Classifications

• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to the field of medicinal chemical crystallization technology, and in particular to a method for preparing a single crystalline form of sitagliptin phosphate crystal form I. Background technique
• Sitagliptin Phosphate is the first clinically approved dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes, which prevents and treats type 2 diabetes, hyperglycemia, insulin resistance, obesity and high Blood pressure and certain complications.
• DPP-4 dipeptidyl peptidase-4
• Sitagliptin phosphate was developed by Merck, and was launched in Mexico and the United States in 2006. It was approved by the European Union for the treatment of type 2 diabetes in 2007. At present, sitagliptin phosphate tablets have become the second largest drug for oral diabetes drugs in the United States.
• Dipeptidyl peptidase-4 is a novel target for the treatment of type 2 diabetes, which rapidly inactivates incretin glucagon-like peptide-1 (GLP-1) and sugar-dependent insulin-releasing peptides. (GIP) and other hormones. DDP-4 inhibitors prolong and increase the activity of endogenous GLP-1 and GIP, which triggers the pancreas to increase insulin production and stop the liver from producing glucose, ultimately achieving a clinical effect of lowering blood glucose levels.
• sitagliptin phosphate stimulates insulin secretion while reducing hunger and hunger, and does not increase weight, nor does it cause hypoglycemia and edema. It is suitable for poor glycemic control and frequent hypoglycemia. Used by people with diabetes.
• sitagliptin phosphate is (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3 - ⁇ ]pyrazine-7(8H)yl]-1-(2,4,5-trifluorophenyl)butyl)-2-amine phosphate, having the chemical structural formula shown below:
• the crystal form screening and crystal form process of sitagliptin phosphate is of great significance for its drug development.
• the document WO2005003135A1 discloses the crystal form of sitagliptin phosphate monohydrate, but the application of the hydrate crystal form tends to cause an increase in the moisture content of the sample and a decrease in stability.
• the document WO2006033848A1 discloses an amorphous form of sitagliptin phosphate.
• the preparation process of the amorphous crystal form is generally difficult to control, and the crystal form has poor initiality and fluidity, and is not suitable for formulation application.
• Document CN1845674A discloses the anhydrous crystalline forms I and III of sitagliptin phosphate, and it is believed that the anhydrous crystalline form has advantages in the preparation of pharmaceutical compositions, which simplifies processing and handling, and in particular exhibits improved physical and chemical properties such as solubility and pressure stability. Sex and dissolution rate, very suitable for the manufacture of various pharmaceutical dosage forms.
• Example 1 discloses dissolving a mixture of sitagliptin free base and phosphoric acid solution in a mixed solvent of ethanol and water, heating to 75-78 C, and maintaining at 68 ° C for 4-8 hours, forming an ethanol solvate during the aging period. It was cooled overnight, filtered and dried to give a mixture of crystals without I and III.
• Example 2 In the case of the isoamyl alcohol-water system disclosed in Example 2, it is necessary to dry the wet sample at 75 to 80 ° C to obtain a mixed crystal of crystalless type I and III.
• CN1845674A Although a characteristic X-ray diffraction pattern, a characteristic DSC curve and a thermogravimetric analysis (TG) curve of the sitagliptin phosphate-free crystal form I are given, a preparation example of the amorphous form I is not given.
• the examples obtained in Examples 1 and 2 were mixed crystals of crystal-free type I and ruthenium.
• the quality standard of the mixed crystal is difficult to establish, and the application of the mixed crystal also makes the quality control of the preparation difficult.
• the crystallization temperature in CN1845674A is close to the boiling point temperature of the solvent, and the drying temperature is high. When the energy consumption is consumed, the process operation is complicated, which is not conducive to industrial production.
• the object of the present invention is to overcome the deficiencies of the prior art and to provide a method for preparing a crystalline form of sitagliptin phosphate which is low temperature crystallization, reasonable in process, improved in yield, low in cost, and obtains a single crystal form.
• the inventors have conducted intensive studies to achieve the object of the present invention by the following technical solutions.
• the invention provides a method for preparing sitagliptin phosphate anhydrous crystal form I, which comprises: stirring a crystal suspension of sitagliptin phosphate solid at a crystallization temperature, and then separating, washing and drying the precipitated crystal to obtain ⁇ The acid sitagliptin is not crystalline I; wherein the solvent of the sitagliptin solid suspension is selected from acetone or acetonitrile; or the solvent of the sitagliptin solid suspension is selected from C M a mixture of an alkanol and water, a mixture of ethylene glycol and water, a mixture of acetone and water or a mixture of acetonitrile and water In.
