WO2014147641A2 - Sel de phosphate de sitagliptine et de ptérostilbène, son procédé de préparation et composition pharmaceutique en contenant - Google Patents

Sel de phosphate de sitagliptine et de ptérostilbène, son procédé de préparation et composition pharmaceutique en contenant Download PDF

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WO2014147641A2
WO2014147641A2 PCT/IN2014/000150 IN2014000150W WO2014147641A2 WO 2014147641 A2 WO2014147641 A2 WO 2014147641A2 IN 2014000150 W IN2014000150 W IN 2014000150W WO 2014147641 A2 WO2014147641 A2 WO 2014147641A2
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Prior art keywords
sitagliptin
pterostilbene phosphate
solution
pterostilbene
phosphate
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PCT/IN2014/000150
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WO2014147641A3 (fr
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Satyanarayana Chava
Seeta Ramanjaneyulu Gorantla
Venkata Sunil Kumar Indukuri
Ashwini Nangia
Krishna Sumanth Peraka
Udaya Bhaskara Rao KHANDAVILLI
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Laurus Labs Private Limited
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Publication of WO2014147641A2 publication Critical patent/WO2014147641A2/fr
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    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • the present invention generally relates to Sitagliptin Pterostilbene phosphate salt, processes for the preparation and a pharmaceutical composition containing the same.
  • 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 JANUVIATM in its monohydrate form JANUVIATM is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
  • Pterostilbene trans-3,5-dimethoxy-4'-hydroxystilbene
  • pterostilbene and resveratrol are:
  • Pterostilbene phosphate salt is represented as the following chemical structure:
  • Pterostilbene has been characterized as a nutraceutical, being found in nature in a number of tree barks and a variety of berries, including grapes, as well as plants commonly used in traditional folk medicine. Both resveratrol and pterostilbene have been reported to exhibit a range of biological activities including anti-cancer, antioxidant, anti-inflammatory and other potential health benefits. A number of in vitro and in vivo studies of pterostilbene have been conducted in which it demonstrated cytotoxic activity against cancer cell lines in vitro and decreased plasma glucose levels by 42% in hyperglycemic rats (comparable to the commercially available drug, metformin, which reduces glucose levels by 48%).
  • the LDL/HDL cholesterol ratio was significantly lowered in hypercholesterolemic hamsters that were fed 25 ppm pterostilbene in their diet compared to the control animals.
  • the use of pterostilbene to ameliorate oxidative stress and improve working memory and compositions containing pterostilbene are described in published U.S. application 2009/0069444, which is incorporated herein by reference.
  • Sitagliptin Ptero phosphate salt has the following chemical structure:
  • Sitagliptin Pterostilbene phosphate U.S. Patent No. 6,699,871 (“the '871 patent”) discloses a class of beta-amino- tetrahydrotriazolo [4,3-a]pyrazines such as Sitagliptin and its hydrochloride salt form, a potent inhibitor of DPP-IV enzyme. Other pharmaceutically acceptable salts of this compound are genetically 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 processes 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.
  • WO 2009/085990 sulfuric acid, hydrobromic acid, methane sulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, mandelic acid, fumaric acid, di-p-tolyl-L-tartaric acid and lactic acid
  • WO 2010/000469 hydroochloric acid, sulfuric acid, methane sulfonic acid, fumaric acid, malonic acid, malic acid, succinic acid, lactic acid, gly colic acid, maleic acid, citric acid, aspartic acid and mandelic acid
  • WO 2010/012781 ethanedisulfonic acid, galactaric acid, thiocyanic acid, and glutaric acid, L-malic acid, D-gluconic acid, succinic acid, hydrobromic acid, thiocyanic acid, oxalic acid, L- aspartic acid, pyroglutamic acid and acetic acid
  • WO 2010/0920
  • Patent Publication No. CNl 01863891 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.
  • 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. 3528/CHE/2011 discloses anti-oxidant acid addition salts of sitagliptin such as caffeic acid, ferulic acid and coumaric acid salts of sitagliptin.
  • 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 scanning calorimetry (“DSC”), X-ray diffraction pattern (XRPD), infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermogravimetric analysis
  • DSC differential scanning 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 pterostilbene phosphate 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 from diversity, more desired morphology, or other property described herein.
  • the present invention provides sitagliptin pterostilbene phosphate or hydrates or solvates thereof.
