WO2014147641A2 - Sitagliptin pterostilbene phosphate salt, process for the preparation and pharmaceutical composition thereof - Google Patents

Sitagliptin pterostilbene phosphate salt, process for the preparation and pharmaceutical composition thereof Download PDF

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Publication number
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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French (fr)
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WO2014147641A3 (en
Inventor
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/en
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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

The present invention relates to Sitagliptin Pterostilbene phosphate salt and its polymorphic forms, a process for its preparation. The present invention also relates to a pharmaceutical composition using the Sitagliptin Pterostilbene phosphate and its polymorphic forms.

Description

SITAGLIPTIN PTEROSTILBENE PHOSPHATE SALT, PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITION THEREOF
PRIORITY
This application claims the benefit under Indian Provisional Application No. 1230/CHE/2013 filed on 21 March 2013 and entitled "SITAGLIPTIN PTEROSTILBENE PHOSPHATE SALT, PROCESS FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITION THEREOF", the content of which is incorporated by reference herein.
FIELD OF THE INVENTION
The present invention generally relates to Sitagliptin Pterostilbene phosphate salt, processes for the preparation and a pharmaceutical composition containing the same.
BACKGROUND OF THE INVENTION
Sitagliptin, ^ (3R)-3-amino- 1 -[9-(trifluoromethyl)- 1 ,4,7,8-tetrazabicyelo[4.3.0]nona-6,8- dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-l-one, has the following chemical structure:
Figure imgf000002_0001
Sitagliptin
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 JANUVIA™ in its monohydrate form JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
Pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene) is a naturally occurring stilbenoid compound, and a non-ionizable methylated structural analog of resveratrol. The chemical structures of pterostilbene and resveratrol are:
l
Figure imgf000003_0001
Pterostilbene Resveratrol
Pterostilbene phosphate salt is represented as the following chemical structure:
Figure imgf000003_0002
Pterostilbene phosphate
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%). Additionally, 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:
Figure imgf000003_0003
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.
Several pharmaceutically acceptable acid salts of sitagliptin are described in the literature, for example WO 2005/072530 (hydrochloric acid, tartaric acid, benzene sulfonic acid, p-toluene sulfonic acid and 10-camphor sulfonic acid); WO 2007/035198 (dodecyl sulfate salt).
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 (hydrochloric 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 2010/092090 (D-glucuronic acid, L-glucuronic acid, glutaric acid, sulfuric acid, L-Lactic acid, D-Lactic acid, ethane sulfonic acid, oxalic acid, acetic acid, L-mandelic acid, D-mandelic acid, capric acid, benzoic acid, hippuric cid, trans-cinnamic acid, malonic acid, citric acid, l-hydroxy-2- naphtolic acid, crotonic acid and ascorbic acid); and WO 2010/117738 (dibenzoyl-D- tartaric acid, fumaric acid, malic acid, oxalic acid, Quinic acid, succinic acid, mandelic acid, lactic acid, maleic acid, S-mandelic acid, L-malic acid, R-(-)-mandelic acid and Orotic acid). Patent Publication No. CNl 01863891 ("the '891 publication") 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 complex salts of 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. In addition, 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. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. 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.
. '
In view of the foregoing, it would be desirable to provide new salt forms of sitagliptin. 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.
SUMMARY OF THE INVENTION
It has now been found that new acid addition salt forms of sitagliptin; in particular sitagliptin pterostilbene phosphate can be obtained which have improved properties as compared to presently-known form of such compound. In an aspect, 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. Accordingly, in one embodiment, the present invention provides sitagliptin pterostilbene phosphate or hydrates or solvates thereof. In accordance with a second embodiment, the present invention further provides sitagliptin pterostilbene phosphate exist in the form of polymorphs of salts, co-crystals, or polymorphs of co-crystals. I
In accordance with a third embodiment, the present invention provides a process for preparing sitagliptin pterostilbene phosphate, comprising:
a) providing a solution of pterostilbene phosphate in ah organic solvent,
b) combining the step a) solution and sitagliptin free base, and
c) isolating the sitagliptin pterostilbene phosphate.
In accordance with a fourth embodiment, the present invention provides a process for preparing sitagliptin pterostilbene phosphate, comprising:
a) providing a solution of pterostilbene phosphate in an organic solvent,
b) combining the step a) solution and sitagliptin free base, and
c) isolating the sitagliptin pterostilbene phosphate.
wherein the organic solvent is selected form the group consisting of alcohols, esters, ketones, ethers, halogenated solvents, hydrocarbons, nitriles, glycols, alkyl nitrates, water or mixtures thereof.
In accordance with a fifth embodiment, the present invention provides sitagliptin pterostilbene phosphate in crystalline form.
In accordance with a sixth embodiment, 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.
In accordance with a seventh embodiment, the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure. 03.
In accordance with an eighth embodiment, the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by a Thermo gravimetric analysis (TGA) substantially in accordance with Figure. 04.
In accordance with a ninth embodiment, the present invention provides sitagliptin pterostilbene phosphate in an amorphous form.
In accordance with a tenth embodiment, 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. In accordance with an eleventh embodiment, 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. In accordance with a twelfth embodiment, 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.
In accordance with a thirteenth embodiment, 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.
In accordance with a fourteenth embodiment, 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.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the 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.
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.
DETAILED DESCRIPTION OF THE INVENTIO
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.
Accordingly, in one embodiment, 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.
In another embodiment, the present invention provides a process for preparing sitagliptin pterostilbene phosphate, comprising:
a) providing a solution of pterostilbene phosphate in an organic solvent,
b) combining the step a) solution and sitagliptin free base, and
c) isolating the sitagliptin pterostilbene phosphate. 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.
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'. Alternatively, 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. If, so 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. Examples of such 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.
Preferably, 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. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. Preferably, 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.
Preferably, 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. In another embodiment, 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.
In another embodiment, 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.
In another embodiment, the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure. 03. In another embodiment, the present invention provides sitagliptin pterostilbene phosphate in crystalline form characterized by a Thermo gravimetric analysis (TGA) substantially in accordance with Figure. 04.
In another embodiment, the present invention provides a process for preparing sitagliptin pterostilbene phosphate in crystalline form, comprising:
a) providing a solution of pterostilbene phosphate in an organic solvent,
b) combining the step a) solution and sitagliptin free base, and
c) isolating the sitagliptin pterostilbene phosphate.
wherein 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. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. Preferably, 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.
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.
In another embodiment, the present invention provides sitagliptin pterostilbene phosphate in an amorphous Form.
In another embodiment, 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.
In another embodiment, 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.
In another embodiment, 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.
In another embodiment, 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.
In another embodiment, the present invention provides a process for preparing sitagliptin pterostilbene phosphate in amorphous Form A, comprising:
a) providing a solution of pterostilbene phosphate in an organic solvent selected from ethanol, acetone or mixtures thereof,
b) combining the step a) solution and sitagliptin free base,
c) optionally, concentrating the solution to obtain residue,
d) optionally, adding hydrocarbon solvent to precipitate the sitagliptin pterostilbene phosphate, and
e) isolating the sitagliptin pterostilbene phosphate amorphous Form A.
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. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. Preferably, 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. Optionally, 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.
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.
In another embodiment, the present invention provides a process for preparing sitagliptin pterostilbene phosphate in amorphous Form B, comprising:
a) providing a solution of pterostilbene phosphate in halogenated solvent such as chloroform,
b) combining the step a) solution and sitagliptin free base,
c) adding hydrocarbon solvent to precipitate the sitagliptin pterostilbene phosphate, and
d) isolating the sitagliptin pterostilbene phosphate amorphous Form B.
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. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. Preferably, 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.
The step of isolating the sitagliptin pterostilbene phosphate amorphous form by adding hydrocarbon solvent such as n-hexane, n-heptane and the like to precipitate 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 B.
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.
In another embodiment, the present invention provides a process for preparing sitagliptin pterostilbene phosphate in amorphous Form C, comprising:
a) providing a solution of pterostilbene phosphate in ether solvent,
b) combining the step a) solution and sitagliptin free base,
c) adding an alcohol solvent to precipitate the sitagliptin pterostilbene phosphate, and
d) isolating the sitagliptin pterostilbene phosphate amorphous Form C.
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. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. Preferably, 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.
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.
In another embodiment, the present invention provides a process for preparing sitagliptin pterostilbene phosphate in amorphous form D, comprising:
a) providing a solution of pterostilbene phosphate in ketone solvent,
b) combining the step a) solution and sitagliptin free base,
c) adding an alcohol solvent to precipitate the sitagliptin pterostilbene phosphate, and
d) isolating the sitagliptin pterostilbene phosphate amorphous Form D.
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. Typically, the solution is heated at a temperature of at least about 30°C to about reflux. Preferably, 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.
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. 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. The X- Ray powder diffraction can be measured by an X-ray powder diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step width=0.020°; and scan speed=5°/minute.
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 thermogravimetric analysis of sitagliptin pterostilbene phosphate recorded on TGA Q500 V 20.8 build 34 in platinum pan with a temperature rise of about 5°C/min in the range of about 30°C to about 300°C. In another embodiment, 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. Accordingly, 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.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
Unless stated to the contrary, any use of the words such as "including," "containing," "comprising" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.
For purposes of the present invention, the following terms are defined below. The term "composition" includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof. The term 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.
The term "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.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES:
Example 1: Preparation of sitagliptin pterostilbene phosphate.
Charged 0.84 gms of pterostilbene phosphate disodium, 20 ml of water and 20 ml of ethyl acetate in a round bottom flask at temperature 25°C to 35°C. Adjusted the pH of the solution to 1.8 to 2 with aqueous hydrochloric acid and then layers were separated. The resultant organic layer was evaporated under vacuum at a temperature below 50°C to obtain a residue. To the residue, charged 10 ml of isopropanol and mixed with 0.81 gms of sitagliptin free base in 10 ml of isopropanol at temperature 45°C to 50°C. The reaction mixture was heated to reflux temperature and maintained for 2 hours at same temperature. The 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.
Yield:.1.35 gms.
The H'-NMR is set forth in Figure. 01
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.
Yield: 0.55 gms.
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.
Yield: 0.57 gms.
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 4: Preparation of sitagliptin pterostilbene phosphate (amorphous Form)
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.
Yield: 0.58 gms.
The XRPD is set forth in Figure. 05.
Example 5: Preparation of sitagliptin pterostilbene phosphate (amorphous Form)
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.
Yield: 0.56 gms.
The XRPD is set forth in Figure. 05.
Example 6: Preparation of sitagliptin pterostilbene phosphate (amorphous Form)
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.
Yield: 0.56 gms.
The XRPD is set forth in Figure. 06.
Example 7: Preparation of sitagliptin pterostilbene phosphate (amorphous Form)
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.
Yield: 0.56 gms.
The XRPD is set forth in Figure. 07.
Example 8: Preparation of sitagliptin pterostilbene phosphate (amorphous Form)
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.
Yield: 0.55 gms.
The XRPD is set forth in Figure. 08.

