from but not limited to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as dimethyl
  • the first aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said polymorph is herein after designated as form-Mi and it is characterized by its PXRD pattern as illustrated in figure- 1.
  • the crystalline form-Mj of compound of formula- la of the present invention is found to be 2-butanol solvate form.
  • An embodiment of the present invention provides a process for the preparation of novel crystalline form-Mi of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, comprising of;
  • the second aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-diniethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said polymorph is herein after designated as form-M 2 and it is characterized by its PXRD pattern as illustrated in figure-2.
  • the crystalline form-M 2 of compound of formula- la of the present invention is found to be cyclohexanol solvate form.
  • An embodiment of the present invention provides a process for the preparation of novel crystalline form-M 2 of compound of formula- la, comprising of;
  • the third aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said polymorph is herein after designated as form-M 3 and it is characterized by its PXRD pattern as illustrated in figure-3.
  • An embodiment of the present invention provides a process for the preparation of novel crystalline form-M3 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, comprising of;
  • the fourth aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said polymorph is herein after designated as form-IVL t and it is characterized by its PXRD pattern as illustrated in figure-4.
  • An embodiment of the present invention provides a process for the preparation of novel crystalline form-M 4 of compound of formula- la, comprising of;
  • the fifth aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said polymorph is herein after designated as form-Ms and it is characterized by its PXRD pattern as illustrated in figure-5.
  • An embodiment of the present invention provides a process for the preparation of novel crystalline form-M 5 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, comprising of;
  • the compound of formula- 1 which is used as input for the preparation of crystalline form-M4, form r M 5 of the present invention can be prepared by any of the known processes.
  • One embodiment of the present invention provides isopropyl alcohol solvate form of compound of formula- la.
  • the said isopropyl alcohol solvate form is characterized by its PXRD pattern as illustrated in figure-6.
  • the other embodiment of the present invention provides a process for the preparation of isopropyl alcohol solvate form of compound of formula- la, comprising of;
  • the sixth aspect of the present invention provides crystalline polymorph of l-[2-(2,4- dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said crystalline polymorph is characterized by its PXRD pattern having peaks at 7.9, 15.9 and 19.1 ⁇ 0.2° of 2 ⁇ .
  • the said polymorph is further characterized by its PXRD pattern as illustrated in figure-7.
  • An embodiment of the present invention provides a process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure-7, comprising of;
  • step-b) the suitable temperature ranges from 35°C to reflux temperature of the solvent used.
  • step-e) the suitable temperature ranges from 30°C to -70°C.
  • heating of the reaction mixture to a suitable temperature ranges from 35°C to reflux temperature of the solvent used and cooling the reaction mixture to a suitable temperature ranges from 30°C to -70°C.
  • An embodiment of the present invention provides crystalline polymorph of compound of formula- la characterized by its PXRD pattern as shown in figure-7 having particle size distribution of D 90 less than 300 ⁇ , preferably less than 200 ⁇ , more preferably less than 100 ⁇ , most preferably less than 50 ⁇ .
  • the seventh aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said novel crystalline polymorph is herein after designated as form-E.
  • the crystalline form-E of compound of formula- la of the present invention is characterized by its PXRD pattern as illustrated in figure-8.
  • the eighth aspect of the present invention provides a process for the preparation of novel crystalline form-E of compound of formula- la, comprising of;
  • step-a) and step-b) the suitable temperature ranges from -30°C to 30°C.
  • the ninth aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said novel crystalline polymorph is hereinafter designated as form-F.
  • the crystalline form-F of compound of formula- la of the present invention is characterized by its PXRD pattern as illustrated in figure-9.
  • the tenth aspect of the present invention provides a process for the preparation of novel crystalline form-F of compound of formula- la, comprising of;
  • step-a) filtering the solid and drying to provide crystalline form-F of compound of formula- la.
  • the suitable temperature ranges from -30°C to 30°C;
  • step-b) stirring of the reaction mixture can be carried out for a suitable time ranges from 0.5-10 hrs.
  • An embodiment of the present invention provides a process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure- 10, comprising of;
  • step-a) and step-b) filtering the precipitated solid and drying the material to provide crystalline polymorph of compound of formula- la.
  • the suitable temperature ranges from -30°C to 100°C.
  • Another embodiment of the present invention provides a process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure- 11 , comprising of;
  • step-a) and step-b) the suitable temperature ranges from -30°C to 100°C.
  • the eleventh aspect of the present invention provides novel crystalline form of l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
  • the said novel crystalline polymorph is herein designated as crystalline form-G.
  • the crystalline form-G of compound of formula- la of the present invention is characterized by its PXRD pattern as illustrated in figure- 12 or figure-13.