  • the present invention further provides sitagliptin pterostilbene phosphate exist in the form of polymorphs of salts, co-crystals, or polymorphs of co-crystals.
  • the present invention provides a process for preparing sitagliptin pterostilbene phosphate, comprising:
  • step b) combining the step a) solution and sitagliptin free base, and
  • the present invention provides a process for preparing sitagliptin pterostilbene phosphate, comprising:
  • step b) combining the step a) solution and sitagliptin free base, and
  • organic solvent is selected form the group consisting of alcohols, esters, ketones, ethers, halogenated solvents, hydrocarbons, nitriles, glycols, alkyl nitrates, water or mixtures thereof.
  • the present invention provides sitagliptin pterostilbene phosphate in crystalline form.
  • the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by an X-ray powder diffraction pattern (XRPD) substantially in accordance with Figure. 02.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure. 03.
  • DSC differential scanning calorimetric
  • the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by a Thermo gravimetric analysis (TGA) substantially in accordance with Figure. 04.
  • TGA Thermo gravimetric analysis
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous form.
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous form characterized by an X-ray powder diffraction pattern (XRPD) substantially in accordance with Figure. 05.
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous form characterized by an X-ray powder diffraction pattern (XRPD) substantially in accordance with Figure. 06.
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous form characterized by an X-ray powder diffraction pattern (XRPD) substantially in accordance with Figure. 07.
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous form characterized by an X-ray powder diffraction pattern (XRPD) substantially in accordance with Figure. 08.
  • XRPD X-ray powder diffraction pattern
  • the present invention provides a pharmaceutical composition comprising therapeutically effective amount of a sitagliptin pterostilbene phosphate in crystalline form or a therapeutically effective amount of a sitagliptin pterostilbene phosphate in amorphous forms prepared by the processes of the present invention.
  • Figure 1 is a characteristic H ⁇ Nuclear magnetic resonance (F ⁇ NMR) spectra of Sitagliptin pterostilbene phosphate in crystalline Form.
  • Figure 2 is the characteristic powder X-ray diffraction (XRD) pattern of Sitagliptin pterostilbene phosphate in crystalline Form.
  • Figure 3 is the characteristic DSC thermogram of Sitagliptin pterostilbene phosphate in crystalline Form.
  • Figure 4 is the characteristic thermo gravimetric analysis (TGA) curve of Sitagliptin pterostilbene phosphate in crystalline Form.
  • Figure 5 is the characteristic powder X-ray diffraction (XRD) pattern of Sitagliptin pterostilbene phosphate in an amorphous form A as obtained in Example 4.
  • XRD X-ray diffraction
  • Figure 6 is the characteristic powder X-ray diffraction (XRD) pattern of Sitagliptin pterostilbene phosphate in an amorphous form B as obtained in Example 6.
  • Figure 7 is the characteristic powder X-ray diffraction (XRD) pattern of Sitagliptin pterostilbene phosphate in an amorphous form C as obtained in Example 7.
  • Figure 8 is the characteristic powder X-ray diffraction (XRD) pattern of Sitagliptin pterostilbene phosphate in an amorphous form D as obtained in Example 8.
  • XRD X-ray diffraction
  • the present invention addresses a need in the art by providing new salt form of sitagliptin, or hydrates or solvates thereof; in particular sitagliptin pterostilbene phosphate or hydrates or solvates thereof and processes for their preparation.
  • the present inventors have identified new salt form of sitagliptin, particularly sitagliptin pterostilbene phosphate.
  • the salt form may be in the form of solvates, hydrates, polymorphs of salts, co-crystals, or polymorphs of co-crystals.
  • the sitagliptin pterostilbene phosphate 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 pterostilbene phosphate 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, pterostilbene phosphate can be used as an anti-diabetic agent as similar to known anti-diabetic agents, for example metformin.
  • the sitagliptin pterostilbene phosphate 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 present invention provides sitagliptin pterostilbene phosphate or hydrates or solvates thereof.
  • the ratio of sitagliptin to pterostilbene phosphate compound may be stoichiometric or non-stoichiometric according to the present invention. For example, 1:1, 1.5:1, 1:1.5, 2:1 and 1 :2 ratios of sitagliptin: pterostilbene phosphate is acceptable.
  • the present invention provides a process for preparing sitagliptin pterostilbene phosphate, comprising:
  • step b) combining the step a) solution and sitagliptin free base, and
  • 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.
