WO2013174035A1

WO2013174035A1 - Method for preparing anhydrous crystal form i of sitagliptin phosphate

Info

Publication number: WO2013174035A1
Application number: PCT/CN2012/076341
Authority: WO
Inventors: 李永新; 盛晓霞; 张群辉; 黄光东
Original assignee: 浙江海翔药业股份有限公司; 浙江普健制药有限公司
Priority date: 2012-05-25
Filing date: 2012-05-31
Publication date: 2013-11-28
Also published as: CN103421011B; CN103421011A

Abstract

The present invention relates to a method for preparing an anhydrous crystal form I of sitagliptin phosphate. The method comprises: crystallizing by stirring a suspension of sitagliptin phosphate solid at a crystallization temperature, then separating the crystallized crystals, washing, and drying so as to obtain an anhydrous crystal form I of the sitagliptin phosphate, wherein the solvent for the suspension of the sitagliptin phosphate solid is selected from acetone or acetonitrile, or the solvent for the suspension of the sitagliptin phosphate solid is selected from a mixture of a C_1-4 alkanol and water, a mixture of ethylene glycol and water, a mixture of acetone and water, or a mixture of acetonitrile and water. A single crystal form of sitagliptin phosphate in an anhydrous crystal form I can be prepared by the method of the present invention. The method facilitates the control of product quality and the establishment of a quality standard, and has advantages such as a simple and convenient crystallization process, mild reaction conditions, and a high product yield without a high temperature reaction for a long time.

Description

Method for preparing sitagliptin-free crystal form I

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. 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 (DPP-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.

The effect of sitagliptin phosphate is that it 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.

The chemical name of sitagliptin phosphate is (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3 -α]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. 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. In addition, 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.

Accordingly, there is a need in the art to develop a process for improving the process, simplifying operation, suitable for formulation applications, and obtaining a single crystalline form of sitagliptin phosphate anhydrous Form I. Summary of the invention

SUMMARY OF THE INVENTION 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 嶙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.

Preferably, the solvent of the sitagliptin glutamate solid suspension is selected from the group consisting of acetone or acetonitrile.

Preferably, 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.

Preferably, the CM alkanol is ethanol or isopropanol.

When the 0. ₄ alkanol is ethanol, the volume ratio of ethanol to water is preferably from 1:1 to 10:1, more preferably from 3:1 to 10:1.

When the C _M alkanol is isopropanol, 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.

In the solid suspension of sitagliptin phosphate, 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.

In one embodiment of the present invention, 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. For example, at the above temperature, 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.

In a specific embodiment, 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.

In another embodiment of the present invention, the sitagliptin phosphate solid suspension can be

-10 ° C ~ 50 C, preferably 4 ° C ~ 35 ° C, more preferably room temperature by phosphoric acid or phosphoric acid solution and sitagliptin free base solution; preferably, at the above temperature from tannic acid or phosphoric acid The solution is directly added to the sitagliptin free base solution to obtain a direct reaction. Wherein 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. For example, at the above temperature, 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.

In practice, 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.

It will be understood by those skilled in the art that, in practice, for convenience, 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. When 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.

Further, in the method of the present invention, the sitagliptin phosphate solid suspension may be added A seed crystal of sitagliptin phosphate without crystal form. Wherein, 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.

After the crystallization process of the process of the invention is completed, 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. In the case of a mixture of water, 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. After drying (for example, vacuum drying), 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.

In the method of the present invention, 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.

Preferably, 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.

Preferably, 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.

Preferably, when the solid suspension of sitagliptin is obtained by reacting a solution of streptoic acid or phosphoric acid with a free solution of sitagliptin, 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.

The "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.

Compared with the prior art, 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.

The 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.

Furthermore, 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 and a resin; a release rate controlling agent such as hydroxypropylcellulose, hydroxymethylcellulose , hydroxypropyl decyl cellulose, ethyl cellulose, methyl oxime, methacrylate methacrylate, wax, and the like. Other pharmaceutically acceptable excipients that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like.

The sitagliptin phosphate crystal form I prepared by the method of the present invention is suitable for preparation into various dosage forms. For example, 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. Dosage form. In the tablet, 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. For example, 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. At the time of preparation, 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. DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS 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 invention will be further understood by the following examples, but is not intended to limit the invention.

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 (DSC analysis) 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 250Γ 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 (TGA 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.

