WO2015001568A2 - Sel de lipoate sitagliptin, son procédé de préparation et composition pharmaceutique le contenant - Google Patents

Sel de lipoate sitagliptin, son procédé de préparation et composition pharmaceutique le contenant Download PDF

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WO2015001568A2
WO2015001568A2 PCT/IN2014/000438 IN2014000438W WO2015001568A2 WO 2015001568 A2 WO2015001568 A2 WO 2015001568A2 IN 2014000438 W IN2014000438 W IN 2014000438W WO 2015001568 A2 WO2015001568 A2 WO 2015001568A2
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sitagliptin
lipoate
mixtures
solvent
process according
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PCT/IN2014/000438
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English (en)
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WO2015001568A3 (fr
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Venkata Sunil Kumar Indukuri
Krishna Sumanth Peraka
Seeta Ram Anjaneyulu GORANTLA
Satyanarayana Chava
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Laurus Labs Private Limited
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Publication of WO2015001568A3 publication Critical patent/WO2015001568A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention generally relates to Sitagliptin Lipoate salt, processes for its preparation and a pharmaceutical composition containing the same.
  • Sitagliptin, (3R)-3-ammo-l-[9-(trifluoromethyl)-l,4,7,8-tetrazabicyclo[4.3.0]nona-6,8- dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, has the following chemical structure:
  • Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP-IV) enzyme inhibitor that improves glycemic control in patients with Type 2 diabetes mellitus by slowing the inactivation of incretin hormones.
  • Sitagliptin may be used as a monotherapy, as an adjunct to diet and exercise, or in combination with Metformin or a PPARy agonist (e.g., thiazolidinediones).
  • Sitagliptin is currently marketed in its phosphate salt in the United States under the trade name JANTJVTATM in its monohydrate form. JANUVIATM is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
  • -Lipoic acid or thioctic acid is l,2-dithiacyclopentane-3 -valeric acid and is widely distributed in plants and animals in the form of the R-enantiomer.
  • the chemical structure of a-lipoic acid has the following chemical structure.
  • a-Lipoic acid -Lipoic acid is a naturally occurring antioxidant and a cofactor of the glucose- metabolizing pyruvate dehydrogenase (Packer L. et al, Free Radicals in Biology & Medicine 19(2): 227-250, 1995) and is widely used for treating diabetic polyneuropathy (Ziegler D. et al, Diabetologia 38: 1425-1433; 1995).
  • U.S. Patent Nos. 5,650,429 and 5,532,269 disclose the use of lipoic acids in the treatment of circulatory disorders.
  • U.S. Patent No. 5,621 ,1 17 teaches that the D and L enantiomers of a-lipoic acid have different properties, with the D-enantiomer being primarily antiphlogistic and the L-enantiomer being mainly antinociceptive (analgesic).
  • U.S. Patent No. 5,334,612 describes certain alkylated derivatives of lipoic acid and their use in treatment of retroviral diseases.
  • U.S. Patent No. 5,084,481 discloses the use of reduced lipoic acid (DHLA) and salts thereof in treating iriflarnmatory diseases.
  • U.S. Patent No. 5,693,664 discloses use of LA and DHLA in the treatment of diabetes.
  • U.S. Patent No. 5,508,275 discloses a variety of lipid-selective antioxidants, including lipoic acid derivatives.
  • U.S. Patent No. 6,699,871 discloses a class of beta-amino- tetrahydrotriazolo[4,3-a]pyrazines such as Sitagliptin and its hydrochloride salt, a potent inhibitor of DPP-TV enzyme.
  • Other pharmaceutically acceptable salts of this compound are generically encompassed within the scope of the '871 patent. It also discloses a process for the preparation of sitagliptin and related compounds.
  • U.S. Patent No. 7,326,708 discloses dihydrogen phosphate salt of sitagliptin and crystalline hydrate thereof, in particular a crystalline monohydrate and process for the preparation thereof. Crystalline polymorphs of sitagliptin dihydrogen phosphate anhydrate such as Form I, Form II, Form III and Form IV are disclosed in Patent publication No. WO 2005/020920 and WO 2005/030127. Amorphous sitagliptin dihydrogen phosphate is disclosed in Patent publication No. WO 2006/033848.