  • the pterostilbene phosphate used in the present invention, can be prepared by any known method for example pterostilbene phosphate may be synthesized as disclosed in PCT publication No.WO2010/010578 ' .
  • pterostilbene phosphate can be prepared from the corresponding pterostilbene phosphate alkali salts for example pterostilbene phosphate disodium by neutralization or from the any methods known in the art.
  • the pterostilbene phosphate disodium as mentioned above can be prepared by any method known in the art and thereafter adjusting the pH with an acid in a water immiscible organic solvent to produce pterostilbene phosphate, which is immediately processed in a same or alternate solvent medium through the subsequent steps defined above.
  • the pH adjustment can be made by the addition of about 1 molar equivalent of a suitable acid.
  • suitable acid comprise but not limited to, all acids that neutralizes the base, e.g. hydrochloric acid and the like.
  • the step of providing a solution of pterostilbene phosphate may include dissolving any form of pterostilbene phosphate (including hydrates, solvates etc) obtained as above, in an organic solvent.
  • Suitable organic solvents include, but are not limited to alcohols, esters, ketones, ethers, halogenated solvents, hydrocarbons, nitriles, glycols, alkyl nitrates, water or mixtures thereof.
  • the suitable organic solvents includes, but are not limited to methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), isopropyl ether (IPE), tert.
  • butyl methyl ether 1,4-dioxane, acetonitrile, propionitrile, methylene chloride, chloroform, toluene, anisole, cyclohexane, hexane, heptane, ethylene glycol, nitromethane and the like and mixtures thereof; more preferably ethanol, isopropanol, acetone, methyl isobutyl ketone, tetrahydrofuran, isopropyl ether, chloroform, nitromethane and the like and mixtures thereof.
  • the step of providing a solution of pterostilbene phosphate may include heating to dissolve the pterostilbene phosphate in the organic solvent.
  • the temperature suitable for dissolving the pterostilbene phosphate in the organic solvent depends on the solvent used and the amount of pterostilbene phosphate 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.
  • the step b) of the foregoing process may include combining the solution obtained from step a) with sitagliptin base.
  • the sitagliptin base may be taken as solid or as a solution in a suitable solvent.
  • the solution of sitagliptin free base may include dissolving any form of sitagliptin free base (including hydrates, solvates etc), in a suitable solvent.
  • suitable solvents include, but are not limited to alcohols, esters, ketones, ethers, halogenated solvents, hydrocarbons, nitriles, glycols, alkyl nitrates, water or mixtures thereof.
  • the suitable organic solvents of step b) includes, but are not limited to methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), isopropyl ether (IPE), ter.
  • butyl methyl ether 1,4-dioxane, acetonitrile, propionitrile, methylene chloride, chloroform, toluene, anisole, cyclohexane, hexane, heptanes, ethylene glycol, nitromethane and the like and mixtures thereof; more preferably ethanol, isopropanol, acetone, chloroform, tetrahydrofuran, methyl isobutyl ketone, nitromethane and the like and mixtures thereof.
  • the step c) of the foregoing process may include isolating the sitagliptin pterostilbene phosphate by any conditions which forming the sitagliptin pterostilbene phosphate from solution may be used whereby sitagliptin pterostilbene phosphate formed, for example concentrated by subjecting the solution to heating, cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • ATFE agitated thin film evaporator
  • the present invention provides sitagliptin pterostilbene phosphate 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 sitagliptin pterostilbene phosphate obtained by the process as described above may have improved properties as compared to the sitagliptin salt form with other salt forming agents.
  • the present invention provides sitagliptin pterostilbene phosphate in crystalline form. In another embodiment, the present invention provides crystalline sitagliptin pterostilbene phosphate in crystalline form, characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 02.
  • XRD X-Ray diffraction
  • the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure. 03.
  • the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by a Thermo gravimetric analysis (TGA) substantially in accordance with Figure. 04.
  • the present invention provides a process for preparing sitagliptin pterostilbene phosphate in crystalline form, comprising:
  • step b) combining the step a) solution and sitagliptin free base, and
  • the organic solvent is selected form the group consisting of alcohols, esters, ethers, hydrocarbons, alkyl nitrates, water or mixtures thereof; preferably the organic solvent includes, but are not limited to methanol, isopropanol, isopropyl ether, nitromethane, water or mixtures thereof.
  • the step of providing a solution of pterostilbene phosphate may include heating to dissolve the pterostilbene phosphate in the organic solvent.