• the crystallization temperature is -10 ° C to 50 ° C; preferably 4O to 35 ° C; more preferably room temperature ( ⁇ 25 ° C).
• the crystallization process of the present invention is that the sitagliptin phosphate for crystallization is unstable in the solvent and will be converted to a more stable other crystal form, for example, to an amorphous form I. Compared with the unstable crystal form, the more stable crystal form energy is lower and the solubility is smaller, so the unstable crystal form will continuously dissolve into the solution, and then the solute will precipitate in a more stable crystal form, and the process will continue. Until the crystal form is completely converted.
• the solvent of the sitagliptin glutamate solid suspension is selected from the group consisting of acetone or acetonitrile.
• the C M mixture of alkanol and water the volume ratio C M alkanol to water is 0.5: 1-40: 1; a mixture of ethylene glycol with water, ethylene glycol and The volume ratio of water is 5:1 ⁇ 100:1, preferably 5:1 ⁇ 20:1; in the mixture of acetone and water, the volume ratio of acetone to water is ⁇ 20:1, preferably ⁇ 40:1; In the mixture of acetonitrile and water, the volume ratio of acetonitrile to water is ⁇ 200:1, preferably ⁇ 400:1.
• the alkanol is a CM linear or branched monohydric alcohol comprising decyl alcohol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.
• the CM alkanol is ethanol or isopropanol.
• the volume ratio of ethanol to water is preferably from 1:1 to 10:1, more preferably from 3:1 to 10:1.
• the volume ratio of isopropanol to water is preferably from 16:1 to 40:1, more preferably from 20:1 to 35:1.
• the solid suspension of sitagliptin phosphate refers to a solid-liquid mixture system (so the solution is a saturated solution) in which the sitagliptin phosphate solid (crystal) is contained.
• the particle size of the sitagliptin phosphate solid is not particularly limited.
• the ratio of sitagliptin phosphate to solvent is 5 mg to 500 mg: 1 mL; the preferred ratio is 50 mg to 200 mg: 1 mL.
• the sitagliptin phosphate solid suspension may be citrate phosphate at -10 ° C to 50 ° C, preferably 4 ° C to 35 ° C, more preferably at room temperature.
• the dispersion is obtained directly in the above solvent.
• sitagliptin phosphate is added to an appropriate amount of solvent to form a solid suspension solution.
• the sitagliptin phosphate in the solid suspension of sitagliptin phosphate can be derived from the amorphous, crystalline form, hydrate, solvate, and any combination thereof of sitagliptin citrate. Preferably, it is derived from the amorphous form of sitagliptin phosphate, the crystalline form, the 7j compound, and any combination thereof.
• the sitagliptin phosphate in the solid suspension of sitagliptin phosphate can be It is derived from amorphous sitagliptin phosphate or sitagliptin phosphate without crystalline IV or sitagliptin monohydrate.
• the amorphous, non-crystalline, hydrated, solvate of sitagliptin phosphate may be prepared according to any method in the prior art.
• the sitagliptin phosphate solid suspension can be any suitable sitagliptin phosphate solid suspension.
• the solvent of the sittastatin phosphate solid suspension is selected from the group consisting of a mixture of a C14 alkanol and water, a mixture of ethylene glycol and water, a mixture of acetone and water, or a mixture of acetonitrile and water.
• a phosphoric acid is added dropwise to the sitagliptin free base solution to directly react to obtain a suspension containing sitagliptin phosphate solid (crystal).
• the sitagliptin free base can be prepared according to any method in the prior art.
• the silicic acid is a commercially available aqueous phosphoric acid solution in which the content of phosphoric acid is generally 83 to 98% by weight.
• the solution of the solution is a solution formed by further adding a solvent to the phosphoric acid.
• the solvent is selected from the group consisting of ⁇ _4 alkanols, ethylene glycol, acetone, acetonitrile, and water.
• the sitagliptin free base solution is a solution of sitagliptin free base dissolved in a solvent selected from the group consisting of CM alkanols, ethylene glycol, acetone, acetonitrile, and water. Since the phosphoric acid or phosphoric acid solution contains water, it is preferred that the solvent of the sitagliptin free base solution is selected from the group consisting of C M alkanols, ethylene glycol, acetone and acetonitrile.
• the solid suspension of sitagliptin which is obtained by reacting a solution of citric acid or citric acid with the sitagliptin free base solution, can be directly used in the subsequent crystallization step without treatment, thus, phosphoric acid or phosphoric acid
• the composition of the solvent of the solution combined with the solvent of the sitagliptin free base solution should satisfy the above requirements for the solvent of the sitagliptin solid suspension, that is, the solvent of the sitagliptin phosphate solid suspension is selected from the solvent a mixture of CM chain sterol and water, a mixture of ethylene glycol and water, a mixture of acetone and water, or a mixture of acetonitrile and water.