  • Patent Publication No. CN101863891 discloses inorganic salts of sitagliptin such as sodium bisulfate, potassium bisulfate, cesium bisulfate and ammonium bisulfate salt of sitagliptin; sodium dihydrogen phosphate, potassium dihydrogen phosphate, cesium dihydrogen phosphate and ammonium dihydrogen phosphate salt of sitagliptin.
  • the '891 publication further discloses a complex salts of sitagliptin such as sitagliptin sulfate or phosphate salt complex with aminobutanetriol, aminopropanediol, amino ethanol, glucosamine, arginine, ornithine, citrulline or lysine.
  • sitagliptin such as sitagliptin sulfate or phosphate salt complex with aminobutanetriol, aminopropanediol, amino ethanol, glucosamine, arginine, ornithine, citrulline or lysine.
  • Our co-pending Patent application No. WO2013/054364 discloses anti-oxidant acid addition salts of sitagliptin such as caffeic acid, ferulic acid and coumaric acid.
  • Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability.
  • polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g. measured by thermogravimetric analysis (“TGA”), or differential scanriing calorimetry (“DSC”), X-ray diffraction pattern (XRPD), infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermogravimetric analysis
  • DSC differential scanriing calorimetry
  • XRPD X-ray diffraction pattern
  • solid state NMR spectrum e.g., X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life.
  • sitagliptin and lipoic acid individually are known to be anti-diabetic agents and when these drugs are combined, may act synergistically leading to enhanced efficacy compared to the two drugs administered individually. Further, it would be desirable to have reliable processes for producing these salt forms of sitagliptin. Additionally, the various salt forms of sitagliptin could be used to prepare improved pharmaceutical compositions.
  • sitagliptin lipoate can be obtained which have improved properties as compared to presently-known form of such compound.
  • the improved property is selected from the group consisting of: increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, decreased form diversity, more desired morphology, or other property described herein.
  • Sitagliptin Lipoate salt having the following structural Formula:
  • the present invention further provides sitagliptin lipoate exist in the form of polymorphs of salts, co-crystals, or polymorphs of co-crystals.
  • the present invention provides RR- Sitagliptin lipoate.
  • the present invention provides a process for the preparation of RR-Sitagliptin lipoate, comprising:
  • the present invention provides a process for the preparation of RR-Sitagliptin lipoate, comprising:
  • organic solvent is selected form the group comprising alcohols, esters, ketones and the like and mixtures thereof; and the antisolvent is selected from the group comprising aliphatic hydrocarbons, ethers and the like and mixtures thereof.
  • the present invention provides RR-Sitagliptin lipoate in crystalline Form.
  • the present invention provides RR-Sitagliptin lipoate in crystalline Form characterized by powder X-ray diffraction pattern substantially in accordance with Figure 2.
  • the present invention provides RR-Sitagliptin lipoate in crystalline Form characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 3.
  • DSC differential scanning calorimetric
  • the present invention provides RR, RS-Sitagliptin lipoate.
  • the present invention provides a process for the preparation of RR, RS-Sitagliptin lipoate, comprising:
  • the present invention provides a process for the preparation of RR, RS-Sitagliptin lipoate, comprising: a) providing a solution of sitagliptin free base and RS-lipoic acid in an organic solvent,
  • organic solvent is selected form the group comprising alcohols, esters, nitriles, ketones, aromatic hydrocarbons, halogenated hydrocarbons, nitroalkanes and the like and mixtures thereof; and the antisolvent is selected from the group comprising aliphatic hydrocarbons, ethers and the like and mixtures thereof.
  • the present invention provides RR, RS- Sitagliptin lipoate in crystalline Form.
  • the present invention provides RR, RS- Sitagliptin lipoate in crystalline Form-I characterized by powder X-ray diffraction pattern substantially in accordance with Figure 4.
  • the present invention provides RR, RS- Sitagliptin lipoate in crystalline Form-I characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 5.
  • DSC differential scanning calorimetric
  • the present invention provides a process for the preparation of RR, RS-Sitagliptin lipoate in crystalline Form-I, comprising:
  • organic solvent is selected form the group comprising esters, nitriles, halogenated hydrocarbons, nitroalkanes and the like and mixtures thereof; and the antisolvent is selected from the group comprising aliphatic hydrocarbons, ethers and the like and mixtures thereof.