  • the temperature suitable for dissolving the pterostilbene phosphate in the organic solvent depends on the solvent used and the amount of pterostilbene phosphate 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.
  • the step b) of the foregoing process may include combining the solution obtained from step a) with sitagliptin base.
  • the sitagliptin base may be taken as solid or as a solution in a suitable solvent.
  • the solution of sitagliptin free base may include dissolving any form of sitagliptin free base (including hydrates, solvates etc), in a suitable solvent.
  • the suitable solvents include, but are not limited to alcohols, esters, ethers, hydrocarbons, alkyl nitrates, water or mixtures thereof; preferably the organic solvent includes, but is not limited to methanol, isopropanol, isopropyl ether, nitromethane, water or mixtures thereof.
  • the step of isolating the formed sitagliptin pterostilbene phosphate by any conditions which forming the sitagliptin pterostilbene phosphate from solution may be used whereby sitagliptin pterostilbene phosphate formed, for example concentrated by subjecting the solution to heating, cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like.
  • ATFE agitated thin film evaporator
  • the sitagliptin pterostilbene phosphate recovered using the process of the present invention is substantially in crystalline Form.
  • the crystalline sitagliptin pterostilbene phosphate can be characterized by one or more techniques such as an X-Ray diffraction (XRD) pattern substantially in accordance with Figure .02, a DSC thermogram substantially in accordance with Figure .03 or a Thermo gravimetric analysis (TGA) substantially in accordance with Figure .04.
  • XRD X-Ray diffraction
  • TGA Thermo gravimetric analysis
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous Form.
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous Form (herein after referred to as "amorphous Form A”), characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 05.
  • amorphous Form A characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 05.
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous Form (herein after referred to as "amorphous Form B”), characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 06.
  • amorphous Form B characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 06.
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous Form (herein after referred to as "amorphous Form C”), characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 07.
  • amorphous Form C characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 07.
  • the present invention provides sitagliptin pterostilbene phosphate in an amorphous Form (herein after referred to as "amorphous Form D"), characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 08.
  • the present invention provides a process for preparing sitagliptin pterostilbene phosphate in amorphous Form A, comprising:
  • step b) combining the step a) solution and sitagliptin free base,
  • the step of providing a solution of pterostilbene phosphate may include heating to dissolve the pterostilbene phosphate in an organic solvent, preferably ethanol, acetone or mixtures thereof.
  • the temperature suitable for dissolving the pterostilbene phosphate in an organic solvent depends on the solvent used and the amount of pterostilbene phosphate 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.
  • the step b) includes combining the pterostilbene phosphate solution obtained as just above with sitagliptin base.
  • the sitagliptin base may be taken as solid or as a solution in a suitable solvent.
  • the solution of sitagliptin free base may include dissolving any form of sitagliptin free base (including hydrates, solvates etc), in ethanol, acetone or mixtures thereof.
  • the resultant solution may be concentrated using methods known in the art, for example concentrating under vacuum; followed by adding hydrocarbon solvent such as n-hexane, n-heptane and the like to the obtained residue and isolating the sitagliptin pterostilbene phosphate form A.
  • the step of isolating the formed sitagliptin pterostilbene phosphate amorphous form by any conditions which forming the sitagliptin pterostilbene phosphate from solution may be used whereby sitagliptin pterostilbene phosphate formed, for example concentrated by subjecting the solution to heating, cooling the solution to precipitation, crystallization, solvent precipitation, spray drying, freeze drying, agitated thin film evaporator (ATFE) and the like; preferably cooling the solution to about 2G°C to precipitate out the sitagliptin pterostilbene phosphate amorphous form A.
  • ATFE thin film evaporator
  • the sitagliptin pterostilbene phosphate recovered using the process of the present invention is substantially in an amorphous Form A.
  • the amorphous sitagliptin pterostilbene phosphate Form A can be characterized by one or more techniques such as an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 05.
  • XRD X-Ray diffraction
  • the present invention provides a process for preparing sitagliptin pterostilbene phosphate in amorphous Form B, comprising:
  • step b) combining the step a) solution and sitagliptin free base,
  • the step of providing a solution of pterostilbene phosphate may include heating to dissolve the pterostilbene phosphate in halogenated solvent.
  • the temperature suitable for dissolving the pterostilbene phosphate in halogenated solvent depends on the solvent used and the amount of pterostilbene phosphate 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 60°C.