• the crystallization temperature is lower than or equal to the temperature at which the above-described solid suspension of sitagliptin phosphate is prepared.
• the molar ratio of pure phosphoric acid to sitagliptin free base in the solution or phosphoric acid solution is preferably from 1 to 3:1, more preferably from 1 to 1.5:1.
• the molar ratio exceeds 3:1, the pH of the solution decreases; when the pH is less than 1, the purity of the crystal decreases and the yield decreases.
• the sitagliptin phosphate solid suspension may be added A seed crystal of sitagliptin phosphate without crystal form.
• the molar amount of the seed crystal is 1% to 10% of the molar amount of sitagliptin; preferably 1% to 3%.
• the stirring and crystallization is carried out for 6 to 48 hours, preferably 10 to 24 hours.
• the precipitated crystals are separated from the solution.
• the separation can be by any conventional separation method known in the art, such as filtration or centrifugation.
• the isolated solid is then washed.
• the solvent used for washing may be identical to the organic solvent in the solid suspension of sitagliptin phosphate, the organic solvent being selected from the group consisting of C14 alkanol, ethylene glycol, acetone or acetonitrile; or
• the solvent of the solid suspension of statin is consistent, wherein the solvent of the solid suspension of sitagliptin phosphate is selected from the group consisting of a mixture of d- 4 alkanol and water, a mixture of ethylene glycol and water, a mixture of acetone and water or acetonitrile.
• the water content of the solvent used for washing does not exceed the water content of the solvent of the solid suspension of the sitagliptin sulphate.
• the drying temperature is 40 to 60 ° C, and then the sitagliptin phosphate crystal form I can be obtained.
• the drying time is not particularly limited and can be easily determined by those skilled in the art based on actual conditions.
• the sitagliptin phosphate anhydrous form I can be prepared by using the solvent of the sitagliptin solid suspension in a mixed solvent or a single solvent.
• a single solvent is used, in which case the solvent is easily recovered, the recovery cost is low, and the formation of a hydrate is prevented.
• acetone a mixture of acetone and water, a mixture of ethanol and water, a mixture of isopropyl alcohol and water, wherein the solvent is low in toxicity, inexpensive, has a low boiling point, and is easily dried to remove solvent residues.
• the unit operation step can be reduced, which is advantageous for industrial production.
• the crystalline form I of sitagliptin phosphate obtained by the method of the present invention can be detected by a crystal form detection method conventional in the art, for example, by X-ray powder diffraction, thermogravimetric analysis (TGA analysis), differential scanning calorimetry (DSC). Analytical methods and other methods for testing.
• TGA analysis thermogravimetric analysis
• DSC differential scanning calorimetry
• single crystal form of sitagliptin phosphate crystalless type refers to a crystalline form of sitagliptin phosphate which is a single crystal form by X-ray powder diffraction.
• the method for preparing sitagliptin phosphate anhydrous form I of the present invention has the following advantages:
• the result is a single crystal form of sitagliptin phosphate without crystalline form I, rather than a mixed form of monohydrate or amorphous form I and III.
• the crystalline form of the drug has a higher active ingredient content relative to the monohydrate; Compared to the mixed crystal form, a single crystal form is more conducive to the control of product quality and the establishment of quality standards.
• the solvates of the prior art are not formed in the process of the present invention, thereby avoiding the formation of different amorphous forms and mixtures thereof during solvate desolvation.
• sitagliptin phosphate crystal form I prepared by the method of the present invention is stable within the experimental conditions described herein and does not undergo interconversion between crystal forms. High yields can be obtained under the preferred solvent system and process.
• the method of the invention has the advantages of low-temperature crystallization, mild reaction crystallization, no need to raise the reaction temperature to near the boiling point of the solvent, no need to react for a long time under high temperature conditions, and the process operation is simple, and the yield is increased to over 90%. The cost is reduced, which is more conducive to industrial production.
• the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of sitagliptin phosphate anhydrous Form I and one or more pharmaceutically acceptable excipients prepared by the method of the present invention.
• the pharmaceutically acceptable excipients include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tricalcium phosphate, mannitol, sorbitol, Sugar, etc.; binders such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl decyl cellulose, polyethylene glycol, etc.; disintegrating agents such as starch, glycolic acid Sodium starch, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; lubricants such as stearic acid, magnesium stearate, zinc stearate, benzoic acid Sodium, sodium acetate, etc.; a glidant such as colloidal silica; a complex forming agent such as various grades of cyclodextrin
• the sitagliptin phosphate crystal form I prepared by the method of the present invention is suitable for preparation into various dosage forms.
