WO2012017029A1 - Nouveaux sels de saxagliptine comportant des diacides organiques - Google Patents

Nouveaux sels de saxagliptine comportant des diacides organiques Download PDF

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Publication number
WO2012017029A1
WO2012017029A1 PCT/EP2011/063423 EP2011063423W WO2012017029A1 WO 2012017029 A1 WO2012017029 A1 WO 2012017029A1 EP 2011063423 W EP2011063423 W EP 2011063423W WO 2012017029 A1 WO2012017029 A1 WO 2012017029A1
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formula
acid
organic
crystalline compound
saxagliptin
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PCT/EP2011/063423
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English (en)
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Fritz Blatter
Katharina REICHENBÄCHER
Arthur Pichler
Robert Ziegert
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Sandoz Ag
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Priority to EP11741455.7A priority Critical patent/EP2601176A1/fr
Publication of WO2012017029A1 publication Critical patent/WO2012017029A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the present invention relates to novel salts of saxagliptin with organic di-acids.
  • the present invention also relates to methods of making the novel salts of saxagliptin with organic di-acids.
  • acetyl]-2-azabicyclo[3.1 .0]hexane-3-carbonitrile and its hydrochloride salt is an orally active reversible dipepdidyl peptidase-4 (DPP4) inhibitor, which is used as a therapeutic agent for treatment of type-2 diabetes mellitus, obesity or related diseases. It is disclosed for example in US 6,395,767, example 60.
  • saxagliptin free base and specific acid addition salts including saxagliptin hydrochloride polymorphs, a fumarate (2: 1 ), a tartrate, a benzoate, a trifluoroacetate, a bromide, an iodide, an ammoniumsulfate complex and a nitrate are disclosed in WO 2008/131 149.
  • salts of saxagliptin disclosed in WO 2008/131 149 are pharma- ceutically not acceptable, while the free base is susceptible to intramolecular cyclysation.
  • Saxagliptin is marketed in a form wherein the base is formulated with an excess of hydrochloric acid.
  • the formulation disclosed for example in US 2005/0266080 comprises a coated tablet formulation and a mix of saxagliptin hydrochloride polymorphs. As different polymorphs typically exhibit different properties with regard to solubility and dissolution kinetics, it can be expected to be difficult to produce a finished dosage form with reproducible dissolution properties based on such a mix of polymorphs.
  • the saxagliptin hydrochloride poly- morphs while in general showing good solubility in water, are quite prone to conversion to a number of different distinct hydrates upon exposure to environments differing in relative humidity, making it hard to control the polymorphic state during pharmaceutical processing.
  • the above mentioned patent application US2005/0266080 also describes a capsule formulation of the benzoate hydrate as showing insufficient stability.
  • the benzoate salt is described to have a limited solubility of less than 15 g/l in water.
  • the disclosed salts of saxagliptin are all hydrated forms having relatively high water content.
  • High-water content forms can have certain drawbacks, in
  • a crystalline compound comprising a mixture of a compound of formula I (INN: Saxagliptin) formula I and an organic C4-diacid of formula II,
  • the crystalline compound comprising saxagliptin (compound of formula I) and the organic C4-diacid of formula II may be a salt.
  • Saxagliptin may be a protonated cation, for example saxagliptin protonated at the nitrogen atom of the primary amino group and the counterion may be a respective monocarboxylate anion.
  • the crystalline compound comprises saxagliptin and the organic C4-diacid in the denoted molar ratio.
  • the molar ratio of the compound of formula I to the organic C4-diacid of formula II is of from 1 :0.9 to 1 : 1 .1 and most preferred is 1 : 1 .
  • the organic acid of formula II is selected from the group consisting of maleic acid, malic acid, L-malic acid, D-malic acid and succinic acid.
  • the crystalline compound of the invention preferably is an essentially anhydrous form having a water content of below 1 wt-% at 50% relative humidity (20°C) as determined by the Karl Fischer method.
  • the present invention relates to a crystalline compound having a water content of below 0.8 wt-%, more preferably below 0.5 wt-% when allowed to equilibrate by storage at 50% r.h. at 20°C.
  • the organic acid is maleic acid and the crystalline compound has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ 0.2° 2 ⁇ (CuKa radiation)) at 7.5°, 14.3°, 15.5°, 16.8° and 22.5°, referred to as form A.