  • the twelfth aspect of the present invention provides a process for the preparation of crystalline form-G of compound of formula- la, comprising of;
  • step-a) Dissolving the compound of formula- la in a suitable alcohol solvent selected from propylene glycol or ethanol at a suitable temperature, b) combining the solution with aqueous methanol at a suitable temperature, c) filtering the precipitated solid and drying the material to provide crystalline form-G of compound of formula- la.
  • a suitable alcohol solvent selected from propylene glycol or ethanol
  • step-b) the suitable temperature ranges from 20°C to reflux temperature of the solvent used
  • step-b) the suitable temperature ranges from -40°C to 40°C.
  • Any physical form of compound of formula- la viz.., crystalline form or amorphous form can be used as input for the preparation of various crystalline polymorphs of compound of formula- 1 a of the present invention.
  • the said input compound can be prepared by any of the known processes.
  • the said compound can be prepared by the process as described in our co-pending Indian patent application IN5018/CHE/2015.
  • the crystalline polymorphs of compound of formula- la of the present invention are useful as input for the preparation of other polymorphic forms of compound of formula- la viz.., crystalline polymorphs as well as amorphous form of compound of formula-la.
  • the crystalline polymorphs of compound of formula- la of the present invention are useful and well suitable for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- la is present in the composition in particular polymorphic form mentioned.
  • Such pharmaceutical compositions may comprise compound of formula- la present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
  • An embodiment of the present invention provides use of crystalline polymorphs of compound of formula- la of the present invention for the preparation of pharmaceutical compositions.
  • the other embodiment of the present invention provides pharmaceutical composition comprising any of the crystalline polymorphs of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
  • the PXRD analysis of compounds of the present invention was carried out using BRUKER/D8 ADVANCE X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.03°/min.
  • DSC Differential scanning calorimetric
  • Apparatus A liquid chromatograph equipped with variable wavelength UV detector; Column: YMC-Triart CI 8, 250 x 4.6 mm, 5 ⁇ , 12 nm or equivalent; Column temperature: 25 °C; Wave length: 230 nm; Injection volume: 5 ⁇ ,; Elution: Gradient; Diluent: Acetonitrile: Water (50:50 v/v); Buffer: Take accurately 5.0 mL of perchloric acid (70%) in 1000 mL of milli-Q-water (pH ⁇ 1.7) and filter this solution through 0.22 ⁇ Nylon membrane filter paper; Mobile phase-A: BuffenAcetonitrile (70:30 v/v); Mobile phase-B: Acetonitrile: Water (95:05 v/v).
  • the crystalline polymorphs of compound of formula- la of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.
  • Milling/micronization may be performed before drying or after drying of the product.
  • Example-1 Preparation of crystalline form-Mi of l-[2-(2,4-dimethyl-phenyIsuIfanyl)- phenyl] -piperazine hydrobromide (Formula-la)
  • Example-2 Preparation of crystalline form-M2 of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide (Formula-la)
  • Example-3 Preparation of crystalline form-M3 of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide (Formula-la)
  • Example-5 Preparation of crystalline form-Ms of compound of formula-la
  • Example-6 Preparation of isopropyl alcohol solvate form of compound of formula-la Isopropyl alcohol (10 ml) was added to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]- piperazine hydrobromide compound of formula-la (0.5 gm) at 25-30°C. Slowly heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 5 min at the same temperature. Filtered the solid and then dried the material to provide the title compound.
  • Example-7 Preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsuIfanyl)- phenylj-piperazine hydrobromide (Formula-la)
  • Methyl tert.butyl ether (300 ml) and cyclohexane (1200 ml) were added to the reaction mixture at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid and washed with cyclohexane.
  • 2-Butanol (450 ml) was added to the obtained solid at 25-30°C. Heated the reaction mixture to 65-70°C, water (30 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material.
  • 2-butanol (515 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 65-70°C, water (35 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material.
  • 2-Butanol (450 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 65-70°C, water (40 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with 2-butanol. Cooled the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material to get the title compound.
  • Example-8 Preparation of crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide (Formula-la)
  • Example-ll Preparation of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide (Formula-la)
  • Example-12 Preparation of crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenylj-piperazine hydrobromide (Formula-la)
  • the obtained solution was added to a pre-cooled mixture of methanol (20 ml) and water (80 ml) at -5°C to -10°C and stirred the reaction mixture for 3 hrs at the same temperature.
  • Example-13 Preparation of crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenylj-piperazine hydrobromide (Formula-la)
  • a mixture of compound of formula- la (2 gm) and ethanol (40 ml) was slowly heated to 60-65 °C and stirred the reaction mixture for 30 min at the same temperature.
