Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention provides a novel process for the preparation of amorphous alogliptin benzoate.
• the present invention also provides amorphous alogliptin benzoate co-precipitated on copovidone, process for its preparation and pharmaceutical compositions comprising it.
• the present invention further provides novel salts of alogliptin, processes for their preparation and pharmaceutical compositions comprising them.
• the present invention further provides crystalline hydrochloride salt of alogliptin, process for its preparation and pharmaceutical compositions comprising it.
• the present invention further provides crystalline tartrate salt of alogliptin, process for its preparation and pharmaceutical compositions comprising it.
• Alogliptin chemically 2-( ⁇ 6-[(3i?)-3-aminopiperidin- l -yl]-3-methyl-2,4-dioxo- 3,4-dihydropyrimidin- l (2H)-yl ⁇ methyl)benzonitrile and has the structural formula:
• Alogliptin benzoate is an investigational anti-diabetic drug in the DPP-4 inhibitor class, being developed by Takeda Pharmaceutical Company.
• Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
• polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules.
• Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
• Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
• XRD X-ray diffraction
• DSC Differential Scanning Calorimetry
• IR Infrared spectrometry
• Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
• Alogliptin and its salts can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
• PCT publication no. WO 2010/ 109468 described acetate, trifluoroacetate, citrate, hydrochloric acid, L-lactate, succinate, benzoate and L-tartrate salts of alogliptin.
• alogliptin such as fumarate, malate, sulfate, tosylate, oxalate and nitrate.
• one object of the present invention is to provide a novel process for the preparation of amorphous alogliptin benzoate.
• Another object of the present invention is to provide amorphous alogliptin benzoate co-precipitated on copovidone, process for its preparation and pharmaceutical compositions comprising it.
• Another object of the present invention is to provide a fumarate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.
• Another object of the present invention is to provide a malate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.
• Another object of the present invention is to provide a sulfate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.
• Another object of the present invention is to provide a tosylate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.
• Another object of the present invention is to provide an oxalate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.
• Another object of the present invention is to provide a nitrate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.
• Another object of the present invention is to provide crystalline alogliptin hydrochloride, process for its preparation and pharmaceutical composition comprising it.
• Another object of the present invention is to provide crystalline alogliptin tartrate, process for its preparation and pharmaceutical composition comprising it.
• the salts of the present invention may also serve as intermediate for preparation of alogliptin free base or another salt of alogliptin.
• the present invention provides a process for the preparation of amorphous alogliptin benzoate, which comprises:
• step (b) optionally adding an anti solvent to the solution obtained in step (b);
• the present invention provides a process for the preparation of amorphous alogliptin benzoate, which comprises:
• step (a) cooling the solution obtained in step (a) at below 10°C;
• step (c) slurrying the residual mass obtained in step (c) with aromatic solvent; and e) isolating amorphous alogliptin benzoate.
• the present invention provides an amorphous alogliptin benzoate co-precipitated on copovidone.
• the present invention provides a process for the preparation of amorphous alogliptin benzoate co-precipitated on copovidone, which comprises:
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising amorphous alogliptin benzoate co-precipitated on copovidone and pharmaceutically acceptable excipients.
• the present invention provides a fumarate salt of alogliptin, that is, alogliptin fumarate.
• the present invention provides a process for the preparation of alogliptin fumarate, which comprises:
• step (a) adding fumaric acid to the solution obtained in step (a);
• the present invention provides a pharmaceutical composition comprising alogliptin fumarate and a pharmaceutically acceptable excipient.
• the present invention provides a malate salt of alogliptin, that is, alogliptin malate.
• the present invention provides a process for the preparation of alogliptin malate, which comprises:
• step (a) adding malic acid to the solution obtained in step (a);
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising alogliptin malate and a pharmaceutically acceptable excipient.
• the present invention provides a sulfate salt of alogliptin, that is, alogliptin sulfate.
• the present invention provides a process for the preparation of alogliptin sulfate, which comprises:
• step (b) adding sulfuric acid to the solution obtained in step (a);
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising alogl iptin sulfate and a pharmaceutically acceptable excipient.