  • the present invention provides RR, RS- Sitagliptin lipoate in crystalline Form-II characterized by powder X-ray diffraction spectra substantially in accordance with Figure 6.
  • the present invention provides RR, RS- Sitagliptin lipoate in crystalline Form-II characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 7.
  • the present invention provides a process for the preparation of RR, RS-Sitagliptin lipoate in crystalline Form-II, comprising:
  • organic solvent is selected form the group comprising alcohols, ethers, ketones, aromatic hydrocarbons, halogenated hydrocarbons and the like and mixtures thereof; and the antisolvent is selected from the group comprising aliphatic hydrocarbons, ethers and the like and mixtures thereof.
  • the present invention provides a pharmaceutical composition comprising therapeutically effective amount of a sitagliptin lipoate salt prepared by the processes of the present invention.
  • Figure 1 is the characteristic 'H-Nuclear magnetic resonance ('HNMR) spectra of Sitagliptin lipoate.
  • Figure 2 is the characteristic powder X-ray diffraction (XRD) pattern of RR-Sitagliptin lipoate in crystalline Form.
  • Figure 3 is the characteristic DSC thermogram of RR-Sitagliptin lipoate in crystalline Form.
  • Figure 4 is the characteristic powder X-ray diffraction (XRD) pattern of RR, RS-Sitagliptin lipoate in crystalline Form-I.
  • Figure 5 is the characteristic DSC thermogram of RR., RS-Sitagliptin lipoate in crystalline Form-I.
  • Figure 6 is the characteristic powder X-ray diffraction (XRD) pattern of RR, RS-Sitagliptin lipoate in crystalline Form-II.
  • Figure 7 is the characteristic DSC thermogram of RR, RS-Sitagliptin lipoate in crystalline Form-II.
  • Figure 8 is the characteristic DSC thermogram of Sitagliptin phosphate monohydrate obtained as per example-15.
  • Figure 9 is the characteristic thermo gravimetric analysis (TGA) of Sitagliptin phosphate monohydrate obtained as per example-15.
  • Figure 10 is the characteristic powder X-ray diffraction (XRD) pattern of Sitagliptin phosphate monohydrate obtained as per example-15.
  • the present invention addresses a need in the art by providing new salt form of sitagliptin, or hydrates or solvates thereof; in particular sitagliptin lipoate or hydrates or solvates thereof and processes for their preparation.
  • the present inventors have identified new salt form of sitagliptin, particularly sitagliptin lipoate.
  • the salt form may be in the form of solvates, hydrates, polymorphs of salts, co- crystals, or polymorphs of co-crystals.
  • the sitagliptin lipoate of the present invention may give rise to improved properties of the sitagliptin, as compared to the sitagliptin in a free form (including free base, hydrates, solvates etc.), particularly with respect to: solubility, dissolution, bioavailability, stability, Cmax, Tmax, processability, longer lasting therapeutic plasma concentration, hygroscopicity, decrease in form diversity (including polymorphism and crystal habit), change in morphology or crystal habit, etc.
  • the lipoic acid used in the present invention is not only intended for formation of pharmaceutically acceptable salt form of sitagliptin, itself can advantageously be useful for therapeutic application, for example, lipoic acid can be used as an anti-diabetic agent as similar to known anti-diabetic agents, for example metformin.
  • the sitagliptin lipoate is more effective with respect to therapeutic activity of the sitagliptin as compared to the sitagliptin salt form with other salt forming agents described in the afore mentioned literature.
  • the lipoate salt of the present invention has a center of asymmetry at the stereogenic carbon atom indicated with a * and can thus occur as a racemate, and single enantiomers.
  • Lipoic acid exists as two enantiomers, (i?)-(+)-lipoic acid and (5)-(-)-lipoic acid and hence (R)-Sitagliptin lipoate exists as three possible isomers (RR), (RS) and as racemate (RR, RS). Accordingly, in one embodiment, the present invention provides sitagliptin lipoate or solvates or hydrates or stereoisomer' s thereof.
  • the ratio of sitagliptin to lipoic acid compound may be stoichiometric or non- stoichiometric. For example, 1 : 1 , 1.5:1 , 1 : 1.5, 2: 1 and 1 :2 ratios of sitagliptin: lipoic acid is acceptable. According to the present invention the molar ratio of sitagliptin to lipoic acid is about 1 : 1.
