Classifications

• • 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

• a novel crystalline compound comprising saxagliptin and phosphoric acid
• the present invention relates to a novel crystalline compound comprising saxagliptin and phosphoric acid and hydrates thereof.
• the present invention also relates to methods of making the novel crystalline compound.
• 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 polymorphs 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 US 2005/0266080 also describes the 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.
• an improved salt form of saxagliptin with both good processability/polymorphic stability and good solubility would be desirable.
• a crystalline compound comprising a mixture of a compound of formula I (INN: Saxagliptin)
• the invention also provides processes for forming the crystalline compound and pharmaceutical compositions comprising said crystalline compound.
• the following-abbreviations apply unless explicitly stated otherwise:
• the crystalline compound comprising saxagliptin (compound of formula I) and phosphoric acid 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 respective counterion may be a dihydrogenphosphate anion.
• the crystalline compound comprises saxagliptin and phosphoric acid in the denoted molar ratio.
• the molar ratio of the compound of formula I and phosphoric acid is of from 1 :0,85 to 1 : 1 , 15, more preferably of from 1 :0,9 to 1 : 1 , 1 and most preferred 1 : 1 .
• the crystalline compound preferably has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ 0,2° 2 ⁇ (CuKa radiation)) at 5,6°, 7,3°, 17,6° and 18,0°, referred to as form A.
• form A has at least one further peak at 4,6°, 10,8°, 1 1 ,3°, 15,0°, 19,3°, 19,5°, 22,8° and 23,2°
• FIG. 1 An X-ray powder diffractogram of a sample of form A of the first aspect is shown in figure 1 and the present invention, in a preferred embodiment, relates to form A of the first aspect displaying a XRPD pattern which is substantially in accordance with figure 1 .
• form A of the first aspect can be described by a FT-Raman spectrum comprising peaks at wave numbers of 3098, 2924, 2245, 1655, 1458, 1436, 1 184, 1 157, 772, and 698cm "1 ⁇ 1 cm "1 .
• An FT Raman spectrum of a sample of form A of the first aspect is shown in figure 2.
• form A of the first aspect is characterized by an FT Raman spectrum substantially in accordance with figure 2.
• the crystalline compound of the present invention further comprises water and the molar ratio of the compound of formula I and water is in the range of from 1 :0,3 to 1 :5 and even more preferred of from 1 :0,3 to 1 :2.
• the water content of the crystalline compound of the present invention may also be characterized in terms of weight percentages.
• said water content can be determined by Karl Fischer Titration (KF titration).
• the crystalline compound has a water content of from 2 wt-% to 4 wt-% and more preferably from 2, 1 wt-% to 3 wt-%.
• the molar ratio of the compound of formula I and water is in the range of from 1 :0,3 to 1 :0,7, being preferably form A.
• form A has a water content of from 2 wt-% to 4 wt-%, more preferably from 2, 1 wt-% to
• the crystalline compound form A of the first aspect is sometimes also simply referred to as the "hemihydrate".
• the crystalline compound form A of the first aspect reveals a molar ratio of the compound of formula I and phosphoric acid of 1 : 1 confirmed by elemental composition analysis. Elemental analysis of the hemihydrate revealed a water content of 2,3% by calculation. According to the Karl-Fischer method a water content of 2,39% was found after drying. After storage at 76% relative humidity a water content of 2,25% was found.
• form A of the first aspect is surprisingly hardly hygroscopic.
• This provides the advantage that the crystalline phosphate salt of saxagliptin of the first aspect of the invention does not require special precautions for the typical manufacture processes for pharmaceutical compositions.
• saxagliptin hydrochlorides disclosed in the art which - dependent on the relative humidity to which they are exposed - convert to a number of different distinct hydrates, there is no need for stringent drying or controlling exposure time to high relative humidity during manufacture or storage of pharmaceutical compositions.
• the solubility of the crystalline compound form A of the first aspect of the invention in water was determined to be > 138 g /I and is thus more than 9-fold higher than that of saxagliptin benzoate.
• the polymorphic stability of the crystalline phosphate salt of saxagliptin of the first aspect of the invention is very high. Equilibration of form A of the first aspect in a variety of solvents or solvent mixtures gave no observable change to any other polymorph.
• form A of the first aspect stays stable over the whole range of relative humidity conditions to which a solid oral composition is typically exposed. Furthermore, its chemical stability is comparable to that of known hydrochlorides with regard to the increase in the content of the cyclic amidine impurity disclosed for example in US2005/0266080 designated as cis-cyclic amidine (CA ) when kept dry and when stored in a closed vial at 60°C for 7 days.
• CA cis-cyclic amidine
• the present invention also relates to pharmaceutical compositions comprising the crystalline compound of the present invention and preferably form A of the first aspect of the invention, wherein the crystalline salt in said composition is present as a stable polymorph, preferably in a physical phase purity of more than 80%, even more preferably in a phase purity of better than 90%, and most preferred in a phase purity of more than 95%.