• the present invention provides a tosylate salt of alogliptin, that is, alogliptin tosylate.
• the present invention provides a process for the preparation of alogliptin tosylate, which comprises:
• step (b) adding /?-tol uenesulfonic acid to the solution obtained in step (a);
• the present invention provides a pharmaceutical composition comprising alogliptin tosylate and a pharmaceutically acceptable excipient.
• the present invention provides an oxalate salt of alogliptin, that is, alogliptin oxalate.
• the present invention provides a process for the preparation of alogliptin oxalate, which comprises:
• step (b) adding oxalic acid to the solution obtained in step (a);
• the present invention provides a pharmaceutical composition comprising alogliptin oxalate and a pharmaceutically acceptable excipient.
• the present invention provides a nitrate salt of alogliptin, that is, alogliptin nitrate.
• the present invention provides a process for the preparation of alogliptin nitrate, which comprises:
• step (b) adding nitric acid to the solution obtained in step (a);
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising alogl iptin nitrate and a pharmaceutically acceptable excipient.
• the present invention provides a crystalline alogliptin hydrochloride.
• the present invention provides a process for the preparation of crystalline alogl iptin hydrochloride, which comprises:
• step (a) a) dissolving alogl iptin in a suitable solvent; b) adding hydrochloric acid to the solution obtained in step (a);
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising crystal l ine alogliptin hydrochloride and a pharmaceutically acceptable excipient.
• the present invention provides a crystalline alogliptin tartrate.
• the present invention provides a process for the preparation of crystalline alogl iptin tartrate, which comprises:
• step (a) adding tartaric acid to the solution obtained in step (a);
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising crystalline alogliptin tartrate and a pharmaceutically acceptable excipient.
• Figure 1 is X-ray powder diffraction spectrum of amorphous alogliptin benzoate.
• Figure 2 is X-ray powder diffraction spectrum of amorphous alogliptin benzoate co-precipitated on copovidone.
• Figure 3 is X-ray powder diffraction spectrum of crystalline alogliptin fumarate.
• Figure 4 is X-ray powder diffraction spectrum of crystalline alogliptin malate.
• Figure 5 is X-ray powder diffraction spectrum of crystalline alogliptin sulfate.
• Figure 6 is X-ray powder diffraction spectrum of crystalline alogliptin tosylate.
• Figure 7 is X-ray powder diffraction spectrum of crystalline alogliptin oxalate.
• Figure 8 is X-ray powder diffraction spectrum of crystalline alogliptin nitrate.
• Figure 9 is X-ray powder diffraction spectrum of crystalline alogliptin hydrochloride.
• Figure 10 is X-ray powder diffraction spectrum of crystalline alogliptin tartrate.
• X-Ray Powder Diffractogram was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.019 to 0.020 degrees two theta per step and a step time of 10.6 to 1 19 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 V and current 35 mA.
• room temperature refers to a temperature of about 25°C to about 35°C.
• amorphous alogliptin benzoate which comprises:
• step (b) optionally adding an anti solvent to the solution obtained in step (b);
• the solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, isobutyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, benzene, xylene, toluene, cyclohexane, hexane and n-heptane. More preferably the solvents are water, acetone, methanol and toluene.
• the anti solvent used in step (c) may preferably be a solvent or mixture of solvents selected from 1,4-dioxane, teterahydrofuran, tert-butyl methyl ether and diethyl ether, and more pre ferably the solvent is 1 ,4-dioxane.
• the reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0°C.
• Amorphous alogliptin benzoate may be isolated in step (e) by methods known such as filtration or centrifugation. According to another aspect of the present invention, there is provided a process for the preparation of amorphous alogliptin benzoate, which comprises:
• step (a) cooling the solution obtained in step (a) at below 10°C;
• step (c) slurrying the residual mass obtained in step (c) with aromatic solvent; and e) isolating amorphous alogl iptin benzoate.
• the alcohol ic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropanol, tert-butyl alcohol and n-butanol, and more preferably the alcohol ic solvent is methanol.
• the nitrile solvent used in step (a) may be a solvent or mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and benzonitrile. More preferably the nitri le solvent is acetonitrile.