Claims

Sitagliptin Pterostilbene phosphate.
The Sitagliptin Pterostilbene phosphate, wherein the ratio of sitagliptin and pterostilbene phosphate is 1 : 1.
Crystalline sitagliptin pterostilbene phosphate.
The crystalline sitagliptin pterostilbene phosphate of claim 3, characterized by an XRD pattern substantially in accordance with Figure 02.
The crystalline sitagliptin pterostilbene phosphate of claim 3, characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure. 03.
The crystalline sitagliptin pterostilbene phosphate of claim 3, characterized by a Thermo gravimetric analysis (TGA) substantially in accordance with Figure. 04.
A process for preparing crystalline sitagliptin pterostilbene phosphate, comprising:
a) providing a solution of pterostilbene phosphate in an organic solvent,
b) combining the step a) solution and sitagliptin free base, and c) isolating the sitagliptin pterostilbene phosphate.
The process of claim 7, wherein the organic solvent is selected from the group consisting of alcohols, esters, ethers, hydrocarbons, alkyl nitrates, water or mixtures thereof.
The process of claim 8, wherein the organic solvent is selected from the group consisting of methanol, isopropanol, isopropyl ether, nitromethane, water or mixtures thereof.
Claim 10: The process of claim 7, wherein the sitagliptin free base is combining in the form of its solution in an organic solvent. Claim 11 : The process of claim 10, wherein the organic solvent is selected from the group consisting of alcohols, esters, ethers, hydrocarbons, alkyl nitrates, water or mixtures thereof. The process of claim 11, wherein the organic solvent is selected from the group consisting of methanol, isopropanol, isopropyl ether, nitromethane, water or mixtures thereof.
The process of claim 7, wherein the step c) of isolating the sitagliptin pterostilbene phosphate is carried out by concentrated by subjecting the solution to heating, cooling the solution to precipitation, crystallization, Solvent precipitation, spray drying, freeze drying or agitated thin film evaporator (ATFE).
The process of claim 13, wherein the step c) is carried out by cooling the solution to precipitation or solvent precipitation.
The process of claim 14, further comprising adding another solvent prior to step c).
The process of claim 15, wherein another solvent is isopropyl ether.
Amorphous sitagliptin pterostilbene phosphate.
Amorphous Form A of sitagliptin pterostilbene phosphate.
Amorphous Form A of sitagliptin pterostilbene phosphate, characterized by an XRD pattern substantially in accordance with Figure 05.
A process for preparing sitagliptin pterostilbene phosphate in amorphous Form A, comprising:
a) providing a solution of pterostilbene phosphate in an organic solvent selected from ethanol, acetone or mixtures thereof, b) combining the step a) solution and sitagliptin free base, c) optionally, concentrating the solution to obtain residue, d) optionally, adding hydrocarbon solvent to precipitate the sitagliptin pterostilbene phosphate, and
e) isolating the sitagliptin pterostilbene phosphate amorphous Form A.
The process of claim 20, wherein the step a) solution is formed at a temperature of about 30°C to about 80°C.
The process of claim 20, wherein the sitagliptin free base is combining in the form of its solution in an organic solvent.
The process of claim 22, wherein the organic solvent is ethanol, acetone or mixtures thereof. Claim 24: The process of claim 20, wherein the hydrocarbon solvent is selected from n-hexane, n-heptane or mixtures thereof.
Claim 25: Amorphous Form B of sitagliptin pterostilbene phosphate.
Claim 26: Amorphous Form B of sitagliptin pterostilbene phosphate, characterized by an XRD pattern substantially in accordance with Figure 06.
Claim 27: A process for preparing sitagliptin pterostilbene phosphate in amorphous
Form B, comprising:
a) providing a solution of pterostilbene phosphate in chloroform, b) combining the step a) solution and sitagliptin free base, c) adding hydrocarbon solvent to precipitate the sitagliptin pterostilbene phosphate,
d) isolating the sitagliptin pterostilbene phosphate amorphous form B.
Claim 28: The process of claim 27, wherein the step a) solution is formed at a temperature of about 30°C to about 60°C. Claim 29: The process of claim 27, wherein the sitagliptin free base of step b) is combining in the form of its solution in chloroform.
Claim 30: The process of claim 27, wherein the hydrocarbon solvent is selected from n-hexane, n-heptane or mixtures thereof.
Claim 31: Amorphous Form C of sitagliptin pterostilbene phosphate.