• it can be formulated into: solid oral dosage forms, including powders, granules, pills, tablets, and capsules; liquid oral dosage forms, including syrups, suspensions, dispersions, and emulsions; injectable preparations, including solutions, dispersions, and Lyophilized composition.
• the formulation may be adapted for rapid dry release, delayed release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation. Routes of administration include oral, intravenous, subcutaneous, transdermal, rectal, nasal, and the like.
• the pharmaceutical composition can be formulated into an oral preparation, and the oral preparation includes, but is not limited to, any one of a tablet, a capsule, a granule, a powder, a chewable tablet, a buccal tablet, an effervescent tablet, and an effervescent granule.
• the active ingredient sitagliptin free base has a unit preparation content of 25 mg, 50 mg and 100 mg, and the corresponding content of sitagliptin phosphate-free crystal I is 31 mg, 62 m and 124 mg, respectively.
• the tablets may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated, which provides taste barrier and additional stability to the final tablet.
• the film coating component may comprise: a mixture of hydroxypropylcellulose and hydroxypropylmethylcellulose, or a mixture of polyvinyl alcohol and polyethylene glycol, which may contain titanium dioxide and/or other colorants, and / Or a plasticizer, dispersant, antioxidant, etc.; or other suitable quick release film coating agent.
• Opadiy® is available as a commercial film coating.
• the pharmaceutical composition can be prepared using methods well known to those skilled in the art in the art.
• the sitagliptin phosphate anhydrous Form I prepared by the process of the present invention is admixed with one or more pharmaceutically acceptable excipients, optionally with one or more other active ingredients.
• the solid preparation can be prepared by a process such as direct mixing, dry granulation, or the like.
• Figure 1 is an X-ray powder diffraction pattern (X-PRD) of the sitagliptin phosphate crystal form I prepared in Example 4.
• Figure 2 is a differential scanning calorimetry (DSC) curve of the sitagliptin phosphate crystal form I prepared in Example 4.
• Figure 3 is a thermogravimetric analysis (TGA) curve of the sitagliptin phosphate crystal form I prepared in Example 4.
• Figure 4 is an X-ray powder diffraction pattern (X-PRD) of sitagliptin acid-free IV.
• Figure 5 is an X-ray powder diffraction pattern (X-PRD) of sitagliptin monohydrate.
• the instrument used for the X-ray powder diffraction detection (X-PRD) spectrum was Bruker D8 Advance.
• the detection process is as follows: Ka X-ray with a Cu target wavelength of 1.54 nm is used to collect data at a scanning speed of 47 min under the operating conditions of 40 kV and 40 mA, and the data collection time is generally about 10 min.
• the sample is usually placed on a glass slide during the test.
• the instrument used for differential scanning calorimetry was TA-Q200-1716-DSC.
• Differential scanning calorimetry data was taken from TA Instruments Q200 MDSC; The detection process is as follows: Usually, the sample of l ⁇ 10m is placed in the aluminum crucible, and the sample is raised from room temperature to 250 ⁇ under the protection of 30°50/min dry N 2 at a heating rate of 10 ° C/min, and the sample is recorded. The change in heat during the heating process.
• the instrument used for thermogravimetric analysis was TA-Q500- 1503-TGA. Thermogravimetric analysis data was taken from the TA Instruments Q500 TGA His-Res.
• the detection process is as follows: Usually, 5 ⁇ 15mg sample is placed in platinum crucible, and the sample is raised from room temperature to 25CTC under the protection of 30 °C/min dry N 2 at a heating rate of 10 °C/min, and the sample is recorded. The change in weight during the heating process.
• sitagliptin free base is:
• sitagliptin phosphate monohydrate is specifically as follows: 27.4 g of sitagliptin free base and 7.80 g of 85% aqueous phosphoric acid solution are added to a 500 ml three-necked flask, and 43.0 mL of water and 105.0 mL of different amounts are added thereto. The propanol was mixed with a solvent, and the system was heated to 75 ° C to completely dissolve the system. After cooling to 6CTC, the seed crystal of sitagliptin monohydrate was added.
• sitagliptin phosphate anhydrous IV is specifically as follows: taking 10.Og of sitagliptin phosphate monohydrate in a vacuum drying oven, vacuum pressure is greater than or equal to 0.09 MPa, drying at 120 ° C for 10 h, obtaining citrate Lenin is not crystalline IV (yield 96.6%) and its X-ray powder diffraction pattern (X-PRD) is shown in Figure 4.