• a stable polymorph is to be understood as no decrease in phase purity of more than 2% during a storage period of 6 months, more preferably of 12 months, even more preferably of 18 months and in particular 24 months. Said phase purity can be determined by x-ray crystallography.
• the second aspect of the present invention preferably refers to a crystalline compound having an XRPD pattern with at least one characteristic peak
• form B has at least one further peak (expressed in 2 ⁇ ⁇ 0,2° 2 ⁇ (CuKa radiation)) at 6, 1 °, 16, 1 °, 16,4°, 18,0°, 19,3°, 20,3°, 20,6°, 21 ,0° and 22,8°.
• an X-ray powder diffractogram is measured with copper K-alpha radiation.
• An X-ray powder diffractogram of a sample of form B of the second aspect is shown in figure 3 and the present invention.
• form B has an XRPD pattern substantially in accordance with figure 3.
• form B can be described by a FT-Raman spectrum comprising peaks at wavenumbers of 3093, 2928, 2241 , 1655, 1436, 1 183, 1 157, 773, and 698cm "1 ⁇ 1 cm "1 .
• an FT-Raman spectrum of a sample of form B of the second aspect is shown in figure 4 and the present invention, in a preferred embodiment, relates to form B characterized by an FT Raman spectrum substantially in accordance with figure 4.
• the molar ratio of the compound of formula I and water is in the range of from 1 :0,7 to 1 :4, being preferably form B.
• Form B of the second aspect is sometimes also simply referred to as the "higher hydrate".
• Form B of the second aspect is also useful as a new intermediate in the preparation of the crystalline compound form A of the present invention.
• slurrying of form B in a suitable solvent leads to form A.
• the present invention further refers to a process for obtaining the crystalline compound of the present invention comprising the steps of:
• step b) adding phosphoric acid to the mixture of step a)
• step b) optionally concentrating the composition of step b)
• step d) optionally equilibrating the obtained suspension of step d) and
• the molar ratio of the compound of formula I in step a) and the phosphoric acid of step b) is in the range of from 1 :0,5 to 1 :3 and even more preferred in the range of from 1 :0,5 to 1 : 1 ,2.
• step b) neat phosphoric acid or phosphoric acid in a suitable solvent like water or any other polar solvent may be added to the mixture of step a).
• the process further comprises step g) of slurrying the isolated precipitate of step f) in a further suitable solvent or mixture of solvents being preferably acetonitrile and step h) of isolating the obtained precipitate.
• a further suitable solvent or mixture of solvents being preferably acetonitrile
• step h) of isolating the obtained precipitate Preferably, form B can be converted into form A when form B is slurryied in acetonitrile.
• 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 .
• 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 is selected from the group consisting of C2-C4 alcohols, a C3-C6 ketone, an ether or an acetic ester C1 -C4 alkylester, acetonitril, a hydrocarbon or mixtures thereof.
• step d) and/or g) the obtained mixture may be stirred.
• Step d), e) and/or g) may be carried out at a temperature of from 0°C to 70°C.
• Suspension equilibration in step e) and/or slurrying in step g) are preferably carried out at a
• 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 per- formed 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.
• form B can be converted into form A when in step e) and/or g) form B is slurryied in acetonitrile.
• the water activity for formation of the form A in step b) and/or c) is of from 0, 1 to 0,8.
• the obtained precipitate is kept in an environment wherein the relative humidity is above 90%.
• the molar ratio of phosphoric acid to saxagliptin base of formula I is not critical, e.g. 1 to 3 equivalents of phosphoric acid per mol of saxagliptin base, preferably 1 to 2 equivalents of phosphoric acid per mol of saxagliptin base can be used, and even more preferred one equivalent of phosphoric acid is used.
• the starting material saxagliptin may be any form of saxagliptin base, e.g. amorphous saxagliptin base or crystalline saxagliptin base or any solvate or hydrate thereof.
• the molar ratio of saxagliptin of formula 1 to phosphoric acid may vary from 1 :0,9 to 1 : 1 . In a preferred embodiment the ratio of saxagliptin of formula I to phosphoric acid equals 1 : 1 .
• the invention relates to a process for the preparation of the crystalline phosphate salt of saxagliptin (form A) of the first aspect comprising the steps of a) equilibrating amorphous or crystalline saxagliptin phosphate in a solvent selected from a C1 -C4 alcohol, a C3-C6 ketone, e.g. acetone, methylethyl- ketone, an ether e.g. THF or methyl tert. butylether, an acetic acid C 1 -C4 alkyl- ester or hydrocarbons optionally in presence of seed crystals of saxagliptin phosphate form A and/or in presence of water;
• a solvent selected from a C1 -C4 alcohol, a C3-C6 ketone, e.g. acetone, methylethyl- ketone, an ether e.g. THF or methyl ter
• Preferred alcohols are 1 -propanol, 2-propanol, and ethanol
• preferred ketones are acetone, methylethylketone and methylisobutylketone
• selected ethers are diiospropylether, tetrahydrofurane and methyl tert. butylether
• preferred hydrocarbons include hexanes, heptanes and toluene.