• the reaction mass may preferably be cooled in step (d) at about 0 to 5°C.
• Removal of the solvent in step (c) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distil led off.
• the aromatic solvent used in step (d) may be a solvent or mixture of solvents selected from benzene, xylene, toluene, cyclohexane, hexane and n-heptane, and more preferably the aromatic solvent is hexane.
• Isolation of amorphous alogl iptin benzoate in step (e) may preferably be performed by conventional techniques such as centrifugation or filtration.
• an amorphous alogliptin benzoate co-precipitated on copovidone there is provided an amorphous alogliptin benzoate co-precipitated on copovidone.
• the powdered x-ray diffractogram (PX R.D) of amorphous alogliptin benzoate co-precipitated on copovidone is shown in figure 2.
• amorphous alogliptin benzoate co-precipitated on copovidone which comprises:
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitri !e, propionitrile.
• butyronitrile benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether.
• the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate.- and still more preferably the solvents are water, methanol, ethanol and acetonitri le.
• the reaction mass may preferably be cooled in step (c) at about 0 to 30°C and more preferably at about 0 to 1 0 (I C.
• Drying in step (b) may preferably be carried out at about 60 to 70°C under high vacuum.
• a pharmaceutical composition comprising amorphous alogliptin benzoate co-precipitated on copovidone and pharmaceutical ly acceptable excipients, and optionally other therapeutic ingredients.
• the amorphous alogliptin benzoate co-precipitated on copovidone may preferably be formu lated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• an alogliptin fumarate there is provided an alogliptin fumarate.
• the alogl iptin fumarate may preferably be a solid.
• the powdered x-ray d i ffractogram (PXR.D) of alogliptin fumarate is shown in figure 3.
• a process for the preparation of alogiiptin fumarate which comprises:
• step (a) adding fumaric acid to the solution obtained in step (a);
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitri le, propionitri le, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide.
• the sol vents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofuran and acetonitrile.
• the reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0°C.
• Alogiiptin fumarate may be isolated in step (e) by methods known such as filtration or centrifugation.
• a pharmaceutical composition comprisi ng alogiiptin fumarate and pharmaceutically acceptable excip ients, and optional ly other therapeutic ingredients.
• the alogiiptin fumarate may preferably be formu lated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• an alogiiptin malate According to another aspect of the present invention, there is provided an alogiiptin malate.
• the alogi i pt i n malate may pre ferably be a solid.
• the powdered x-ray diffractogram (PXRD) of alogliptin malate is shown in figure
• a process for the preparation o f alogliptin malate which comprises:
• step (b) adding mal ic acid to the solution obtained in step (a);
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitri le, propionitri le. butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride.
• solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl
• the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofuran and acetonitrile.
• the reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0 l) C.
• Isolation of alogliptin malate in step (e) may preferably be performed by conventional techniques such as centrifugation or filtration.
• a pharmaceutica l composition comprising alogliptin malate and pharmaceutically acceptable e.xcipients. and optional ly other therapeutic ingredients.
• the alogliptin malate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutica l forms.
• an alogliptin sul fate preferably be a solid.
• a process for the preparation of alogl iptin su lfate which comprises:
• step (b) adding sulfuric acid to the solution obtained in step (a);
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propionitri le, butyronitrile, benzonitrile, dirnethylformamide, dimethylsu lfoxide, benzene, tol uene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene d ichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tctrahydrofuran.
• solvents selected from water, methanol, ethanol, isopropanol, ter
• the sol vents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dirnethylformamide, dimethylsu l oxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrnhydrofuran and acetonitrile.
• the reaction mass may preferabl y be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0°C.
• Alogliptin sulfate may be isolated in step (e) by methods known such as filtration or centrifugation.
• a pharmaceutical composition comprising alogliptin sulfate and pharmaceutically acceptable excipients, and optional ly other therapeutic ingredients.
• the alogliptin sulfate may preferably be formu lated i nto tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• an alogliptin tosylate there is provided.
• the alogliptin tosylate may preferably be a solid.
• a process for the preparation of alogliptin tosylate which comprises:
• step (b) adding p-toluenesulfonic acid to the solution obtained in step (a);
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propion itri le, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether.