  • the present invention provides Sitagliptin lipoate.
  • the present invention provides Sitagliptin lipoate characterized by l H NMR spectrum substantially in accordance with Figure 1.
  • the present invention provides (R,R)-Sitagliptin lipoate.
  • the present invention provides a process for the preparation of RR- Sitagliptin lipoate, comprising:
  • the Sitagliptin free base, used in the present invention can be prepared by any known method for example sitagliptin free base may be synthesized as disclosed in U.S. Patent No. 6,699,871.
  • Lipoic acid and its enantiomers used in the present invention, can be prepared by any known methods for example, Lipoic acid may be synthesized as disclosed in Bioorg. Med. Chem. 1997, 5, 253-61 ; J. Scientific & Industrial Res. 1990, 49, 400 ⁇ 09; Tetrahedron Lett 1989, 42, 5705; Synth. Commun. 17, 1987a, 1 1 , 1339-1347; Tetrahedron Lett. 28, 1987b, 19, 2183-2186; Perkin Transaction I, 1988, 9-12; Chemical Communication 1983, 1051-53; J. Am. Chem.
  • Step a) of the foregoing process may include adding any form of sitagliptin free base and R-lipoic acid in an organic solvent.
  • Suitable organic solvents include, but are not limited to alcohols, esters, ketones and the like and mixtures thereof.
  • the suitable organic solvents includes, but are not limited to methanol, ethanol, isopropanol, t-butanol, methyl acetate, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone and the like and mixtures thereof.
  • the step of providing a solution of sitagliptin free base and R-lipoic acid may include heating to dissolve the sitagliptin free base and R-lipoic acid in the organic solvent.
  • the temperature suitable for dissolving the sitagliptin free base and R-lipoic acid in the organic solvent depends on the solvent used and the amount of sitagliptin free base and R-lipoic acid in the solution.
  • the solution is heated at a temperature of at least about 30°C to about reflux.
  • the solution is heated at about 30°C to about 80°C.
  • Step b) of the foregoing process may include allowing the clear solution obtained in step a) to gradually cool to a temperature of at least 0°C to about 40°C.
  • the solution is cooled gradually to 20°C to about 40°C, more preferably to about 25°C to about 35°C.
  • an anti-solvent may be added to precipitate out the product.
  • Suitable anti- solvents includes, but are not limited to aliphatic hydrocarbons, ethers and the like and mixtures thereof; preferably the anti-solvent is isopropyl ether or n-heptane.
  • Step d) of isolating the RR-Sitagliptin lipoate may be carried out by conventional techniques, for example by filtration.
  • the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 75 °C, preferably from about 40°C to about 55°C.
  • the present invention provides RR-sitagliptin lipoate having a chemical purity greater than or equal to about 97%, as measured by HPLC, preferably about 98% as measured by HPLC, and more preferably about 99.5%, as measured by HPLC.
  • the RR-sitagliptin lipoate obtained by the process as described above may have improved properties as compared to the sitagliptin salt form with other salt forming agents.
  • the RR-sitagliptin lipoate recovered using the process of the present invention is in substantially solid crystalline Form.
  • the present invention provides RR-Sitagliptin lipoate in crystalline Form.
  • the present invention provides RR-Sitagliptin lipoate in crystalline Form, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 2.
  • XRD X-Ray diffraction
  • the present invention provides RR-Sitagliptin lipoate in crystalline Form, characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 3.
  • DSC differential scanning calorimetric
  • the present invention provides RR, RS-Sitagliptin lipoate.
  • the present invention provides a process for the preparation of RR, RS-Sitagliptin lipoate, comprising:
  • the Sitagliptin free base and the RS-lipoic acid used in the present invention can be prepared by any known method for example, Sitagliptin free base and the RS-lipoic acid may be synthesized by the procedure described as above.
  • Step a) of the foregoing process may include adding any form of sitagliptin free base and RS-lipoic acid in an organic solvent.
  • organic solvents include, but are not limited to alcohols, esters, nitriles, ketones, aromatic hydrocarbons, halogenated hydrocarbons, nitroalkanes and the like and mixtures thereof.
  • the suitable organic solvents includes, but are not limited to methanol, ethanol, isopropanol, t-butanol, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, o-xylene, anisole, dichloromethane, chloroform, ethylene glycol, nitromethane and the like and mixtures thereof.