  • the obtained solution was added to a pre-cooled mixture of methanol (20 ml) and water (80 ml) at -5°C to -10°C and stirred the reaction mixture for 3 hrs at the same temperature. Filtered the precipitated solid and dried the material to provide the title compound.

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Abstract

The present invention relates to novel crystalline polymorphs of 1 -[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide represented by the following structural formula- la and process for preparation thereof.

Description

Novel crystalline polymorphs of l-[2-(2,4-dimethyl-phenylsulfanyQ- phenyll-piperazine hydrobromide and process for preparation thereof
Related Applications:
This application claims the benefit of priority of our Indian patent applications 201641007800 filed on March 07, 2016 and 201641037586 filed on November 03, 2016 which are incorporated herein as reference.
Field of the Invention:
The present invention provides novel crystalline polymorphs of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide represented by the following structural formula- l a and processes for their preparation.
Figure imgf000003_0001
Formula- la
Background of the Invention:
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide is an atypical antidepressant made by Lundbeck and Takeda. It was approved by USFDA on September 30, 2013 and by European Medicines Agency on December 18, 2013 for the treatment of major depressive disorder (MDD) in adults. l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and its pharmaceutically acceptable salts were first described in US7144884B2 (herein after referred as US'884 patent). This patent discloses process for the preparation of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine free base and its analogs. US7144884B2 discloses the preparation of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine free base using solid phase synthesis. The crude product obtained was purified by preparative LC-MS and subsequently by ion-exchange chromatography. This patent didn't mention any physical characteristics data of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl]-piperazine.
The above mentioned US '884 patent didn't provide any specific method for the preparation of HBr salt of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.
Different polymorphic forms of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]- piperazine hydrobromide have been reported in the literature.
US8722684B2 discloses various crystalline polymorphic forms of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide and processes for their preparation. Those polymorphs include alpha form, beta form, gamma form, hemihydrate form, mixture of ethyl acetate solvate and alpha form.
US8598348B2 patent discloses crystalline isopropanol solvate form of l-[2-(2,4- dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for its preparation.
WO2014044721A1 discloses delta crystalline form and crystalline hydrate (monoclinic) form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Still, there is a significant need in the art to develop novel polymorphic forms of the said compound which are having advantageous physical properties such as free flowability, greater stability and greater bioavailability. Brief description of the invention:
The first aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-Mi.
The second aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-M2. The third aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-M3. The fourth aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-M^
The fifth aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein after designated as form-Ms.
The sixth aspect of the present invention is to provide crystalline polymorph of l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, characterized by its PXRD pattern as illustrated in figure-7.
The seventh aspect of the present invention is to provide novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, which is herein designated as form-E.
The eighth aspect of the present invention is to provide a process for the preparation of novel crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la.
The ninth aspect of the present invention is to provide novel crystalline form of l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein designated as form-F.
The tenth aspect of the present invention is to provide a process for the preparation of crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The eleventh aspect of the present invention is to provide novel crystalline form of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, herein designated as form-G. The twelfth aspect of the present invention is to provide a process for the preparation of crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. Brief Description of the Drawings :
Figure-1: Illustrates the PXRD pattern of crystalline form-Mi of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-2: Illustrates the PXRD pattern of crystalline form-M2 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-3: Illustrates the PXRD pattern of crystalline form-M3 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide .
Figure-4: Illustrates the PXRD pattern of crystalline form-M4 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-5: Illustrates the PXRD pattern of crystalline form-M5 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide .
Figure-6: Illustrates the PXRD pattern of crystalline isopropyl alcohol solvate form of l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide.
Figure-7: Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide obtained according to example-7.
Figure-8: Illustrates the PXRD pattern of crystalline form-E of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la.
Figure-9: Illustrates the PXRD pattern of crystalline form-F of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la.
Figure-10: Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained according to example- 10.
Figure-11: Illustrates the PXRD pattern of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la obtained according to example- 11. Figure-12: Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained according to example- 12.
Figure-13: Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained according to example-13.
Figure-14: Illustrates the PXRD pattern of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained by drying the compound obtained according to example-13 for 10 hrs at 60°C.
Figure-15: Illustrates the DSC thermogram of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la obtained by drying the compound obtained according to example-13 for 10 hrs at 60°C.
Figure-16: Illustrates the PXRD pattern of crystalline l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide compound of formula- la obtained by drying the compound obtained according to example-13 for 15 hrs at 100°C.