• amorphous sitagliptin phosphate is specifically as follows: 10.0 g of sitagliptin phosphate (any salt of the salt which can be a hydrate or an anhydrate) is dissolved in 100 mL of ethanol and 100 mL of water at 60 ° C. In the mixed solvent system, after the solution was completely clarified, it was transferred to a vacuum rotary evaporator and rapidly spin-dried at 45 ° C to obtain 9.8 g of amorphous sitagliptin phosphate.
• the phosphoric acid used in all the examples was 85 wt. / Aqueous phosphoric acid solution.
• sitagliptin phosphate-free IV was added to 25 mL of acetone to obtain a solid suspension of cesetrol.
• the solid suspension was stirred at 1 CTC for 24 h, and the resulting crystal slurry was filtered, washed with acetone, and filtered cake. It was dried in a vacuum oven at 50 ° C for 6 h to obtain sitagliptin phosphate crystal form I (yield 92.0%).
• sitagliptin free base was dissolved in 108 mL of acetone to obtain a sitagliptin free base solution.
• 2.8 g of phosphoric acid was added to 5 mL of water to obtain a phosphoric acid solution.
• the above phosphoric acid solution was slowly added dropwise to the above sitagliptin free base solution at 4 ° C to obtain a solid suspension of sitagliptin citrate, and then the solid suspension of sitagliptin phosphate was stirred at 4 ° C.
• sitagliptin free base was dissolved in 100 mL of acetone to obtain a sitagliptin free base solution.
• the above acid solution was slowly added dropwise to the above sitagliptin free base solution at 25 ° C to obtain a solid suspension of sitagliptin phosphate, and the solid suspension was stirred at 25 ° C for 18 h to obtain the resulting crystal slurry.
• the mixture was filtered, washed with acetone, and the filter cake was dried in a vacuum oven at 40 ° C for 6 hours to obtain sitagliptin phosphate crystal form I (yield 92.3%).
• sitagliptin free base was dissolved in 100 mL of acetone to obtain sitagliptin free base solution, and the temperature was lowered to 0 °C.
• 3.1 g of phosphoric acid was added to 2 mL of water to obtain a phosphoric acid solution.
• the above scaly acid solution was slowly added dropwise to the above sitagliptin free base solution at 0 ° C to obtain a solid suspension of sitagliptin phosphate, and 370 mg of sitagliptin phosphate was added to the solid suspension.
• sitagliptin free base was dissolved in 42 mL of acetone to obtain a sitagliptin free base solution.
• 2.8 g of phosphoric acid was slowly added dropwise to the above sitagliptin free base solution at 35 ° C to obtain a solid suspension of sitagliptin phosphate.
• To the solid suspension was added 124 mg of sitagliptin phosphate without crystal.
• Type I seed crystals then stirred at 35 ° C for 10 h, the resulting crystal slurry was filtered, washed with acetone, and the filter cake was placed in a vacuum oven at 60 ° C for 6 h to obtain sitagliptin sartite without crystal form I (yield 94.6%).
• sitagliptin free base was dissolved in 150 mL of acetone to obtain a sitagliptin free base solution.
• 4.2 g of phosphoric acid was slowly added dropwise to the above sitagliptin free base solution at 25 ° C to obtain a solid suspension of sitagliptin phosphate, and then the solid suspension was stirred at 30 ° C for 18 h, and the obtained crystal paddle was obtained.
• the mixture was filtered, washed with acetone, and the filter cake was dried in a vacuum oven at 40 ° C for 2 hours to obtain sitagliptin phosphate crystal form I (yield 94.9%).
• sitagliptin free base was dissolved in 50 mL of acetone to obtain a sitagliptin free base solution.
• 1.4 g of phosphoric acid was added to 25 mL of acetone to obtain a phosphoric acid solution.
• the above-mentioned solution of the above-mentioned acid was slowly added dropwise to the above sitagliptin free base solution at 25 V to obtain a solid suspension of sitagliptin phosphate, and then the sitagliptin phosphate-free crystal form I was added to the solid suspension.
• sitagliptin free base was dissolved in 50 mL of methanol to obtain sitagliptin free base solution, and the solution was cooled to 0 °C. 8.4 g of phosphoric acid was added to 23.6 mL of water to obtain a phosphoric acid solution. The above-mentioned gravel acid solution was slowly added dropwise to the above sitagliptin free base solution at 0 ° C to obtain a solid suspension of sitagliptin phosphate. To the read solid suspension, 310 mg of sitagliptin citrate was added without crystal.
• sitagliptin phosphate anhydrous IV was added to 50 mL of sterol to obtain a solid suspension of sitagliptin citrate.