  • the step of providing a solution of sitagliptin free base and RS-lipoic acid may include heating to dissolve the sitagliptin free base and RS-lipoic acid in the organic solvent.
  • the temperature suitable for dissolving the sitagliptin free base and RS-lipoic acid in the organic solvent depends on the solvent used and the amount of sitagliptin free base and RS- lipoic acid in the solution.
  • the solution is heated at a temperature of at least about 30°C to about reflux.
  • the solution is heated at about 30°C to about 80°C.
  • Step b) of the foregoing process may include allowing the clear solution obtained in step a) to gradually cool to a temperature of at least 0°C to about 40°C.
  • the solution is cooled gradually to 20°C to about 40°C, more preferably to about 25°C to about 35°C.
  • an anti-solvent may be added to precipitate out the product.
  • Suitable anti- solvents includes, but not limited to aliphatic hydrocarbons, ethers and the like and mixtures thereof; preferably the anti-solvent is isopropyl ether or n-heptane.
  • Step d) of isolating the RR, RS-Sitagliptin lipoate may be carried out by conventional techniques, for example by filtration.
  • the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 75°C, preferably from about 40°C to about 55°C.
  • the present invention provides RR, RS-Sitagliptin lipoate having a chemical purity greater than or equal to about 97%, as measured by HPLC, preferably about 98% as measured by HPLC, and more preferably about 99.5%, as measured by HPLC.
  • the RR, RS-Sitagliptin lipoate obtained by the process as described above may have improved properties as compared to the sitagliptin salt form with other salt forming agents.
  • the RR, RS-Sitagliptin lipoate recovered using the process of the present invention is in substantially solid crystalline Form.
  • the present invention provides RR, RS-Sitagliptin lipoate in crystalline Form.
  • the present invention provides RR, RS-Sitagliptin lipoate in crystalline Form-I.
  • the present invention provides RR, RS-Sitagliptin lipoate in crystalline Form-I, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 4.
  • XRD X-Ray diffraction
  • the present invention provides RR, RS-Sitagliptin lipoate in crystalline Form-I characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 5.
  • DSC differential scanning calorimetric
  • the present invention provides RR, RS-Sitagliptin lipoate in crystalline Form-II. In another embodiment, the present invention provides RR, RS-Sitagliptin lipoate in crystalline Form-II, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 6. In another embodiment, the present invention provides RR, RS-Sitagliptin lipoate in crystalline Form-II characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 7.
  • DSC differential scanning calorimetric
  • the present invention provides a process for the preparation of RR, RS-Sitagliptin lipoate crystalline Form-I, comprising:
  • the organic solvent is selected form the group comprising esters, nitriles, halogenated hydrocarbons, nitroalkanes and the like and mixtures thereof; and the antisolvent is selected from the group comprising aliphatic hydrocarbons, ethers and the like and mixtures thereof.
  • the suitable organic solvents includes, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, nitromethane and the like and mixtures thereof.
  • the step of providing a solution of sitagliptin free base and RS-lipoic acid may include heating to dissolve the sitagliptin free base and RS-lipoic acid in the organic solvent.
  • the solution is heated at a temperature of at least about 30°C to about reflux.
  • the solution is heated at about 30°C to about 80°C.
  • Isolating the formed RR, RS-Sitagliptin lipoate crystalline Form-I may include allowing the clear solution obtained in step a) to gradually cool to a temperature of at least 0°C to about 40°C, followed by optional addition of an antisolvent such as isopropyl ether, hexane, heptane and the like to precipitate out the product.
  • an antisolvent such as isopropyl ether, hexane, heptane and the like to precipitate out the product.
  • the resultant RR, RS-Sitagliptin lipoate crystalline Form-I may be separated by conventional techniques, for example by filtration.
  • the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 75°C, preferably from about 40°C to about 55°C.
  • the present invention provides a process for the preparation of RR, RS-Sitagliptin lipoate in crystalline Form-II, comprising:
  • organic solvent is selected form the group comprising alcohols, ethers, ketones, aromatic hydrocarbons, halogenated hydrocarbons and the like and mixtures thereof; and the antisolvent is selected from the group comprising aliphatic hydrocarbons, ethers and the like and mixtures thereof.