Detailed description of the Invention:
The "suitable solvent" used in the present invention can be selected from but not limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso- propanol, n-butanol, 2-butanol, iso-butanol, tert-butanol, n-pentanol (n-amyl alcohol), ethane- 1,2-diol (ethylene glycol), propane- 1,2-diol (propylene glycol), alkyl ethers of ethylene glycol or propylene glycol selected from but not limited to ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethyl ene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether and the like; "polar solvents" such as water; formic acid, acetic acid or mixtures thereof
The first aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said polymorph is herein after designated as form-Mi and it is characterized by its PXRD pattern as illustrated in figure- 1. The crystalline form-Mj of compound of formula- la of the present invention is found to be 2-butanol solvate form. An embodiment of the present invention provides a process for the preparation of novel crystalline form-Mi of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, comprising of;
a) Adding 2-butanol to compound of formula- la,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) filtering the solid and drying to provide crystalline form-Mi of compound of formula- la.
The second aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-diniethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said polymorph is herein after designated as form-M2 and it is characterized by its PXRD pattern as illustrated in figure-2. The crystalline form-M2 of compound of formula- la of the present invention is found to be cyclohexanol solvate form.
An embodiment of the present invention provides a process for the preparation of novel crystalline form-M2 of compound of formula- la, comprising of;
a) Adding a mixture of cyclohexanol and methanol to compound of formula- 1 a,
b) heating the reaction mixture to a suitable temperature, c) combining the obtained solution with methyl tert.butyl ether,
d) filtering the precipitated solid and drying to provide crystalline form-M2 of compound of formula- la. The third aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said polymorph is herein after designated as form-M3 and it is characterized by its PXRD pattern as illustrated in figure-3. An embodiment of the present invention provides a process for the preparation of novel crystalline form-M3 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, comprising of;
a) Adding ethyl acetate to compound of formula- la,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) filtering the solid and drying to provide crystalline form-M3 of compound of formula- la.
The fourth aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said polymorph is herein after designated as form-IVLt and it is characterized by its PXRD pattern as illustrated in figure-4.
An embodiment of the present invention provides a process for the preparation of novel crystalline form-M4 of compound of formula- la, comprising of;
a) Adding 2-butanol to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula- 1 ,
b) heating the reaction mixture to a suitable temperature,
c) adding aqueous HBr solution to the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the precipitated solid and drying to provide crystalline form-M4 of compound of formula- la. The fifth aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said polymorph is herein after designated as form-Ms and it is characterized by its PXRD pattern as illustrated in figure-5.
An embodiment of the present invention provides a process for the preparation of novel crystalline form-M5 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, comprising of;
a) Adding isopropyl alcohol to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula- 1 ,
b) heating the reaction mixture to a suitable temperature,
c) adding aqueous HBr solution to the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the precipitated solid and drying to provide crystalline form-M5 of compound of formula- la.
The compound of formula- 1 which is used as input for the preparation of crystalline form-M4, formrM5 of the present invention can be prepared by any of the known processes. One embodiment of the present invention provides isopropyl alcohol solvate form of compound of formula- la. The said isopropyl alcohol solvate form is characterized by its PXRD pattern as illustrated in figure-6.
The other embodiment of the present invention provides a process for the preparation of isopropyl alcohol solvate form of compound of formula- la, comprising of;
a) Adding isopropyl alcohol to compound of formula- la,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) filtering the solid and drying to provide crystalline isopropyl alcohol solvate form of compound of formula- la. The sixth aspect of the present invention provides crystalline polymorph of l-[2-(2,4- dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said crystalline polymorph is characterized by its PXRD pattern having peaks at 7.9, 15.9 and 19.1 ± 0.2° of 2Θ. The said polymorph is further characterized by its PXRD pattern as illustrated in figure-7.
An embodiment of the present invention provides a process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure-7, comprising of;
a) Adding 2-butanol to compound of formula- 1 a,
b) heating the reaction mixture to a suitable temperature,
c) adding water to the reaction mixture,
d) optionally filtering the reaction mixture,
e) cooling the reaction mixture to a suitable temperature,
f) filtering the solid and drying to provide crystalline polymorph of compound of formula- la having PXRD pattern as shown in figure-7.
Wherein, in step-b) the suitable temperature ranges from 35°C to reflux temperature of the solvent used; and
in step-e) the suitable temperature ranges from 30°C to -70°C.
In all of the above described processes for the preparation of various polymorphic forms of compound of formula- la, heating of the reaction mixture to a suitable temperature ranges from 35°C to reflux temperature of the solvent used and cooling the reaction mixture to a suitable temperature ranges from 30°C to -70°C.