• the solid suspension was stirred at 40 ° C for 6 h, and the resulting crystal slurry was filtered. Washed with decyl alcohol, the filter cake was placed in a vacuum oven at 50 ° C for 4 h to obtain sitagliptin phosphate without crystal type 1 The rate is 92.0%).
• sitagliptin monohydrate in a mixed solvent of 60 mL of ethanol and 30 mL of water, stir at 40 ° C, slowly cool to 25 ° C, add 125 mg of sitagliptin phosphate no Crystal seed I seed crystals were slowly added to 90 mL of ethanol to obtain a solid suspension of sitagliptin phosphate. After stirring for 18 h, the resulting crystal slurry was filtered, and then washed with an ethanol solution containing 40% by volume of water, and the filter cake was placed at 40. After drying in a vacuum oven for 2 hours, the sitagliptin phosphate crystal form I was obtained (yield was 90.1%).
• sitagliptin free base was dissolved in 70 mL of ethanol to obtain a sitagliptin free base solution, and the solution was cooled to 4 °C.
• 4.2 g of phosphoric acid was added to 69.4 mL of water to obtain a phosphoric acid solution.
• the above-mentioned acid solution was slowly added dropwise to the above sitagliptin free-reducing solution at 4 ° C to obtain a solid suspension of sitagliptin phosphate, and 124 mg of sitagliptin phosphate was added to the solid suspension.
• sitagliptin free base was dissolved in 42 mL of ethanol to obtain a sitagliptin free base solution.
• 2.8 g of phosphoric acid was added to 13.6 mL of water to obtain a phosphoric acid solution.
• the above phosphoric acid solution was slowly added dropwise to the above sitagliptin free base solution at 25 Torr to obtain a solid suspension of sitagliptin brick sulphate, and then the solid suspension was stirred at 25 ° C for 8 hours, and the resulting crystal slurry was filtered. After washing with ethanol, the filter cake was dried in a vacuum oven at 40 ° C for 6 hours to obtain sitagliptin phosphate crystal form I (yield 92.5 %).
• sitagliptin free base was dissolved in 25 mL of ethanol to obtain a sitagliptin free base solution.
• 1.7 g of streptoic acid was added to 4.8 mL of water to obtain a phosphoric acid solution.
• the above-mentioned acid solution was slowly added dropwise to the above sitagliptin free base solution at 25 ° C to obtain a solid suspension of sitagliptin phosphate. 180 mg of sitagliptin phosphate was added to the read solid suspension.
• sitagliptin free base was dissolved in 70 mL of ethanol to obtain a sitagliptin free base solution, and the solution was cooled to 15 °C.
• 3.4 g of phosphoric acid was added to 6.5 mL of water to obtain a solution of the solution.
• the above-mentioned gravel acid solution is slowly added dropwise to the above sitagliptin free base solution at 15 ° C to obtain a phosphoric acid West
• the other solid suspension was stirred, and the solid suspension was stirred at 15 ° C for 13 h.
• the obtained crystal slurry was filtered, washed with ethanol, and the filter cake was dried in a vacuum oven at 50 ° C for 6 h to obtain sitagliptin phosphate.
• Crystal type I yield 94.2%).
• amorphous sitagliptin phosphate was added to a 28 mL aqueous solution of ethanol (the ratio of ethanol to water in the solution was 10:1) to obtain a solid suspension, and then the solid suspension was cooled to 4 ° C. After stirring for 16 h, the obtained crystal slurry was filtered, washed with an ethanol solution containing 9.1% by volume of water, and the filter cake was dried in a vacuum oven at 40 ° C for 10 hours to obtain an anhydrous crystalline form of sitagliptin phosphate (yield 94.8%). .
• sitagliptin phosphate anhydrous IV was added to 50 mL of ethanol to obtain a solid suspension, and then the solid suspension was stirred at 40 ° C to add 180 mg of sitagliptin phosphate crystal type I seed crystals, stirred for 24 hours.
• the obtained crystal slurry was filtered, washed with ethanol, and the filter cake was dried in a vacuum oven at 50 ° C for 10 hours to obtain an anhydrous crystalline form of sitagliptin phosphate (yield 93.2%).
• sitagliptin free base was dissolved in 36 mL of isopropanol to obtain a sitagliptin free base solution.
• Phosphate solution was obtained by adding 2.8 phosphoric acid to 2 mL of water.
• the above-mentioned solution of the above-mentioned acid was slowly added dropwise to the above sitagliptin free base solution, and the solid suspension of sitagliptin phosphate was obtained by retanning, and then the solid suspension was stirred at 25 ° C for 20 hours to obtain the obtained crystal slurry.
• sitagliptin free base was dissolved in 50 mL of isopropanol to obtain a sitagliptin free base solution, and the solution was cooled to 4 C.