  • form A has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ 0.2° 2 ⁇ (CuKa radiation)) at 6.9°, 7.5°, 9.1 °, 1 1 .2°, 14.3°, 15.1 °, 15.5°, 16.8°, 17.9°, 18.4°, 19.1 °, 20.8°, 21 .2° and 22.5°.
  • XRPD X-ray powder diffractogram
  • FIG 1 An X-ray powder diffractogram of a sample of the crystalline maleate salt of saxagliptin (form A) is shown in figure 1 and the present invention, in a preferred embodiment, relates to a crystalline salt of saxagliptin of the first aspect displaying a XRPD pattern which is substantially in accordance with figure 1 .
  • crystalline maleate salt (form A) of the first aspect characterized by an FT Raman spectrum substantially in accordance with figure 2.
  • the crystalline maleate salt of the present invention (form A) preferably has a low water content of below 0.5 wt-% (determined by Karl Fischer titration), more preferably of below 0.2 wt-%, and one measured sample provided a water value of 0.15 wt-%. Investigation of the crystalline maleate salt (form A) of the present invention by dynamic vapor sorption showed a negligible mass increase up to a relative humidity of about 60%.
  • the crystalline saxagliptin maleate salt of the first aspect can be prepared by an efficient crystallization process from typical class 3 solvents (according to ICH Q6a) such as esters, e.g. ethyl acetate or isopropyl acetate, ketones, e.g.
  • acetone or methyl ethyl ketone or alcohols, e.g. 1 - or 2-propanol or ethanol.
  • thermogravimetric analysis shows a release of only small amounts of water and organic solvent of less than 2 % ( m/m), although the produced sample was dried under very mild conditions. Therefore, it is expected that the required specifications for residual solvent content according to the ICH guidelines can be reached with short drying times at rather low temperature, which is an
  • aqueous solubility of the maleate salt of the present invention was determined to be about 196 g per liter at a resulting pH of about 4, which is more than 13 -fold higher than that of the known benzoate salt which is
  • the acid is L-malic acid and the crystalline compound has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ 0.2° 2 ⁇ (CuKa radiation)) at 6.3°, 10.2°, 15.7°, 19.1 ° and 20.5°, referred to as form B.
  • form B has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ 0.2° 2 ⁇ (CuKa radiation)) at 6.3°, 10.2°, 10.9°, 12.7°, 14.1 °, 14.4°, 15.7°, 17.3°, 18.6°, 19.1 °, 19.5°, 20.5° and 22.0°.
  • the crystalline L-malate salt of saxagliptin (form B) can be further characterized by a XRPD pattern being substantially in accordance with figure 3.
  • the crystalline L-malate salt (form B) of the invention can be described by an FT-Raman spectrum comprising peaks at wavenumbers of 3064, 2928, 2853, 2242, 1745, 1643, 1436, 1 194, 802, 697 and 556 ⁇ 2 cm "1 .
  • Crystalline saxagliptin L-malate (form B) of the present invention can be further characterized by an FT Raman spectrum substantially in accordance with figure 4.
  • a sample of the crystalline L-malate salt (form B) of the present invention revealed a molar ratio of the compound of formula I and malic acid of about 1 : 1 (determined by 1 H-NMR).
  • the crystalline forms of the malate salt may contain H 2 0 and/or organic solvent.
  • the TG-FTIR investigation of one produced sample of form B shows a small loss of about 0.9 wt-% upon heating to 180°C which is attributable to small amounts of H 2 0 and ethyl acetate.
  • the aqueous solubility of form B was determined to be about 191 g per liter at a resulting pH of about 4 which is more than 10 -fold higher than that of the known benzoate salt which is approximately 15 g/l.
  • the organic acid is succinic acid and the crystalline compound has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ 0.2° 2 ⁇ (CuKa radiation)) at 14.6°, 19.2°, 20.3°, 21 .3° and 22.7°, referred to as form C.
  • form C has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ 0.2° 2 ⁇ (CuKa radiation)) at 6.7°, 7.8°, 9.2°, 13.5°, 14.1 °, 14.6°, 15.9°, 17.2°, 18.2°, 19.2°, 20.3°, 21 .3°, 22.7° and 24.1 °.
  • the crystalline succinate salt of saxagliptin (form C) can be further characterized by a XRPD pattern substantially in accordance with figure 5.