  • the suitable organic solvents includes, but are not limited to methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, isopropyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, o-xylene, anisole, dichloromethane, chloroform and the like.
  • the step of providing a solution of sitagliptin free base and RS-lipoic acid may include heating to dissolve the sitagliptin free base and RS-lipoic acid in the organic solvent.
  • the solution is heated at a temperature of at least about 30°C to about reflux.
  • the solution is heated at about 30°C to about 80°C.
  • Isolating the formed RR, RS-Sitagliptin lipoate crystalline Form-II may include allowing the clear solution obtained in step a) to gradually cool to a temperature of at least 0°C to about 40°C, followed by optional addition of an antisolvent such as isopropyl ether, hexane, heptane and the like to precipitate out the product.
  • an antisolvent such as isopropyl ether, hexane, heptane and the like to precipitate out the product.
  • the resultant RR, RS-Sitagliptin lipoate crystalline Form-II may be separated by conventional techniques, for example by filtration.
  • the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 75°C, preferably from about 40°C to about 55°C.
  • the present invention provides characterization of crystalline forms of sitagliptin lipoate of the present invention characterized by X-ray powder diffraction (XRD) pattern.
  • XRD X-ray powder diffraction
  • the Differential Scanning Calorimetry (DSC) of crystalline forms of sitagliptin lipoateof the present invention recorded by a Differential Scanning Calorimeter (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of sitagliptin lipoate of the present invention with at least one pharmaceutically acceptable carrier or other excipients.
  • the pharmaceutical composition can be useful for the treatment of type 2 diabetes mellitus.
  • EXAMPLE 1 Preparation of JtR-Sitagliptin Lipoate in crystalline Form (Isopropyl Acetate)
  • Lipoic acid content 33.72 % w/w
  • Example 3 Preparation of RR, ⁇ -Sitagliptin Lipoate Form-I (Isopropyl acetate).
  • Example 8 Preparation of RR, RS-Sitagliptin Lipoate Form-II (MIBK + n-heptane).
  • Example 9 Preparation of RR, RS-Sitagliptin Lipoate Form-II (THF + IPE).
  • Example 10 Preparation of RR, RS-Sitagliptin Lipoate Form-II (tert-butanol).
  • a stirred mixture of Sitagliptin free base (l g) and i ⁇ S-Lipoic acid (0.506g) in tert-butanol (10 mL) was heated to 40°C to 50°Cto get a clear solution.
  • the temperature of the reaction mass was maintained at 45-48°C for lh, allowed to gradually cool to 25-35°C and then maintained at the same temperature for another 3h.
  • the solid material was filtered, washed with tert-butanol and dried under vacuum at 50°C to afford &/?,ftS-Sitagliptin Lipoate Form-II as a pale yellow solid material.
  • Example 14 Preparation of RR, RS-Sitagliptin Lipoate Form-II (dichloromethane + n-hexane).
  • a stirred mixture of RR, ⁇ S-Sitagliptin Lipoate (l g) in dichloromethane (10 mL) was heated to 30°C to 40°C to get clear solution.
  • the temperature of the reaction mass was allowed to gradually cool to 25-35°C and filtered.
  • n-hexane (10 mL) added n-hexane (10 mL) and stirred for 4 hr at 25- 35°C.
  • the solid material was filtered, washed with dichloromethane and dried under vacuum at 50°C to afford .Rii.iiS'-Sitagliptin Lipoate Form-II as a pale yellow solid material.
  • Example 15 Preparation of Sitagliptin phosphate monohydrate from Sitagliptin lipoate.
  • the reaction mass was gradually heated to 73 ⁇ 3°C and stirred for another 2h at the same temperature.
  • the reaction mass seeded with sitagliptin phosphate monohydrate (250 mg) and was allowed to cool to 20 ⁇ 3°C, over a period of 6h.
  • the reaction mass was slurried for further 12h.
  • Isopropyl alcohol 125 mL was added to the above mass and slurried for another hour.
  • the precipitated material was filtered, under mild suction.
  • the reaction flask was rinsed with 5% aqueous isopropanol (v/v, 25 mL x 2) and the wet cake was washed with it.
  • the material was dried, at ambient temperature, to afford sitagliptin phosphate monohydrate as a crystalline white powder.
  • the DSC, TGA and XRD are set forth in Figure 8, 9 & 10 respectively.