The preparation process of sitagliptin free base is:

Add 20 mL of acetonitrile to a 50 mL round bottom flask and add (3R)-3-[(l,l-dimethylethoxy)-amino]-4-(2,4,5-trifluorobenzene) Butyric acid (3.32g, O.Olmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-α]piperazine Hydrochloride ( 2.28 g, O.Olmol), the temperature of the reaction system was cooled to 0 V with a water salt bath > 1-hydroxybenzotriazole (HOBT) (1.62 g, 0.012 mol), 1-ethyl-3- (3-Didecylaminopropyl)carbimide acid salt (EDC-HC1 ) ( 2.29g, 0.012mol ), 3g of triethylamine was added dropwise, stirred at room temperature for 24 h, and the reaction solution was diluted with 3 x 20 mL of water. The organic layer was dried over anhydrous magnesium sulfate for 1 hour, then filtered and evaporated. NMR (500 MHz, CDCI3) δ 7.08 (dd, J = 16.7, 8.8 Hz, 1H), 6.98-6.75 (m, 1H), 5.33 (d, J = 8.6 Hz, 1H), 4.95 (s, 2H), 4.18 (s, 4H), 3.99 (s, 1H), 2.82 (dd, J = 128.2, 7.2 Hz, 4H), 1.89 (d, J = 25.9 Hz, 1H), 1.36 (s, 9H). ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 169.92, 155.24, 149.60, 121.45, 119.10, 105.50, 105.33, 105.10, 79.55, 48.22, 43.66, 43.21, 42.55, 41.78 39.17, 38.04, 36.91, 32.95, 28.17o

The above product (5.07 g, 10 mmol) was added to a 250 mL round bottom flask, dissolved in 50 mL of methanol, and 50 mL of a mixed solution of concentrated hydrochloric acid:methanol = 1:5 (v/v) was placed in a round bottom flask, and stirred at room temperature. After the hour, the TCL was monitored until the reaction was complete. The solvent was evaporated to dryness. The mixture was evaporated to dryness. The mixture was extracted with 2 mol/L of aqueous ammonia. The aqueous phase was extracted with 3×100 mL of ethyl acetate. The organic phase was combined and washed with 200 mL of saturated brine. It was dried over magnesium sulfate for 1 hour, filtered, concentrated, dissolved in 20 mL of ethanol, cooled to 0 ° C, crystallized, filtered, and dried to give 3.55 g of sitagliptin free base. ^l R NMR (500 MHz, DMSO) δ 7.56 (dd, = 17.2, 9.2 Hz, 1H), 7.45 (s, 1H), 7.08 (s, 5H), 4.90 (dq ₅ J= 35.0, 17.1 Hz, 2H), 4.23 (d, J = 4.8 Hz , 1H), 4.17-3.76 (m, 2H), 3.64 (s, 1H), 2.98 (s, 2H), 2.79 (d, J = 9.5 Hz, 1H). ¹³ C NMR (126 MHz, DMSO) δ 169.54 , 151.26, 149.67 147.71, 143.14, 142.83, 121.44, 120.25, 119.94, 117.79, 106.12, 48.03, 44.05, 43.44, 42.09, 41.48, 38.87, 37.91, 35.49, 32.00.

The preparation process of 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. After stirring for 2 hours, the temperature of the system was lowered to room temperature (~25 °C) by slowing down and then rapidly decreasing for 12 h, then adding 310 mL of isopropyl in 20 min. Alcohol, after vacuum filtration for 25 min, the sample was washed with 100 mL of 12 wt/isopropanol, and the sample was dried overnight in air to obtain sitagliptin phosphate monohydrate (yield 97%), X-ray powder diffraction The map (X-PRD) is shown in Figure 5.

The preparation process of 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.

The preparation process of 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.

Other raw materials and reagents are commercially available products.

Example 1

At room temperature, 1.25 g of 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%).

Example 2

At 40 ° C, 1.25 g of amorphous sitagliptin was added to 50 mL of acetone to obtain a solid suspension of sitagliptin citrate, and then 62.5 mg of sitagliptin phosphate crystal without crystal form I was added with stirring at 40 ° C. Kind, After stirring for 12 h, the obtained crystal slurry was filtered, washed with acetone, and the filter cake was placed in 4 (TC vacuum drying oven for 2 hours to obtain sitagliptin phosphate crystal form I (yield 92.5%).