  • form C can be described by an FT-Raman spectrum comprising peaks at wavenumbers of 3096, 2931 , 2855, 2241 , 1668, 1437, 1 181 , 1031 , 960 and 699 ⁇ 2 cm “1 .
  • Crystalline saxagliptin succinate (form C) of the present invention can be further characterized by an FT Raman spectrum substantially in accordance with figure 6.
  • a sample of the crystalline succinate salt (form C) of the present invention revealed a molar ratio of the compound of formula I and succinic acid of about 1 : 1 (determined by 1 HNMR).
  • the aqueous solubility was determined to be about 216 g per liter at a resulting pH of about 4.5, which is more than 10 -fold higher than that of the known benzoate salt which is approximately 15 g/l.
  • the present invention further refers to a process for obtaining the crystalline compound comprising the steps of: a) providing a compound of formula I (INN: Saxagliptin)
  • step b) optionally concentrating the composition of step b)
  • step d) optionally equilibrating the obtained suspension of step d) and
  • step b) neat organic C4-diacid of formula II or organic C4-diacid of formula II in a suitable solvent may be added to the mixture of step a).
  • suitable solvents are for instance polar and/or protic solvents like ethanol, isopropanol, acetone, water or mixtures thereof.
  • the solution of the C4-diacid of formula II in the solvent is preferably a saturated or nearly saturated solution of the respective acid.
  • the organic acid of formula II is selected from the group consisting of maleic acid, malic acid, L-malic acid, D-malic acid and succinic acid.
  • the molar ratio of the compound of formula I in step a) and the acid of formula II of step b) is in the range of from 1 :0.5 to 1 :2, even more preferred of from 1 :0.5 to 1 : 1 .2, preferably of from 1 :0.5 to 1 : 1 .1 and most preferred is 1 : 1 .
  • the process further may comprise step g) of slurrying the isolated precipitate of step f) in a further suitable solvent or mixture of solvents being preferably acetonitril, ethylacetate and/or 2-propanol and h) isolating the obtained precipitate.
  • step c) a part of the solvent is removed by for instance distillation or evaporation under reduced pressure or in a flow of a carrier gas like N 2 .
  • step c) the entire solvent is removed by for instance distillation or evaporation under reduced pressure or in a flow of a carrier gas like N 2 and the residue is dissolved in a suitable solvent or mixture of solvents and water.
  • the solvent may be selected from the group consisting of C2-C4 alcohols, a C3-C6 ketone, an ether or an acetic ester C1 -C4 alkylester, acetonitrile, a hydrocarbon or mixtures thereof.
  • step d) e) and/or g) the obtained mixture may be stirred.
  • Step d), e) and/or g) may be carried out at a temperature of from 10°C to 30°C.
  • Suspension equilibration in step e) and/or slurrying in step g) are preferably carried out at a temperature from 10 °C to 30 °C and most preferred at ambient temperature.
  • Step e) and/or g) are typically carried out for one day.
  • samples may be recovered from the suspension and analyzed by XRPD. Filtration is performed when the XRPD analysis indicates that the desired form is obtained in a reasonable purity.
  • step d) e) and/or g) seed crystals are added.
  • Said seed crystals preferably are the desired form of the crystalline compound of the present invention which is to be obtained.
  • a process for the preparation of the novel crystalline salts of saxagliptin with organic acid is also subject of the invention.
  • the crystalline maleate salt (form A) of the invention may be prepared by combining saxagliptin free base with maleic acid in a suitable solvent.
  • the molar ratio of saxagliptin to maleic acid is not critical; typically 0.9 equivalents of maleic acid to about 2 equivalents of maleic acid are used.
  • Preferably 1 to 1 .5 equiva- lents of maleic acid is employed, even more preferably one equivalent of maleic acid is used.
  • Suitable solvents include esters, e.g. ethylacetate, alcohols, ketones, or nitriles, e.g. acetonitrile or mixtures thereof.
  • the solution or suspension may be concentrated in order to induce crystallization or in order to complete crystallization.
  • a preferred temperature for the crystallization step is from about 10° to about 70°C, preferred is ambient temperature of about 15 to 40°C.
  • the obtained crystals may be isolated in usual manner, e.g. by filtration and drying in vacuo.
  • the crystalline L-malate salt (form B) of the invention may be prepared by combining saxagliptin free base with L-malic acid in a suitable solvent.