  • the step b) includes combining the pterostilbene phosphate solution obtained as just above with sitagliptin base.
  • the sitagliptin base may be taken as solid or as solution with step a) solvent.
  • the solution of sitagliptin free base may include dissolving any form of sitagliptin free base (including hydrates, solvates etc) in the solvent such as chloroform.
  • hydrocarbon solvent such as n-hexane, n-heptane and the like
  • the sitagliptin pterostilbene phosphate recovered using the process of the present invention is substantially in an amorphous Form B.
  • the amorphous sitagliptin pterostilbene phosphate Form B can be characterized by one or more techniques such as an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 06.
  • the present invention provides a process for preparing sitagliptin pterostilbene phosphate in amorphous Form C, comprising:
  • step b) combining the step a) solution and sitagliptin free base,
  • the step of providing a solution of pterostilbene phosphate may include heating to dissolve the pterostilbene phosphate in ether solvent.
  • the ether solvent include but are not limited to tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tertiary butyl ether and the like or mixtures thereof.
  • the temperature suitable for dissolving the pterostilbene phosphate in ether solvent depends on the solvent used and the amount of pterostilbene phosphate 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.
  • the step b) includes combining the pterostilbene phosphate solution obtained as just above with sitagliptin base.
  • the sitagliptin base may be taken as solid or as a solution with step a) solvent.
  • the solution of sitagliptin free base may include dissolving any form of sitagliptin free base (including hydrates, solvates etc) in the solvent.
  • the step of isolating sitagliptin pterostilbene phosphate amorphous form is by adding an alcohol solvent such as methanol, ethanol, isopropanol and the like to precipitate sitagliptin pterostilbene phosphate followed by isolating the product by any methods known in the art, for example cooling the solution to about 20°C and then filtration to obtain the sitagliptin pterostilbene phosphate amorphous form C.
  • an alcohol solvent such as methanol, ethanol, isopropanol and the like
  • the sitagliptin pterostilbene phosphate recovered using the process of the present invention is substantially in an amorphous Form C.
  • the amorphous sitagliptin pterostilbene phosphate Form C can be characterized by one or more techniques such as an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 07.
  • the present invention provides a process for preparing sitagliptin pterostilbene phosphate in amorphous form D, comprising:
  • step b) combining the step a) solution and sitagliptin free base,
  • the step of providing a solution of pterostilbene phosphate may include heating to dissolve the pterostilbene phosphate in ketone solvent.
  • the ketone solvent include but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like or mixtures thereof.
  • the temperature suitable for dissolving the pterostilbene phosphate in ketone solvent depends on the solvent used and the amount of pterostilbene phosphate 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.
  • the step b) includes combining the pterostilbene phosphate solution obtained as just above with sitagliptin base.
  • the sitagliptin base may be taken as solid or as a solution with step a) solvent.
  • the solution of sitagliptin free base may include dissolving any form of sitagliptin free base (including hydrates, solvates etc) in the solvent.
  • the step of isolating the sitagliptin pterostilbene phosphate amorphous form is by adding an alcohol solvent such as methanol, ethanol, isopropanol and the like to precipitating the sitagliptin pterostilbene phosphate followed by isolating the product by any methods known in the art, for example cooling the solution to about 20°C and then filtration to obtain the sitagliptin pterostilbene phosphate amorphous form D.
  • an alcohol solvent such as methanol, ethanol, isopropanol and the like
  • the sitagliptin pterostilbene phosphate recovered using the process of the present invention is substantially in an amorphous Form D.
  • the amorphous sitagliptin pterostilbene phosphate Form D can be characterized by one or more techniques such as an X-Ray diffraction (XRD) pattern substantially in accordance with Figure. 08.
  • XRD X-Ray diffraction
  • the sitagliptin pterostilbene phosphate in crystalline form or amorphous forms obtained by the processes as described above may have improved properties as compared to the sitagliptin salt form with other salt forming agents.
  • the present invention provides characterization of sitagliptin pterostilbene phosphate of the present invention characterized by X-ray powder diffraction (XRD) pattern.
  • XRD X-ray powder diffraction
  • the Differential Scanning Calorimetry (DSC) of sitagliptin pterostilbene phosphate recorded by a Differential Scanning Calorimeter (DSC Q200, TA instrumentation, Waters) at a scan rate of 2°C per minute with an Indium standard.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of sitagliptin pterostilbene phosphate with at least one pharmaceutically acceptable carrier or other excipients.