Example 3

28 Ό, take 10g of sitagliptin phosphate crystal IV to 200mL of acetone to obtain a solid suspension of sitagliptin citrate, then add 100mg of sitagliptin phosphate crystal type I seed crystals, stir for 24h, the resulting The crystal slurry was filtered, washed with acetone, and the filter cake was dried in a vacuum oven at 40 ° C for 11 hours to obtain sitagliptin phosphate crystal form I (yield 92.5%).

Example 4

At room temperature, 10.Og of 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. After 24 h, the obtained crystal slurry was filtered, washed with acetone, 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 91.3%).

Example 5

At room temperature, 10,0 g of sitagliptin free base was dissolved in 100 mL of acetone to obtain a sitagliptin free base solution. Add 3. lg of phosphoric acid to 2 mL of water to obtain a phosphoric acid 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%).

Example 6

At room temperature, 10.0 g of 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. I seed crystals were then stirred at 0 ° C for 48 h, and the resulting crystal slurry was filtered, washed with acetone, and the filter cake was dried in a vacuum oven at 55 for 13 hours to obtain sitastatin phosphate crystal form I (yield 94.1%).

Example 7

At 35 ° C, 10.0 g of 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%).

Example 8

At 25 ° C, 10 mg of 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%).

Example 9

At 25 ° C, 5.0 g of 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. 500 mg of seed crystals, stirred at 25 ° C for 6 h, the obtained crystal slurry was filtered, washed with acetone, and the filter cake was dried in a vacuum oven at 50 ° C for 2 h to obtain no crystal form I of sitagliptin phosphate (yield 93.4%) ).

Example 10

At room temperature, lO.Og 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. Type I seed crystals, then stirred at 0 ° C for 18 h, the obtained crystal slurry was filtered, washed with methanol, and the filter cake was dried in a vacuum oven at 55 ° C for 6 h to obtain sitagliptin phosphate crystal form I (yield 90.8) %).

Example 11

At 25 ° C, take 6.2 g of sitagliptin citrate without crystal IV, add 25 mL of an aqueous solution of decyl alcohol (the ratio of methanol to water in this solution is 17:1) at 25 ° C to obtain a solid suspension, then The solid suspension was stirred at 25 ° C for 8 h, the obtained crystal slurry was filtered, washed with a methanol solution containing 4.7 vol% water, and the filter cake was dried in a vacuum oven at 40 ° C for 6 h to obtain a sitar. 1 (yield is 90.1% λ Example 12

At 40 ° C, 1.25 g of 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%).

Example 13

At 40 ° C, 5.0 g of 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%).

Example 14

At room temperature, lO.Og 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. I seed crystals, and then stirred at 4 ° C for 8 h, the obtained crystal slurry was filtered, washed with ethanol, and the filter cake was dried in a vacuum oven at 60 ° C for 8 h to obtain an anhydrous crystalline form of sitagliptin phosphate (yield 91.6%). ).

Example 15

At 25 ° C, lO.Og 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 %).

Example 16

At 25 ° C, 5.0 g of 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. I seed crystals, then stirred at 25 ° C for 8 h, the resulting crystal slurry was filtered, washed with ethanol solution containing 16.7 vol% water, and the filter cake was placed in a vacuum oven at 40 ° C for 6 h to obtain sitagliptin phosphate crystal free type. I (yield was 93.2%).

Example 17

At room temperature, 10% of the 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%).

Example 18

At room temperature, 6.2 g of 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%). .

Example 19

40. C, 10 g of 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%).

Example 20

At 25 ° C, 5.0 g of 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. The mixture was filtered, washed with a solution containing 5.9 vol% of water and isopropanol, and the filter cake was dried in a vacuum oven at 60 ° C for 10 hours to obtain an anhydrous crystalline form of sitagliptin phosphate (yield 90.3%). ,

Example 21

At room temperature, 5.0 g of 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%).

Example 22

At 40 ° C, 6.2 g of 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%).

Example 23

At 25 ° C, 5.0 g of 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%).

Example 24

At 30 ° C, 5,0 g of 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. To the solid suspension, 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) %).

Example 25

At 25 ° C, 10 g of amorphous sitagliptin phosphate was added to 50 mL of acetonitrile to obtain a solid suspension. The solid suspension was stirred at 25 ° C for 30 h, and the resulting crystal slurry was filtered, washed with acetonitrile, and the filter cake was placed at 40 After drying in a vacuum oven at °C for 8 hours, the sitagliptin phosphate crystal form I was obtained (yield was 92.1%).