  • the molar ratio of saxagliptin to L-malic acid is not critical; typically 0.9 equivalents of L-malic acid to about 2 equivalents of L-malic acid are used.
  • L-malic acid Preferably 1 to 1 .5 equivalents of L-malic acid is employed, even more preferably one equivalent of L-malic acid is used.
  • suitable solvents include esters, e.g. preferably ethyl- acetate, alcohols, ketones, or nitriles, e.g. preferably acetonitrile or mixtures thereof. If desirable the solution or suspension may be concentrated in order to induce crystallization or in order to complete crystallization.
  • a preferred temperature for the crystallization step is from about 10° to about 70°C, preferred is ambient temperature of about 15 to 40°C.
  • the obtained crystals may be isolated in usual manner, e.g. by filtration and drying in vacuo.
  • the crystalline succinate salt (form C) of the invention may be prepared by combining saxagliptin free base with succinic acid in a suitable solvent.
  • the molar ratio of saxagliptin to succinic acid is not critical; typically 0.9 equivalents of succinic acid to about 1 .5 equivalents of succinic acid are used.
  • Preferably 1 to 1 .2 equivalents of succinic acid is employed, even more preferably one equivalent of succinic acid is used.
  • Suitable solvents include alcohols, e.g.
  • a preferred temperature for the crystallization step is from about 10° to about 70°C, preferred is ambient temperature of about 15 to 40°C.
  • the obtained crystals may be isolated in usual manner, e.g. by filtration and drying in vacuo.
  • novel salts of the invention are stable, e.g. the maleate salt shows no increase in the content of the cyclic amidine impurity disclosed for example in US 2005/0266080 designated as cis-cyclic amidine (CA) when kept dry and when stored in closed vial at 60°C for 7 days.
  • CA cis-cyclic amidine
  • the present invention also relates to pharmaceutical compositions comprising the crystalline salts of the invention. It is preferred that the pharmaceutical composition comprising the crystalline compound of the invention show a high chemical and physical stability.
  • the crystalline compounds are formulated in their anhydrous form (i.e., neither as a hydrate nor as a solvate) and the formulated crystalline compounds do not undergo any phase change during formulation and during their shelf-life which is at least 180 days, preferably at least 2 years.
  • the equilibrium relative humidity of the pharmaceutical compositions comprising the crystalline anhydrous compounds of the invention is measured by determining the relative humidity in % in the air of the test sample, e.g. a pharmaceutical composition of the invention comprising the crystalline compound, after establishment of a humidity equilibrium in a closed system at a constant temperature.
  • the pharmaceutical composition of the invention comprising the novel anhydrous crystalline forms of the invention are preferably stored in a relatively dry environment, and preferably it is to be assured that the storage environment remains relatively dry during the lifetime of the pharmaceutical composition.
  • the invention therefore also relates to a container comprising the crystalline compound of the invention which container is able to keep the equilibrium relative humidity of the composition at below 70%, preferably of below 60%, preferably from about 20% to about 60%.
  • novel crystalline compound of the present invention may be used alone or in combination with one or more types of antidiabetic agents (employed to treat diabetes and related diseases) and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate dosage form or by injection.
  • antidiabetic agents which optionally employed in combination with the novel crystal forms of the compound of formula I are more antidiabetic agents or antihyperglycemic, hypolipidemic or lipid-modulating agents including insulin secretagogues or other antidiabetic agents preferably having a mechanism different from DPP4 inhibition and may include biguanidines, sulfonyl ureas, glucosidase inhibitors, PPAR ⁇ agonists, such as thiazolidinediones, SGLT2 inhibitors, PAR ⁇ / ⁇ dual antagonists, aP" inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, as well as insulin and/or glucagons-like peptide-1 (GLP-1 ) or mimetics thereof or SIRT activators or mimics thereof.
  • biguanidines such as thiazolidinediones, SGLT2 inhibitors, PAR ⁇ / ⁇ dual antagonists, aP" inhibitors, glycogen
  • a pharmaceutical composition will be employed containing the novel crystalline salts of the compound of formula I, with or without another antidiabetic agent and/or other therapeutic agent, in association with a pharmaceutical vehicle or diluent.
  • the pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired
  • the dose for adults is preferably between 1 mg to 1000 mg per day, preferably between 5 and 100 mg per day, which can be administered in a single dose or in the individual doses from 1 -4 times a day.