  • the pharmaceutical composition can be useful for the treatment of type 2 diabetes mellitus.
  • the present invention also provides sitagliptin pterostilbene phosphate as described above for use as a medicament, preferably for the treatment of type 2 diabetes mellitus.
  • the present invention further provides, when a pharmaceutical composition comprising sitagliptin pterostilbene phosphate prepared according to the present invention is formulated for oral administration or parenteral administration.
  • D50 and D90 particle size of the unformulated sitagliptin pterostilbene phosphate of the present invention used as starting material in preparing a pharmaceutical composition generally is less than 500 microns preferably less than about 300 microns, more preferably less than 200 microns. Any milling, grinding, micronizing or other particle size reduction method known in the art can be used to bring the sitagliptin pterostilbene phosphate of the present invention into any desired particle size range as set forth above.
  • Sitagliptin pterostilbene phosphate in accordance with present invention can be embodied for example in the form of tablet, capsules, pellets, granules and suppositories or their combined forms.
  • Pharmaceutical composition in accordance with present invention can be suitable for immediate release or modified release of sitagliptin pterostilbene phosphate of the present invention.
  • Solid pharmaceutical compositions can be for example coated with aim of increasing pelletibility or regulating the disintegration or absorption.
  • composition includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof.
  • composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • a “composition” may contain a single compound or a mixture of compounds.
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion.
  • Example 1 Preparation of sitagliptin pterostilbene phosphate.
  • reaction mixture was allowed to cool to 40°C and charged 10 ml of isopropyl ether and further allowed to cool to 25°C. Stirred for 1 hour and filtered the material and dried under vacuum at 45 °C to 50°C for 12 hours to obtain the title compound.
  • the XRPD is set forth in Figure. 02.
  • the DSC is set forth in Figure. 03
  • the TGA is set forth in Figure. 04
  • Example 2 Preparation of crystalline sitagliptin pterostilbene phosphate.
  • Sitagliptin free base (0.4 gms) was dissolved in nitromethane (6 ml) at temperature 25° to 35°C. To this, charged a solution of pterostilbene phosphate (0.4 gms in 6 ml nitromethane) and heated to reflux. The reaction was maintained for 4 hours at same temperature and then allowed to cool to 25°C. Stirred for 16 hours at same temperature and filtered the material and dried under vacuum at 50°C for 6 hours to obtain the title compound.
  • the XRPD is set forth in Figure. 02.
  • the DSC is set forth in Figure. 03
  • the TGA is set forth in figure. 04
  • Example 3 Preparation of crystalline sitagliptin pterostilbene phosphate.
  • Sitagliptin free base (0.4 gms) was dissolved in isopropanol (10 ml) at temperature 25° to 35°C. To this, charged a solution of pterostilbene phosphate (0.37 gms in 10 ml isopropyl ether) and heated to reflux. The reaction was maintained for 4 hours at same temperature and then allowed to cool to 25°C. Stirred for 16 hours at same temperature and filtered the material and dried under vacuum at 50°C for 6 hours to obtain the title compound.
  • the XRPD is set forth in Figure. 02.
  • the DSC is set forth in Figure. 03
  • Sitagliptin free base (0.4 gms) was dissolved in ethanol (5 ml) at temperature 25° to 35°C. To this, charged solution of pterostilbene phosphate (0.37 gms in 5 ml ethanol) and heated to reflux. The reaction was maintained for 4 hours at same temperature and then concentrated under vacuum at below 50°C. To the residue charged n-hexane (10 ml) and stirred for 16 hours at 25°C to 30°C. Filtered the material and dried under vacuum at 50°C for 6 hours to obtain the title compound.
  • the XRPD is set forth in Figure. 05.
  • Sitagliptin free base (0.4 gms) was dissolved in acetone (5 ml) at temperature 25° to 35°C. To this, charged a solution of pterostilbene phosphate (0.37 gms in 5 ml acetone) and heated to reflux. The reaction was maintained for 4 hours at same temperature and then allowed to cool to 25°C. Stirred for 16 hours at same temperature and filtered the material and dried under vacuum at 50°C for 6 hours to obtain the title compound.
  • the XRPD is set forth in Figure. 05.