• the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofur n and acetonitrile.
• the reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 10°C.
• Isolation of alogl iptin tosylate in step (e) may preferably be performed by conventional techniques such as centri ugation or filtration.
• a pharmaceutical composition comprising alogliptin tosylate and pharmaceutically acceptable excipients, and optional ly other therapeutic ingredients.
• the alogliptin tosylate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• an alogliptin oxalate there is provided an alogliptin oxalate.
• the alogliptin oxalate may preferably be a solid.
• the powdered x-ray di ffractogram (PXRD) of alogliptin oxalate is shown in figure 7.
• a process for the preparation of alogliptin oxal ate which comprises:
• step (a) adding oxalic acid to the sol ution obtained in step (a);
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propion itri le, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, tol uene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene d ich loride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofu ran.
• solvents selected from water, methanol, ethanol, isopropanol, tert-but
• the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydro fu ran and acetonitrile.
• the reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0°C.
• Alogliptin oxalate may be iso lated in step (e) by methods known such as filtration or centrifugation.
• a pharmaceutical composition compri si ng alogliptin oxalate and pharmaceutically acceptable excipients, and optional ly other therapeutic ingredients.
• the alogliptin oxalate may preferably be formu lated into tab lets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• an alogliptin nitrate there is provided an alogliptin nitrate.
• the alogliptin nitrate may preferably be a solid.
• a process for the preparation of alogl iptin n itrate which comprises:
• step (b) adding nitric acid to the solution obtained in step (a);
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propion i tri le.
• the sol vents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, tetei ahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydro furan and acetonitrile.
• the reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0°C.
• Isolation of alogl iptin n itrate i n step (e) may preferably be performed by conventional techniques such as centri fugation and filtration.
• a pharmaceutical composition comprising alogliptin nitrate and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
• the alogliptin nitrate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• a crystalline alogliptin hydrochloride According to another aspect of the present invention, there is provided a crystalline alogliptin hydrochloride.
• the powdered x-ray diffractogram (PXRD) of crystalline alogliptin hydrochloride is shown in figure 9.
• a process for the preparation of crystalline alogliptin hydrochloride which comprises:
• step (a) adding hydrochloric acid to the solution obtained in step (a);
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether.
• the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofuran and acetonitrile.
• the reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 10°C.
• Crystalline alogliptin hydrochloride may be isolated in step (e) by methods known such as filtration or centrifugation.
• a pharmaceutical composition comprising crystalline alogliptin hydrochloride and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
• the crystalline alogliptin hydrochloride may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• a crystalline alogliptin tartrate According to another aspect of the present invention, there is provided a crystalline alogliptin tartrate.
• the powdered x-ray diffractogram (PXRD) of crystalline alogliptin tartrate is shown in figure 10.
• a process for the preparation of crystalline alogliptin tartrate which comprises:
• step (a) adding tartaric acid to the solution obtained in step (a);
• the suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether.
• the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofuran and acetonitrile.
• the reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 10°C.
• Isolation of crystalline alogliptin tartrate in step (e) may preferably be performed by conventional techniques such as centrifugation or filtration.
• a pharmaceutical composition comprising crystalline alogliptin tartrate and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
• the crystalline alogliptin tartrate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
• Step - I Preparation of 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)methyl)benzonitrile
• reaction mass was then cooled to 0 to 5°C and stirred for 1 hour.
• the reaction mass was filtered and washed with water and hexane to obtain a wet solid.
• water 200 ml
• pH 9.0 to 10.0 with sodium hydroxide (IN).
• the reaction mass was stirred for 30 minutes and then added methylene chloride (300 ml) and then the layers were separated.
• the pH of the aqueous layer was adjusted to 4.0 to 5.0 with hydrochloric acid (IN) and stirred for 30 minutes.
• the solid obtained was collected by filtration and then dried to obtain 19.3 gm of 2-((6-chloro-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)benzonitrile.
• Step - II Preparation of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)methyl)benzonitrile
• Step - III Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)benzonitrile (Alogliptin)
• Ethanol 48 ml was added to alogliptin (9.5 gm) and then added benzoic acid (6.8 gm) under stirring for 20 minutes to obtain a solution.