An embodiment of the present invention provides crystalline polymorph of compound of formula- la characterized by its PXRD pattern as shown in figure-7 having particle size distribution of D90 less than 300 μηι, preferably less than 200 μιη, more preferably less than 100 μπι, most preferably less than 50 μπι. The seventh aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said novel crystalline polymorph is herein after designated as form-E. The crystalline form-E of compound of formula- la of the present invention is characterized by its PXRD pattern as illustrated in figure-8.
The eighth aspect of the present invention provides a process for the preparation of novel crystalline form-E of compound of formula- la, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- 1 a in ethylene glycol at a suitable temperature,
b) combining the solution with water at a suitable temperature,
c) filtering the precipitated solid and drying to provide crystalline form-E of compound of formula- la.
Wherein, in step-a) and step-b) the suitable temperature ranges from -30°C to 30°C.
The ninth aspect of the present invention provides novel crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said novel crystalline polymorph is hereinafter designated as form-F. The crystalline form-F of compound of formula- la of the present invention is characterized by its PXRD pattern as illustrated in figure-9.
The tenth aspect of the present invention provides a process for the preparation of novel crystalline form-F of compound of formula- la, comprising of;
a) Combining the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la with n-pentanol at a suitable temperature,
b) stirring the reaction mixture,
c) filtering the solid and drying to provide crystalline form-F of compound of formula- la. Wherein, in step-a) the suitable temperature ranges from -30°C to 30°C;
In step-b) stirring of the reaction mixture can be carried out for a suitable time ranges from 0.5-10 hrs. An embodiment of the present invention provides a process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure- 10, comprising of;
a) Dissolving the compound of formula- 1 a in propylene glycol at a suitable temperature, b) combining the obtained solution with water at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline polymorph of compound of formula- la. Wherein in step-a) and step-b) the suitable temperature ranges from -30°C to 100°C.
Another embodiment of the present invention provides a process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure- 11 , comprising of;
a) Dissolving the compound of formula- la in ethanol at a suitable temperature,
b) combining the obtained solution with water at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline polymorph of compound of formula- 1 a.
Wherein in step-a) and step-b) the suitable temperature ranges from -30°C to 100°C.
The eleventh aspect of the present invention provides novel crystalline form of l-[2- (2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la. The said novel crystalline polymorph is herein designated as crystalline form-G. The crystalline form-G of compound of formula- la of the present invention is characterized by its PXRD pattern as illustrated in figure- 12 or figure-13.
The twelfth aspect of the present invention provides a process for the preparation of crystalline form-G of compound of formula- la, comprising of;
a) Dissolving the compound of formula- la in a suitable alcohol solvent selected from propylene glycol or ethanol at a suitable temperature, b) combining the solution with aqueous methanol at a suitable temperature, c) filtering the precipitated solid and drying the material to provide crystalline form-G of compound of formula- la. Wherein, in step-a) the suitable temperature ranges from 20°C to reflux temperature of the solvent used; and in step-b) the suitable temperature ranges from -40°C to 40°C.
Any physical form of compound of formula- la viz.., crystalline form or amorphous form can be used as input for the preparation of various crystalline polymorphs of compound of formula- 1 a of the present invention.
In one embodiment, the said input compound can be prepared by any of the known processes.
In another embodiment, the said compound can be prepared by the process as described in our co-pending Indian patent application IN5018/CHE/2015.
The crystalline polymorphs of compound of formula- la of the present invention are useful as input for the preparation of other polymorphic forms of compound of formula- la viz.., crystalline polymorphs as well as amorphous form of compound of formula-la. The crystalline polymorphs of compound of formula- la of the present invention are useful and well suitable for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- la is present in the composition in particular polymorphic form mentioned. Such pharmaceutical compositions may comprise compound of formula- la present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents. An embodiment of the present invention provides use of crystalline polymorphs of compound of formula- la of the present invention for the preparation of pharmaceutical compositions.
The other embodiment of the present invention provides pharmaceutical composition comprising any of the crystalline polymorphs of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
The PXRD analysis of compounds of the present invention was carried out using BRUKER/D8 ADVANCE X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.03°/min.