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Abstract

La présente invention concerne du sel de lipoate sitagliptin, ses formes polymorpes et son procédé de préparation. La présente invention concerne également une composition pharmaceutique utilisant le lipoate sitagliptin et ses formes polymorphes.
PCT/IN2014/000438 2013-07-01 2014-07-01 Sel de lipoate sitagliptin, son procédé de préparation et composition pharmaceutique le contenant WO2015001568A2 (fr)

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IN2913CH2013 2013-07-01
IN2913/CHE/2013 2013-07-01

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WO2015001568A2 true WO2015001568A2 (fr) 2015-01-08
WO2015001568A3 WO2015001568A3 (fr) 2015-06-11

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WO2019087054A1 (fr) * 2017-11-01 2019-05-09 Zenvision Pharma Llp Nouvelle composition pharmaceutique comprenant un inhibiteur de dpp-4, de l'acide alpha-lipoïque et de la vitamine b12
CN116082346A (zh) * 2023-04-12 2023-05-09 宙晟智维生命科学(上海)有限公司 一种高流动性的磷酸西格列汀一水合物晶体及其制备方法

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DE4343593C2 (de) * 1993-12-21 1998-05-20 Asta Medica Ag Verwendung von R-(+)-alpha-Liponsäure, R-(-)-Dihydroliponsäure oder der Metabolite sowie deren Salze, Ester, Amide zur Behandlung kompensierter und dekompensierter Insulinresistenz
UA74912C2 (en) * 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
JO2625B1 (en) * 2003-06-24 2011-11-01 ميرك شارب اند دوم كوربوريشن Phosphoric acid salts of dipeptidyl betidase inhibitor 4
CN100457108C (zh) * 2003-09-02 2009-02-04 默克公司 一种二肽基肽酶iv抑制剂的磷酸盐新晶体
WO2005072530A1 (fr) * 2004-01-16 2005-08-11 Merck & Co., Inc. Nouveau sel cristallin d'un inhibiteur de dipeptidyle peptidase-iv
WO2006033848A1 (fr) * 2004-09-15 2006-03-30 Merck & Co., Inc. Forme amorphe d'un sel de l'acide phosphorique d'un inhibiteur de dipeptidyl peptidase-iv
EP1909776A2 (fr) * 2005-07-25 2008-04-16 Merck & Co., Inc. Sel de dodecylsulfate d'un inhibiteur de la dipeptidyl peptidase iv
CL2008000684A1 (es) * 2007-03-09 2008-08-01 Indigene Pharmaceuticals Inc Composicion farmaceutica que comprende metformina r-(+) lipoato y un inhibidor de reductasa hmg-coa; formulacion de dosis unitaria; y uso en el tratamiento de una complicacion diabetica.
WO2009085223A1 (fr) * 2007-12-20 2009-07-09 Indigene Pharmaceuticals, Inc. Combinaison de r-(+)-lipoate de metformine et d'agents antihyperglycémiques pour le traitement de l'hyperglycémie diabétique et des complications diabétiques
CA2707790C (fr) * 2007-12-20 2015-04-21 Dr. Reddy's Laboratories Limited Procedes de preparation de sitagliptine et sels pharmaceutiquement acceptables de celle-ci
PT2586782E (pt) * 2008-07-03 2015-02-03 Ratiopharm Gmbh Sais cristalinos de sitagliptina
WO2010056726A1 (fr) * 2008-11-11 2010-05-20 Indigene Pharmaceuticals, Inc. Compositions et procédés de traitement du diabète
EP2736909B1 (fr) * 2011-07-27 2017-03-29 Farma GRS, d.o.o. Procédé de préparation de sitagliptin et ses sels pharmaceutiquement acceptables
US20140350023A1 (en) * 2011-12-08 2014-11-27 Ranbaxy Laboratories Limited Amorphous form of sitagliptin salts

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019087054A1 (fr) * 2017-11-01 2019-05-09 Zenvision Pharma Llp Nouvelle composition pharmaceutique comprenant un inhibiteur de dpp-4, de l'acide alpha-lipoïque et de la vitamine b12
CN116082346A (zh) * 2023-04-12 2023-05-09 宙晟智维生命科学(上海)有限公司 一种高流动性的磷酸西格列汀一水合物晶体及其制备方法

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