  • Sitagliptin free base (0.4 gms) was dissolved in chloroform (5 ml) at temperature 25° to 35°C. To this, charged a solution of pterostilbene phosphate (0.37 gms in 5 ml chloroform) and heated to reflux. The reaction was maintained for 4 hours at same temperature and then allowed to cool to 25 °C. To this n-hexane (10 ml) was added and stirred for 16 hours at same temperature. Filtered the material and dried under vacuum at 50°C for 6 hours to obtain the title compound.
  • the XRPD is set forth in Figure. 06.
  • Sitagliptin free base (0.4 gms) was dissolved in tetrahydrofuran (5 ml) at temperature 25° to 35°C. To this, charged a solution of pterostilbene phosphate (0.37 gms in 5 ml tetrahydrofuran) and heated to reflux. The reaction was maintained for 4 hours at same temperature and then allowed to cool to 25°C. To this isopropanol (10 ml) was added and stirred for 16 hours at same temperature. Filtered the material and dried under vacuum at 50°C for 6 hours to obtain the title compound.
  • the XRPD is set forth in Figure. 07.
  • Sitagliptin free base (0.4 gms) was dissolved in methyl isobutyl ketone (5 ml) at temperature 25° to 35°C. To this, charged a solution of pterostilbene phosphate (0.37 gms in 5 ml methyl isobutyl ketone) and heated to reflux. The reaction was maintained for 4 hours at same temperature and then allowed to cool to 25°C. To this isopropanol (10 ml) was added and stirred for 16 hours at same temperature. Filtered the material and dried under vacuum at 50°C for 6 hours to obtain the title compound.
  • the XRPD is set forth in Figure. 08.

Abstract

La présente invention concerne un sel de phosphate de sitagliptine et de ptérostilbène et ses formes polymorphes, ainsi que son procédé de préparation. La présente invention concerne également une composition pharmaceutique utilisant ledit phosphate de sitagliptine et de ptérostilbène et ses formes polymorphes.
PCT/IN2014/000150 2013-03-21 2014-03-07 Sel de phosphate de sitagliptine et de ptérostilbène, son procédé de préparation et composition pharmaceutique en contenant WO2014147641A2 (fr)

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JP7486615B2 (ja) 2020-06-12 2024-05-17 アピカル モレキュラー バイオテック カンパニー リミテッド 非アルコール性脂肪性肝疾患および非アルコール性脂肪性肝炎を治療するためのプテロスチルベンアミノ酸含有炭酸塩の新規類縁体

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Publication number Priority date Publication date Assignee Title
WO2005003135A1 (fr) * 2003-06-24 2005-01-13 Merck & Co., Inc. Sel d'acide phosphorique d'un inhibiteur de la dipeptidyl peptidase iv
WO2005020920A2 (fr) * 2003-09-02 2005-03-10 Merck & Co., Inc. Nouvelles formes cristallines d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyl peptidase-iv
WO2005030127A2 (fr) * 2003-09-23 2005-04-07 Merck & Co., Inc. Nouvelle forme cristalline d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyle peptase-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
WO2011097372A2 (fr) * 2010-02-03 2011-08-11 Aptuit Laurus Private Limited Co-cristaux de ptérostilbène
CN103408591A (zh) * 2013-07-17 2013-11-27 张家港威胜生物医药有限公司 一种紫檀芪磷酸酯二钠盐的合成方法

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WO2005003135A1 (fr) * 2003-06-24 2005-01-13 Merck & Co., Inc. Sel d'acide phosphorique d'un inhibiteur de la dipeptidyl peptidase iv
WO2005020920A2 (fr) * 2003-09-02 2005-03-10 Merck & Co., Inc. Nouvelles formes cristallines d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyl peptidase-iv
WO2005030127A2 (fr) * 2003-09-23 2005-04-07 Merck & Co., Inc. Nouvelle forme cristalline d'un sel d'acide phosphorique d'un inhibiteur de dipeptidyle peptase-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
WO2011097372A2 (fr) * 2010-02-03 2011-08-11 Aptuit Laurus Private Limited Co-cristaux de ptérostilbène
CN103408591A (zh) * 2013-07-17 2013-11-27 张家港威胜生物医药有限公司 一种紫檀芪磷酸酯二钠盐的合成方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7486615B2 (ja) 2020-06-12 2024-05-17 アピカル モレキュラー バイオテック カンパニー リミテッド 非アルコール性脂肪性肝疾患および非アルコール性脂肪性肝炎を治療するためのプテロスチルベンアミノ酸含有炭酸塩の新規類縁体

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