• solvent water mixtures exhibiting water activities in the range from about 0, 1 to 0,8, for instance ethanol - water 9: 1 (v/v).
• the starting material Saxagliptin phosphate may be amorphous saxagliptin phosphate and preferably form B.
• a process for the preparation of form A comprises slurrying form B in a suitable solvent being preferably acetonitrile.
• the temperature of the crystallization process is not critical and conveniently it is performed at ambient temperature. However lower temperatures, e.g. performing the slurrying under cooling, e.g. in an ice bath or at elevated temperatures, e.g. 30°C to 40°C or even heating to the boiling point of the solvent may effectively induce the crystallization.
• the invention relates to a process for the preparation of form B comprising the steps of: a) dissolving saxagliptin phosphate in a mixture of a suitable solvent being preferably acetonitrile and water;
• saxagliptin phosphate may be used as starting material in the preparation of saxagliptin phosphate form B.
• suitable starting materials include amorphous saxagliptin phosphate, saxagliptin phosphate hemihydrate (form A) or a mixture containing saxagliptin and phosphoric acid in a molar ratio of about 1 : 1 .
• amorphous saxagliptin phosphate is for example disclosed in example 4.
• the crystalline compound of the present invention and preferably form A and/or form B 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 agent which optionally employed in combination with the crystalline compound of the present invention and preferably form A and/or form are further 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 SIRT activators or mimics thereof.
• biguanidines such as thiazolidinediones, SGLT2 inhibitors, PAR ⁇ / ⁇ dual antagonists, aP"-in
• a pharmaceutical composition will be employed containing the crystalline compound of the present invention (phosphate salt of saxagliptin), with or without a further antidiabetic agent and/or other therapeutic agent, in association with a pharmaceutical vehicle or diluent.
• the pharmaceutical composition can be formulated employing con- ventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration, the administration by an oral route in the form of tablets, capsules, granules or powders.
• the dose for adults is preferably between 5 mg to 1000 mg per day. Preferably between 1 and 100 mg per day of the crystalline compound of the present invention, 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 optionally a disintegrant.
• bulking agents include cellulose derivatives, such as microcrystalline cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, inorganic salts such as calcium salts, e.g. calcium carbonate, calcium phosphate, dicalcium phosphate, dextrin or dextranes, maltodextrin compressible sugars and/or other known bulking agents or fillers.
• binders suitable for use include hydroxypropylcellulose, PVP, starch, cellulose acetate as well as a wax binder such as carnauba wax, polyethylenes or other conventional binding agents or mixtures thereof
• disintegrants include croscarmellose sodium, crospovidone, starch, low substituted hydroxypropyl cellulose as well as other conventional disintegrants.
• the lubricant optionally present include for example magnesium stearate, zinc stearate, calcium sterarate, talc, carnauba wax, stearic acid, palmitinic acid, sodium laurylsulfate or hydrogenated vetable 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 coated on the tablet core and optionally 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 phosphate hemihydrate of the invention contain e.g. , lactose, crosscarmelose, magnesium stearate or e.g. sodium stearyl fumarate.
• DVS 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 from 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 measurement cycle was started at 50% relative humidity (r.h.), decreased in 5% relative humidity steps to 0% r.h.
• the temperature was 25 ⁇ 0, 1 °C.
• the solubility in water 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.
• TSP HPLC UV3000, AS3000, P4000, SCM1000 Soft
• 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.
• 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 diffractometer 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 method 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.
• the XRPD pattern revealed a mixture of amorphous and crystalline material. 3 ml of ethylacetate and seed crystals were added to the solid and the suspension was heated to 50°C to 70°C and was stirred then at ambient temperature for approximately 24 hours.
• the suspension was filtered and 4 ml of 2-propanol/water mixture ( 9: 1 , v:v) was added to the solid yielding a clear solution. After evaporation under a gentle N 2 stream the solid was dissolved in 0,6 ml of H 2 0. 8 ml of 2-propanol was slowly added yielding a clear solution with a few particles.
• the sample was stirred for 30 min at ambient temperature resulting in the formation of a gel.
• the sample was heated to 60°C and was stirred for 2 hours at this temperature.
• the obtained suspension was cooled to 30°C , filtered and the crystals were dried in vacuo ( ⁇ 3 mbar, for approximately 16 hours ).
• XRPD corresponds to figure 1 .
• FT-Raman of example 2 is shown in figure 2.
• Vs is very strong, S is strong, M is medium, W is weak, and Vw is very weak intensity.
• the suspension was filtered and the obtained solid showed the pattern of the hemihydrate (form A) by XRPD.

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