The Differential scanning calorimetric (DSC) analysis was performed on a Q2000 V24.l l Build 124 calorimeter with aluminium pans. Samples held in a closed pan were analyzed at a heating rate of 10°C/min. Compound of formula- la of the present invention was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatograph equipped with variable wavelength UV detector; Column: YMC-Triart CI 8, 250 x 4.6 mm, 5 μιη, 12 nm or equivalent; Column temperature: 25 °C; Wave length: 230 nm; Injection volume: 5 μΐ,; Elution: Gradient; Diluent: Acetonitrile: Water (50:50 v/v); Buffer: Take accurately 5.0 mL of perchloric acid (70%) in 1000 mL of milli-Q-water (pH ~ 1.7) and filter this solution through 0.22 μηι Nylon membrane filter paper; Mobile phase-A: BuffenAcetonitrile (70:30 v/v); Mobile phase-B: Acetonitrile: Water (95:05 v/v). jThe crystalline polymorphs of compound of formula- la of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product. The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention. Examples:
Example-1: Preparation of crystalline form-Mi of l-[2-(2,4-dimethyl-phenyIsuIfanyl)- phenyl] -piperazine hydrobromide (Formula-la)
2-Butanol (10 ml) was added to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]- piperazine hydrobromide compound of formula-la (0.5 gm) at 25-30°C. Slowly heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 5 min at the same temperature. Filtered the solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure- 1.
Yield: 0.6 gm.
Example-2: Preparation of crystalline form-M2 of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide (Formula-la)
A mixture of cyclohexanol and methanol (200 ml; 1 :1 ratio) was added to l-[2-(2,4- dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la (15 gm) at 25-30°C. Slowly heated the reaction mixture to 70-75°C and stirred for 30 min at the same temperature. Filtered the reaction mixture to make it particle free. Slowly added the obtained solution to pre-cooled methyl tert.butyl ether (300 ml) at -45°C to -50°C and stirred the reaction mixture for 2 hrs at the same temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-2.
Yield: 15.5 gm.
Example-3: Preparation of crystalline form-M3 of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula- la (0.5 gm) and ethyl acetate (10 ml) was slowly heated to 50-55°C and stirred the reaction mixture for 5 hrs at the same temperature. Slowly cooled the reaction mixture to 25-30°C. Filtered the solid and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-3.
Yield: 0.4 gm.
ExampIe-4: Preparation of crystalline form-lVLt of l-[2-(2,4-dimethyl-phenyIsulfanyI)- phenylj-piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula-1 (1 gm) and 2-butanol (7 ml) was slowly heated to 70-75°C and stirred the reaction mixture for 30 min at the same temperature. 48% Aqueous HBr solution (0.7 ml) was slowly added to the obtained solution at 70-75°C and stirred the reaction mixture for 1 hr at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-4.
Yield: 0.8 gm.
Example-5: Preparation of crystalline form-Ms of compound of formula-la
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula-1 (1 gm) and isopropyl alcohol (10 ml) was slowly heated to 70-75 °C and stirred the reaction mixture for 1 hr at the same temperature. 48% Aqueous HBr solution (0.7 ml) was slowly added to the obtained solution at 70-75°C and stirred the reaction mixture for 1 hr at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the precipitated solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-5.
Yield: 1.0 gm.
Example-6: Preparation of isopropyl alcohol solvate form of compound of formula-la Isopropyl alcohol (10 ml) was added to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]- piperazine hydrobromide compound of formula-la (0.5 gm) at 25-30°C. Slowly heated the reaction mixture to 50-55°C and stirred for 5 hrs at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 5 min at the same temperature. Filtered the solid and then dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-6.
Yield: 0.7 gm.
Example-7: Preparation of crystalline polymorph of l-[2-(2,4-dimethyl-phenylsuIfanyl)- phenylj-piperazine hydrobromide (Formula-la)
A mixture of phenol (77.96 gm) and 33% HBr in acetic acid (750 ml) was stirred for 1 hr at 25-30°C. Cooled the reaction mixture to 0-5°C and 1 -(2-(2,4-dimethylphenylthio) phenyl)-4-tosylpiperazine (150 gm) was added to it. Raised the temperature of the reaction mixture to 25-30°C and stirred for 24 hrs at the same temperature. Cooled the reaction mixture to 0-5 °C and water was drop wise added to it. Raised the temperature of the reaction mixture to 25-30°C. Methyl tert.butyl ether (300 ml) and cyclohexane (1200 ml) were added to the reaction mixture at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the solid and washed with cyclohexane. 2-Butanol (450 ml) was added to the obtained solid at 25-30°C. Heated the reaction mixture to 65-70°C, water (30 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material. 2-butanol (515 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 65-70°C, water (35 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material. 2-Butanol (450 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 65-70°C, water (40 ml) was added to it and stirred the reaction mixture for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with 2-butanol. Cooled the reaction mixture to 25-30°C and stirred for 4 hrs at the same temperature. Filtered the solid, washed with 2-butanol and dried the material to get the title compound.
The PXRD pattern of the obtained compound is shown in figure-7.