• the solution was then heated to 75 to 80°C and maintained for 2 hours.
• the reaction mass was then cooled to room temperature and then further cooled to -5 to 0°C.
• the contents were stirred for 1 hour at 0°C and filtered.
• the solid obtained was dried to give 12 gm of alogliptin benzoate.
• Alogliptin benzoate (1 gm) was added to isopropanol (50 ml) under stirring at room temperature. The reaction mass was then heated to reflux and then added isopropanol (13 ml), stirred for 15 minutes at reflux to obtain a clear solution. To the solution was added 1,4-dioxane (50 ml) slowly at reflux and then cooled to room temperature. The reaction mass was further cooled to 0 to 5°C and stirred for 20 minutes. The reaction mass was then concentrated and then dried under vacuum at 60°C for 13 hours to obtain 0.8 gm of amorphous alogliptin benzoate.
• Alogliptin benzoate (3 gm) was dissolved in acetone (10 ml) and water (10 ml) at room temperature and then stirred for 30 minutes to obtain a clear solution. The solution was then heated to reflux and stirred for 1 hour. The reaction mass was then cooled to room temperature and then concentrated. The solid thus obtained was dried under vacuum at 60°C for 12 hours to obtain 2.5 gm of amorphous alogliptin benzoate.
• Example 3 Example 3:
• Alogliptin benzoate (3 gm) was dissolved in a mixture of methanol (4 ml), acetonitrile (4 ml) and water (4 ml) under stirring at room temperature to obtain a clear solution. The solution was then cooled to 0 to 5°C and stirred for 30 minutes. The solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added hexane (25 ml) and then concentrated. The solid thus obtained was dried under vacuum at 60°C for 13 hours to obtain 2.6 gm of amorphous alogliptin benzoate.
• Alogliptin benzoate (3 gm) was dissolved in toluene (100 ml) and water (100 ml) at room temperature and then heated to 60°C to obtain a solution. The solution was then cooled to room temperature and stirred for 6 hours. The reaction mass was then concentrated and then dried under vacuum at 60°C for 13 hours to obtain 2.5 gm of amorphous alogliptin benzoate.
• Example 5 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous alogliptin benzoate co-precipitated on copovidone.
• Example 5 was repeated using isopropanol solvent instead of methanol solvent to obtain amorphous alogliptin benzoate co-precipitated on copovidone.
• Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added fumaric acid (1.02 gm) under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 1.7 gm of alogliptin fumarate.
• Example 8 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin fumarate.
• Example 8 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin fumarate.
• Example 8 was repeated using tetrahydrofuran solvent instead of ethanol solvent to obtain alogliptin fumarate.
• Example 8 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin fumarate.
• Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added malic acid
• Example 13 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin malate.
• Example 13 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin malate.
• Example 13 was repeated using tetrahydrofuran solvent instead of ethanol solvent to obtain alogliptin malate.
• Example 13 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin malate.
• Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added sulfuric acid (0.471 ml) slowly under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C and filtered. The solid obtained was dried to give 1.3 gm of alogliptin sulfate.
• Example 18 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin sulfate.
• Example 18 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin sulfate.
• Example 18 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin sulfate.
• Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added p- toluenesulfonic acid (2.28 gm) slowly under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 1.6 gm of alogliptin tosylate.
• Example 23 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin tosylate.
• Example 25 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin tosylate.
• Example 23 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin tosylate.
• Example 23 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin tosylate.
• Example 23 was repeated using tetrahydrofuran solvent instead of ethanol solvent to obtain alogliptin tosylate.
• Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added oxalic acid (0.769 gm) slowly under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C, stirred for 30 minutes and filtered. The solid obtained was dried to give 1.8 gm of alogliptin oxalate.
• Example 28 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin oxalate.
• Example 28 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin oxalate.
• Example 28 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin oxalate.
• Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added nitric acid (0.398 ml) under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 1.4 gm of alogliptin nitrate.
• Example 33 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin nitrate.
• Example 33 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin nitrate.
• g tetrahydrofuran solvent instead of ethanol solvent

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