• 1.4 g of phosphoric acid was added to 2.3 mL of water to obtain a phosphoric acid solution.
• the above phosphoric acid solution was slowly added dropwise to the above sitagliptin free base solution at 4 ° C to obtain a solid suspension of sitagliptin citrate, and 0.6 g of sitagliptin phosphate was added to the solid suspension without crystals.
• Type I seed crystals then stirred at 4 ° C for 24 h, the resulting crystal slurry was filtered, washed with an isopropanol solution containing 5.9 vol% water, and the filter cake was dried in a vacuum oven at 60 ° C for 10 h to obtain sitagliptin phosphate. No crystal type I (yield 92.8%).
• sitagliptin phosphate anhydrous IV was added to a mixed solution of 72 mL of isopropanol and water (the volume ratio of isopropanol to water was 35:1) to obtain a solid suspension, and then The solid The suspension was stirred under stirring with 124 mg of sitagliptin phosphate crystal form I, and then stirred at 40 ° C for 16 h, and the resulting crystal slurry was filtered to contain 2.4 volume ° /. The water was washed with an isopropanol solution, and the filter cake was dried in a vacuum oven at 60 ° C for 10 hours to obtain sitagliptin phosphate crystal form I (yield 93.3%).
• sitagliptin free base was dissolved in 80 mL of isopropanol to obtain a sitagliptin free base solution.
• 1.5 g of phosphoric acid was added to 1.7 mL of water to obtain a phosphoric acid solution.
• the above-mentioned solution of the above-mentioned solution was slowly added dropwise to the above sitagliptin free base solution at 25 ° C to obtain a solid suspension of sitagliptin phosphate, and the solid suspension was stirred at 25 ° C for 20 h to obtain the crystal.
• the slurry was filtered, washed with an isopropyl alcohol solution containing 5.9 vol% of water, and the filter cake was dried in a vacuum oven at 40 ° C for 180 hours to obtain a sitaline phosphate crystal form I (yield 92.6%).
• sitagliptin free base was dissolved in 70 mL of isoamyl alcohol to obtain a sitagliptin free base solution.
• 1.4 g of phosphoric acid was slowly added dropwise to the above sitagliptin free base solution at 30 ° C to obtain a solid suspension of sitagliptin phosphate.
• 186 mg of sitagliptin phosphate was added without crystal form I.
• the seed crystals were then stirred at 30 ° C for 10 h, and the resulting crystal slurry was filtered, washed with isoamyl alcohol, and the filter cake was dried in a vacuum oven at 60 ° C for 8 hours to obtain sitagliptin phosphate crystal form I (yield 90.5) %).
• sitagliptin free base was dissolved in 84 mL of acetonitrile to obtain sitagliptin free base solution.
• 2.8 g of phosphoric acid was slowly added dropwise to the above sitagliptin free base solution to obtain a solid suspension of sitagliptin phosphate, and then the solid suspension was stirred at 20 ° C for 8 h, and the resulting crystal slurry was filtered. After washing with acetonitrile, the filter cake was dried in a vacuum oven at 40 ° C for 8 hours to obtain sitagliptin phosphate crystal form I (yield 90.8 %).
• sitagliptin free base was dissolved in 168 mL of acetonitrile to obtain sitagliptin free base solution.
• 8 g of phosphoric acid was slowly added dropwise to the above sitagliptin free base solution at 40 ° C to obtain a solid suspension of sitagliptin phosphate, and then the solid suspension was stirred at 40 ° C for 10 h, and the resulting crystal slurry was filtered.
• the mixture was washed with acetonitrile, and the filter cake was dried in a vacuum oven at 40 ° C for 8 hours to obtain an anhydrous crystalline form of sitagliptin phosphate (yield 94.3%).
• sitagliptin monohydrate was added to 15 mL of a mixed solution of ethylene glycol and water (in which the volume ratio of ethylene glycol to water was 5:1) to obtain a solid suspension of sitagliptin phosphate.
• a mixed solution of ethylene glycol and water in which the volume ratio of ethylene glycol to water was 5:1
• sitagliptin phosphate-free ice crystal form I seed crystals were added, and the mixture was cooled to 10 ° C and stirred for 24 hours.
• the obtained crystal slurry was filtered, washed with ethylene glycol, and the filter cake was placed in a vacuum of 60 Torr. Drying in a dry box for 5 hours gave sitagliptin phosphate crystal form I (yield 92.1%).
• sitagliptin free base was dissolved in 50 mL of ethylene glycol to obtain a sitagliptin free base solution.
• 2.1 g of phosphoric acid was added to 4.6 mL of water to obtain a phosphoric acid solution.