Yield: 51.0 gm; Purity by HPLC: 99.99%.
Particle size distribution: D(0.1) is 2.43 μπι; D(0.5) is 13.92 μπι; D(0.9) is 39.24 μηι. Example-8: Preparation of crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide (Formula-la)
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la (5.0 gm) was added to pre-cooled ethylene glycol (100 ml) at 0-5°C and stirred the reaction mixture for 15 hrs at the same temperature. Water (100 ml) was added to the obtained solution at 0-5°C and stirred the reaction mixture for 4 hrs at the same temperature. Filtered the precipitated solid and suck dried the material to get the title compound.
The PXRD pattern of the obtained compound is shown in figure- 8.
Yield: 3.2 gm.
ExainpIe-9: Preparation of crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl] -piperazine hydrobromide (Formula-1 a)
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (5.0 gm) was added to n-pentanol (100 ml) at 0-5°C and stirred the reaction mixture for 5 hrs at the same temperature. Filtered the solid and suck dried the material to get the title compound.
The PXRD pattern of the obtained compound is shown in figure-9.
Yield: 3.8 gm. Example-10: Preparation of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl] -piperazine hydrobromide compound of formula-la (1 gm) and propylene glycol (10 ml) was heated to 70-75°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the obtained solution to make it particle free. The obtained solution was added to pre-cooled water (50 ml) at 0- 5°C and stirred the reaction mixture for 3 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound.
The PXRD pattern of the obtained compound is shown in figure- 10.
Yield: 0.6 gm. Example-ll: Preparation of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide (Formula-la)
A mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula-la (1 gm) and ethanol (10 ml) was heated to 70-75°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the obtained solution to make it particle free. The obtained solution was added to pre-cooled water (50 ml) at 0-5°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound.
The PXRD pattern of the obtained compound is shown in figure- 11.
Yield: 0.6 gm.
Example-12: Preparation of crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenylj-piperazine hydrobromide (Formula-la)
A mixture of compound of formula- la (2 gm) and propylene glycol (40 ml) was slowly heated to 60-65°C and stirred the reaction mixture for 30 min at the same temperature.
The obtained solution was added to a pre-cooled mixture of methanol (20 ml) and water (80 ml) at -5°C to -10°C and stirred the reaction mixture for 3 hrs at the same temperature.
Filtered the precipitated solid and dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure- 12.
Yield: 1.8 gm.
Example-13: Preparation of crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenylj-piperazine hydrobromide (Formula-la)
A mixture of compound of formula- la (2 gm) and ethanol (40 ml) was slowly heated to 60-65 °C and stirred the reaction mixture for 30 min at the same temperature. The obtained solution was added to a pre-cooled mixture of methanol (20 ml) and water (80 ml) at -5°C to -10°C and stirred the reaction mixture for 3 hrs at the same temperature. Filtered the precipitated solid and dried the material to provide the title compound.
The PXRD pattern of the obtained compound is shown in figure-13.
Yield: 1.6 gm.

Claims

We Claim:
1. Crystalline form-M] of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure- 1.
2. A process for the preparation of crystalline form-Mi of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la of claim 1, comprising of;
a) Adding 2-butanol to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) filtering the solid and drying to provide crystalline form-Mi of compound of formula- la.
3. Crystalline ίοπη-Μ2 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure-2. 4. A process for the preparation of crystalline form-M2 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la of claim 3, comprising of;
a) Adding a mixture of cyclohexanol and methanol to l-[2-(2,
4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, b) heating the reaction mixture to a suitable temperature,
c) combining the obtained solution with methyl tert.butyl ether,
d) filtering the precipitated solid and drying to provide crystalline form-M2 of compound of formula- la.
5. Crystalline form-M3 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, characterized by its PXRD pattern as illustrated in figUre-3.
6. A process for the preparation of crystalline form-M3 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la of claim 5, comprising of;
a) Adding ethyl acetate to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la,
b) heating the reaction mixture to a suitable temperature,
c) cooling the reaction mixture to a suitable temperature,
d) filtering the solid and drying to provide crystalline form-M3 of compound of formula- la.
7. Crystalline form-M4 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure-4.
8. A process for the preparation of crystalline form-M4 of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la of claim 7, comprising of;
a) Adding 2-butanol to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula- 1,
b) heating the reaction mixture to a suitable temperature,
c) adding aqueous HBr solution to the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the precipitated solid and drying to provide crystalline form-M4 of compound of formula- la.
9. Crystalline form-M5 of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, characterized by its PXRD pattern as illustrated in figure-5.