  • a typical tablet contains one or more excipients such as bulking agents, optionally a binder and a disintegrant.
  • bulking agents include cellulose derivatives, such as microcrystalline cellulose, lactose, sucrose, starch, pre- gelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, inorganic salts such as calcium salts, e.g. calcium carbonate, calcium phosphate, dicalcium phosphate, dextrin or dextrates, maltodextrin compressible sugars and/or other known bulking agents or fillers.
  • binders suitable for use include hydroxypropyl cellulose, PVP, starch, hydroxypropylmethyl cellulose, cellulose acetate as well as a wax binder such as carnauba wax, polyethylenes or other conventional binding agents or mixtures thereof.
  • disintegrants examples include croscarmellose sodium, crospovidone, starch, low substituted hydroxypropyl cellulose as well as other conventional
  • the lubricant optionally present include for example magnesium stearate, zinc stearate, calcium sterarate, talc, carnauba wax, stearic acid, palmitinic acid, sodium laurylsulfate or hydrogenated vegetable oils and fats or other known lubricants or mixtures thereof.
  • Tablets may be coated including a tablet core and a inner seal coating layer coated on the tablet core, a second coating layer containing the crystals of the present invention coated on the inner seal coating on the tablet core and
  • an outer protective coating layer coated on the second coating layer of the tablet as e.g. disclosed in US 2005/0266080.
  • Typical capsules for oral administration contain the novel crystalline compound of the invention contain e.g., lactose, crosscarmelose, magnesium stearate or e.g. sodium stearyl fumarate.
  • the aqueous solubility was determined by suspending the corresponding salt in water. The suspensions were shaken for 24 hours at 25°C and 500 rpm. After filtration the solution was investigated by HPLC using the following method:
  • TSP HPLC UV3000, AS3000, P4000, SCM1000
  • Dynamic (water) vapor sorption is a method well known in the art to monitor the adsorption of water on a solid material. Therefore, DVS is a suitable method to determine the hygroscopic nature of a pharmaceutical active ingredient.
  • DVS was performed with a Surface Measurement Systems Ltd. DVS-1 water sorption analyzer or with SPS1 1 -100 ⁇ moisture sorption instrument form Bio MeBtechnik, Ulm, Germany. Program: The relative humidity was kept at starting value of 50% for two hours, then continuously scanned from 50% to 0 %, kept constant at 0% for four hours, and then scanned to 96% relative humidity, and kept constant for four hours, then r.h. was scanned back to 50% and kept there for two hours. The scanning change rate of relative humidity was 5% per hour. The temperature was 25 ⁇ 0.1 °C.
  • FT- Raman spectroscopy was performed using a Bruker RFS100 ( Nd:YAG 1064 nm exitation, 300 mW laser power, Ge detector, 64 scans, range
  • Differential scanning calorimetry is a well known method in the art that measures the heat flow through a sample upon heating at a defined rate. It is a suitable method to determine the melting temperatures, the glass transition temperature, or other thermal events such as phase conversions or thermal decomposition.
  • DSC was performed using a Perkin Elmer DSC 7. Measurements were performed in closed Au crucibles, at heating rates or 10 or 20°C min "1 , range -50°C to 250°C.
  • XRPD XRPD:
  • the measurements were carried out with a Bruker D8 Advance powder X-ray diffractometer using Cu K radiation in the Bragg-Brentano reflection geometry. Generally, the 2 ⁇ values are accurate within an error of ⁇ 0.1 -0.2°. The relative peak intensities can vary considerably for different samples of the same crystalline form because of different preferred orientations of the crystals.
  • the samples were prepared without any special treatment other than the application of slight pressure to get a flat surface. Silicon single crystal sample holders of either 0.5 mm or 0.1 mm depth and 12 mm cavity diameter were used. The tube voltage and current were 40 kV and 40 mA, respectively.
  • the X-ray diffracto- meter is equipped with a LynxEye detector. A variable divergence slight was used with a 3° window. The step size was 0.02 °2 ⁇ with a step time of
  • TG-FTIR is a suitable methods to identify solvates or hydrates.
  • TG-FTIR was performed on a Netzsch Thermo-Microbalance TG 209, which is coupled to a Bruker FT-IR Spectrometer Vector 22. The measurements were carried out with aluminum crucibles with a micro pinhole under a nitrogen atmosphere and at a heating rate of 10 °C/min over the range 25-250 °C.