Claim 32: Amorphous Form C of sitagliptin pterostilbene phosphate, characterized by an XRD pattern substantially in accordance with Figure 07.
Claim 33: A process for preparing sitagliptin pterostilbene phosphate in amorphous
Form C, comprising:
e) providing a solution of pterostilbene phosphate in ether solvent, f) combining the step a) solution and sitagliptin free base, g) adding an alcohol solvent to precipitate the sitagliptin pterostilbene phosphate, and
h) isolating the sitagliptin pterostilbene phosphate amorphous Form C.
Claim 34: The process of claim 33, wherein the ether solvent is selected form the group consisting of tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tertiary butyl ether or mixtures thereof. Claim 35: The process of claim 33, wherein the step a) solution is formed at a temperature of about 30°C to about 80°C.
Claim 36: The process of claim 33, wherein the sitagliptin free base of step b) is combining in the form of its solution with step a) solvent.
Claim 37: The process of claim 33, wherein the alcohol solvent is selected from methanol, ethanol, isopropanol or mixtures thereof.
Claim 38: Amorphous Form D of sitagliptin pterostilbene phosphate.
Claim 39: Amorphous Form D of sitagliptin pterostilbene phosphate, characterized by an XRD pattern substantially in accordance with Figure 08.
Claim 40: A process for preparing sitagliptin pterostilbene phosphate in amorphous
Form D, comprising:
a) providing a solution of pterostilbene phosphate in ketone solvent, b) combining the step a) solution and sitagliptin free base, c) adding an alcohol solvent to precipitate the sitagliptin pterostilbene phosphate, and
d) isolating the sitagliptin pterostilbene phosphate amorphous Form D.
Claim 41: The process of claim 40, wherein the ketone solvent is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone or mixtures thereof.
Claim 42: The process of claim 40, wherein the step a) solution is formed at a temperature of about 30°C to about 80°C. Claim 43: The process of claim 40, wherein the sitagliptin free base of step b) is combining in the form of its solution with step a) solvent.
Claim 44: The process of claim 40, wherein the alcohol solvent is selected from methanol, ethanol, isopropanol or mixtures thereof.
Claim 45: A pharmaceutical composition comprising sitagliptin pterostilbene phosphate in crystalline form or sitagliptin pterostilbene phosphate in amorphous form according to any of claims 1-44, together with one or more pharmaceutically acceptable excipients.
PCT/IN2014/000150 2013-03-21 2014-03-07 Sitagliptin pterostilbene phosphate salt, process for the preparation and pharmaceutical composition thereof WO2014147641A2 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7486615B2 (en) 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 Novel analogs of pterostilbene amino acid-containing carbonates for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003135A1 (en) * 2003-06-24 2005-01-13 Merck & Co., Inc. Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005020920A2 (en) * 2003-09-02 2005-03-10 Merck & Co., Inc. Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005030127A2 (en) * 2003-09-23 2005-04-07 Merck & Co., Inc. Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2006033848A1 (en) * 2004-09-15 2006-03-30 Merck & Co., Inc. Amorphous form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2011097372A2 (en) * 2010-02-03 2011-08-11 Aptuit Laurus Private Limited Pterostilbene cocrystals
CN103408591A (en) * 2013-07-17 2013-11-27 张家港威胜生物医药有限公司 Pterostilbene phosphate disodium salt synthesis method

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005003135A1 (en) * 2003-06-24 2005-01-13 Merck & Co., Inc. Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005020920A2 (en) * 2003-09-02 2005-03-10 Merck & Co., Inc. Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2005030127A2 (en) * 2003-09-23 2005-04-07 Merck & Co., Inc. Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2006033848A1 (en) * 2004-09-15 2006-03-30 Merck & Co., Inc. Amorphous form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
WO2011097372A2 (en) * 2010-02-03 2011-08-11 Aptuit Laurus Private Limited Pterostilbene cocrystals
CN103408591A (en) * 2013-07-17 2013-11-27 张家港威胜生物医药有限公司 Pterostilbene phosphate disodium salt synthesis method

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7486615B2 (en) 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 Novel analogs of pterostilbene amino acid-containing carbonates for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

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