10. A process for the preparation of crystalline form-Ms of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la of claim 9, comprising of;
a) Adding isopropyl alcohol to l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine free base compound of formula- 1,
b) heating the reaction mixture to a suitable temperature,
c) adding aqueous HBr solution to the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the precipitated solid and drying to provide crystalline form-Ms of compound of formula- la.
11. The processes according to any of the preceding claims-2, 4, 6, 8, 10, wherein heating the reaction mixture to a suitable temperature ranges from 35°C to reflux temperature of the solvent used and cooling the reaction mixture to a suitable temperature ranges from 30°C to -70°C.
12. Crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, characterized by its PXRD pattern as illustrated in figure-8.
13. A process for the preparation of crystalline form-E of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenylj-piperazine HBr compound of formula- la of claim 12, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la in ethylene glycol at a suitable temperature,
b) combining the solution with water at a suitable temperature,
c) filtering the precipitated solid and drying to provide crystalline form-E of compound of formula- la.
14. The process according to claim 13, wherein in step-a) and step-b) the suitable temperature ranges from -30°C to 30°C.
15. Crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, characterized by its PXRD pattern as illustrated in figure-9.
16. Aprocess for the preparation of crystalline form-F of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenylj-piperazine hydrobromide compound of formula- la of claim 15, comprising of; a) Combining the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la with n-pentanol at a suitable temperature,
b) stirring the reaction mixture,
c) filtering the solid and drying to provide crystalline form-F of compound of formula- la.
17. The process according to claim 16, wherein,
in step-a) the suitable temperature ranges from -30°C to 30°C;
in step-b) stirring of the reaction mixture can be carried out for a suitable time ranges from 0.5-10 hrs.
18. A process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure- 10, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- 1 a in propylene glycol at a suitable temperature,
b) combining the obtained solution with water at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline compound of formula- la.
19. A process for the preparation of crystalline polymorph of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la characterized by its PXRD pattern as illustrated in figure-11, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la in ethanol at a suitable temperature,
b) combining the obtained solution with water at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline polymorph of compound of formula- la.
20. The processes according to claims- 18 and 19, wherein in step-a) and step-b) the suitable temperature ranges from -30°C to 100°C.
21. Crystalline form-G of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la, characterized by its PXRD pattern as illustrated in figure- 12 or figure-13.
22. A process for the preparation of crystalline form-G of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la of claim 21, comprising of;
a) Dissolving the l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la in a suitable alcohol solvent selected from propylene glycol or ethanol at a suitable temperature,
b) combining the solution with aqueous methanol at a suitable temperature,
c) filtering the precipitated solid and drying the material to provide crystalline form-G of compound of formula- la.
23. The process according to claim 22, wherein,
in step-a) the suitable temperature ranges from 20°C to reflux temperature of the solvent used; and in step-b) the suitable temperature ranges from -40°C to 40°C. hydrobromide compound of formula- la according to any of the preceding claims for the preparation of pharmaceutical compositions. 25. Pharmaceutical composition comprising crystalline polymorphs of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide compound of formula- la according to any of the preceding claims.
*******
24
PCT/IN2017/000055 2016-03-07 2017-03-03 Novel crystalline polymorphs of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for preparation thereof WO2017154016A1 (en)

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WO2019155352A1 (en) * 2018-02-06 2019-08-15 Piramal Enterprises Limited An improved process for the preparation of vortioxetine and salts thereof
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts

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WO2014044721A1 (en) * 2012-09-19 2014-03-27 Sandoz Ag Novel crystalline form of vortioxetine hydrobromide
WO2015166379A2 (en) * 2014-04-28 2015-11-05 Alembic Pharmaceuticals Limited Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts
US20160015706A1 (en) * 2014-07-18 2016-01-21 Dipharma Francis S.R.L. Crystalline forms of an antidepressant compound
WO2016079751A2 (en) * 2014-11-17 2016-05-26 Megafine Pharma (P) Ltd. A process for preparation of vortioxetine and polymorphs thereof

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WO2007144005A1 (en) * 2006-06-16 2007-12-21 H. Lundbeck A/S 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment
WO2014044721A1 (en) * 2012-09-19 2014-03-27 Sandoz Ag Novel crystalline form of vortioxetine hydrobromide
WO2015166379A2 (en) * 2014-04-28 2015-11-05 Alembic Pharmaceuticals Limited Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts
US20160015706A1 (en) * 2014-07-18 2016-01-21 Dipharma Francis S.R.L. Crystalline forms of an antidepressant compound
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US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts
WO2019155352A1 (en) * 2018-02-06 2019-08-15 Piramal Enterprises Limited An improved process for the preparation of vortioxetine and salts thereof

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