  • Vapor sorption of the sample was performed as described above starting at a relative humidity of 50% to a relative humidity of 70%. A negligible mass increase was observed up to a relative humidity of about 60%. A mass increase of about 2.2 % was observed from about 65% to 70% relative humidity. A water content of 2.5% was found by KF. A sample was stored in a desiccator at 63% relative humidity for 24 hours : H20 by KF : 0.45% Table 1 : XRPD peaks of saxagliptin maleate (form A) at 2-theta angles ⁇ 0.2
  • vs means very strong
  • s means strong
  • m means medium
  • w means weak
  • vw means very weak intensity
  • a sample of the maleate salt (water content by KF 0.15%) was stored in a sealed container at 60°C for 7 days and no increase of cis-cyclic amidine impurity was found after the stress test when using the same HPLC method as for solubility determination which is provided above.
  • the obtained XRPD pattern corresponds to the pattern of figure 3 and the FT-Raman spectrum corresponds to the spectrum shown in figure 4.
  • Karl Fischer titration revealed a water content of 0.22%.
  • a sample of the L-malate salt was stored in a desiccator at about 60% relative humidity for 24 hours and a water content of 0.45% by KF was found.
  • Table 2 XRPD peaks of saxagliptin L-malate (form B) at 2-theta angles ⁇ 0.2
  • the water content by KF was 0.1 1 %.
  • a sample was stored in a desiccator at about 60% relative humidity for 24 hours and a water content of 0.24% by KF was found.

Abstract

La présente invention concerne un composé cristallin comprenant un mélange d'un composé de formule (I) (INN : Saxagliptine) et d'un diacide organique en C4 de formule (II), R représentant H ou OH, et X et Y représentant tous les deux H ou formant une liaison l'un avec l'autre, la double liaison résultante étant en configuration Z, à condition que R représente H si X et Y représentent une liaison, ou un hydrate de celui-ci, le rapport molaire du composé de formule (I) au diacide organique en C4 de formule (II) valant de 1:0,8 à 1:1,2, ainsi qu'un procédé pour son obtention.
PCT/EP2011/063423 2010-08-06 2011-08-04 Nouveaux sels de saxagliptine comportant des diacides organiques WO2012017029A1 (fr)

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WO2014006569A2 (fr) 2012-07-02 2014-01-09 Ranbaxy Laboratories Limited Sels de saxagliptine
CN103896923A (zh) * 2012-12-27 2014-07-02 北京莱博赛路森药物科技有限公司 一种降血糖化合物、其制备方法、包含其的药物组合物及其用途
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US10419344B2 (en) 2016-05-31 2019-09-17 Avago Technologies International Sales Pte. Limited Multichannel input/output virtualization

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WO2013175297A1 (fr) 2012-05-24 2013-11-28 Apotex Pharmachem India Pvt. Ltd Sels de saxagliptine avec des acides organiques
US9994523B2 (en) 2012-05-24 2018-06-12 Apotex Inc. Salts of Saxagliptin with organic acids
WO2014006569A2 (fr) 2012-07-02 2014-01-09 Ranbaxy Laboratories Limited Sels de saxagliptine
WO2014006569A3 (fr) * 2012-07-02 2014-03-06 Ranbaxy Laboratories Limited Sels de saxagliptine
CN103896923A (zh) * 2012-12-27 2014-07-02 北京莱博赛路森药物科技有限公司 一种降血糖化合物、其制备方法、包含其的药物组合物及其用途
WO2014101067A1 (fr) * 2012-12-27 2014-07-03 北京莱博赛路森药物科技有限公司 Composé hypoglycémique et son procédé de préparation, composition pharmaceutique comprenant le composé hypoglycémique, et son application
CN103896923B (zh) * 2012-12-27 2016-03-02 北京莱博赛路森药物科技有限公司 一种降血糖化合物、其制备方法、包含其的药物组合物及其用途
WO2015067223A1 (fr) 2013-11-06 2015-05-14 Zentiva, K., S. Sel de l-tartrate de (1s,3s,5s)-2-[(2s)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile et procédé de préparation
US10419344B2 (en) 2016-05-31 2019-09-17 Avago Technologies International Sales Pte. Limited Multichannel input/output virtualization
US10797999B2 (en) 2016-05-31 2020-10-06 Avago Technologies International Sales Pte. Limited Multichannel input/output virtualization

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