• the above citric acid solution was slowly added dropwise to the above sitagliptin free base solution at 25 ° C to obtain a solid suspension of sitagliptin phosphate, and then the solid suspension was stirred at 20 ° C for 24 h, and the resulting crystal slurry was filtered.
• sitagliptin free base was dissolved in 48 mL of ethylene glycol to obtain sitagliptin free base solution.
• 2.8 g of phosphoric acid was added to 2 mL of water to obtain a phosphoric acid solution.
• the above-mentioned acid solution was slowly added dropwise to the above sitagliptin free base solution at 25 ° C to obtain a solid suspension of sitagliptin phosphate.
• 186 mg of sitagliptin phosphate was added.
• sitagliptin free base was dissolved in 86 mL of ethylene glycol to obtain sitagliptin free base solution; 3.5 g of phosphoric acid was added to 1.2 mL of water to obtain a phosphoric acid solution; the above phosphoric acid solution was slowly dried at 50 ° C Adding to the above sitagliptin free base solution to obtain a solid suspension of sitagliptin phosphate, and then stirring the solid suspension at 50 ° C for 18 h, filtering the resulting crystal slurry, washing with ethylene glycol solution, filtering The cake was dried in a 60-inch vacuum oven for 5 hours to obtain sitagliptin phosphate crystal 1 (yield 91.0%).
• sitagliptin free base was dissolved in 47 mL of ethylene glycol to obtain sitagliptin free base solution.
• 3.1 g of phosphoric acid was slowly added dropwise to the above sitagliptin free base solution at 45 ° C to obtain a solid suspension of sitagliptin phosphate, and 250 mg of sitagliptin phosphate was added to the solid suspension.
• the seed crystals were then stirred at 45 ° C for 12 h, and the resulting crystal slurry was filtered, washed with ethylene glycol, and the filter cake was dried in a vacuum oven at 50 ° C for 6 h to obtain sitagliptin phosphate crystal form I (yield 90.5) %).
• the X-ray powder diffraction pattern, differential scanning calorimetry (DSC) curve and thermogravimetric analysis (TGA) curve of the sitagliptin phosphate-free crystal I prepared in the above Example 4 are shown in Fig. 1, Fig. 2 and image 3.
• DSC analysis showed that the sample had an endothermic peak and began to decompose at around 200 °C.
• the TGA analysis showed no weight loss before the sample was decomposed and the decomposition temperature was about 207° (:.
• Example 4 The sample prepared in the above other examples had the same or similar X-ray powder diffraction pattern, differential scanning calorimetry curve and thermogravimetric analysis curve (not shown) as in Example 4. These examples were prepared to give the same materials as in Example 4.
• Sitagliptin phosphate prepared by the method of the invention has no crystal type I 124 g
• the raw materials are passed through a 80 mesh sieve, and the predetermined amount of the sitagliptin phosphate anhydrous crystal I, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and croscarmellose sodium prepared by the method of the present invention are mixed in a mixer. 15min, The mixture was mixed with magnesium stearate, and the mixed materials were compressed into tablets by direct extrusion. The tableting pressure was controlled at 15 kN, and the pressed tablets were placed in a coating machine, and the tablets were coated with Opadry® white. The coating speed was lOrpm/min, the film bed temperature was controlled at 35-45 °C, and the coating weight was 1.04%.
• sitagliptin phosphate prepared by the method of the invention has no crystal type I 62 g microcrystalline cellulose 120 g lactose 43 g crospovidone 12.5 g magnesium stearate 2.5 g co-made 1000 capsules
• the excipients passed through a 60 mesh sieve, and the prescribed amount of sitagliptin phosphate anhydrous crystal I, microcrystalline cellulose, lactose and crospovidone prepared by the method of the invention were mixed in a mixer for 20 min, and magnesium stearate was added. lOmin, the mixed material is directly filled with plastic bottles.
• sitagliptin brick sulphate prepared by the method of the invention is anhydrous
• a total of 1000 mL of intravenous injection was prepared to weigh the prescribed amount of the sitagliptin phosphate crystal I, glucose, sodium dihydrogen phosphate and disodium hydrogen phosphate prepared by the method of the present invention, and dissolved with an appropriate amount of water for injection, using 50% NaOH (g /mL) solution to adjust the pH of the solution to 4.5, add 0.2% needle with activated carbon (g / mL), stir and adsorb lOmin, filter decarbonization, filtrate and injection water diluted to 1000mL, filter with 0.22 ⁇ microporous membrane to liquid clarification After inspection, it is sealed in a glass bottle that has been cleaned and sterilized, sealed, and sterilized.

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