Example 26

At 30 ,, take L25g sitagliptin acid crystal IV without adding crystal IV to 50mL acetonitrile to obtain a solid suspension, then add 31mg of crystals of sitagliptin phosphate-free crystal I at 30 ° C with stirring. After stirring for 24 h, the obtained crystal slurry was filtered, washed with ethanol, and the filter cake was dried in a vacuum oven at 40 ° C for 6 hours to obtain an anhydrous crystalline form of sitagliptin phosphate (yield 93.6%).

Example 27

At 25 ° C, 10 g of amorphous sitagliptin phosphate was added to 40 mL of acetonitrile to obtain a solid suspension. Then, the solid suspension was stirred and added to 180 mg of sitagliptin phosphate crystal form I, and stirred for 16 h to obtain the crystal. The slurry was filtered, washed with ethanol, 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 93.3%). Example 28

At 20 ° C, lO.Og 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 %).

Example 29

At 40 ° C, lO.Og 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%).

Example 30

At 25 °C, 1.25 g of 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. To the solid suspension, 120 mg of 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%).

Example 31

At 25 ° C, 5.0 g of 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. The mixture was washed with an ethylene glycol solution containing 16.7 vol% of water, and the filter cake was dried in a vacuum oven at 40 ° C for 2 hours to obtain an anhydrous crystalline form of sitagliptin phosphate (yield 92.2%).

Example 32

At 25 ° C, lO.Og 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. To the solid suspension, 186 mg of sitagliptin phosphate was added. I seed crystals, then stirred at 25 ° C for 20 h, the resulting crystal slurry was filtered, washed with ethylene glycol, and the filter cake was placed in a vacuum oven at 60 ° C for 6 h. The sitagliptin phosphate crystal form I was obtained (yield 92.8%).

Example 33

At 50 Γ, 5.0 g of 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%).

Example 34

At 45 ° C, lO.Og 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° (:.

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.

Example 35

Component

Sitagliptin phosphate prepared by the method of the invention has no crystal type I 124 g

Microcrystalline cellulose 130 g

Anhydrous calcium hydrogen phosphate 130 g

Cross-linked sodium carboxymethyl cellulose 8 g

Magnesium stearate 8 g

Opadry® White 16g

A total of 1000 coated tablets

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 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%.

Example 36

Component J * The 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.

Example 37

Component dosage The sitagliptin brick sulphate prepared by the method of the invention is anhydrous

Glucose 12 5 i- 4 4 ο 8 Sodium dihydrogen hydride 克克克克量

Water for Injection

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 0.22μιη microporous membrane to liquid clarification After inspection, it is sealed in a glass bottle that has been cleaned and sterilized, sealed, and sterilized.

Those skilled in the art will appreciate that many modifications or variations can be made in the present invention. Such modifications and variations are also intended to be included within the scope of the appended claims.

Claims

Rights request

1. A method for preparing crystal-free form I of sitagliptin phosphate. The method includes: stirring and crystallizing the solid suspension of sitagliptin phosphate at the crystallization temperature, and then separating, washing, and drying the precipitated crystals. , obtain sitagliptin phosphate crystalline form I; wherein, the solvent of the sitagliptin phosphate solid suspension is selected from acetone or acetonitrile; or the solvent of the sitagliptin phosphate solid suspension is selected from _CM Mixtures of alkanol and water, ethylene glycol and water, acetone and water, or acetonitrile and water.

2. The method according to claim 1, characterized in that the crystallization temperature is -10°C~50°C; preferably 4°C~35°C; more preferably room temperature.

3. The method according to claim 2, characterized in that, in the mixture of C, _-4 alkanol and water, the volume ratio of C _M alkanol to water is 0.5:1~40:1; so In the mixture of ethylene glycol and water, the volume ratio of ethylene glycol and water is 5:1~100:1; in the mixture of acetone and water, the volume ratio of acetone and water is ≥20:1; the acetonitrile In the mixture with water, the volume ratio of acetonitrile to water is ≥200:1.

4. The method according to claim 3, characterized in that, the C-4 alkanol is ethanol or isopropanol; when the C _M alkanol is ethanol, the volume ratio of ethanol to water is 1:1~10:1; When the <^ ₄ alkanol is isopropyl alcohol, the volume ratio of isopropyl alcohol to water is 16:1~40:1.

5. The method according to claim 4, characterized in that when the C _M alkanol is ethanol, the volume ratio of ethanol to water is 3:1~10:1; when the C _1-4 chain When the alkanol is isopropanol, the volume ratio of isopropyl alcohol to water is 20:1 to 35:1; in the mixture of ethylene glycol and water, the volume ratio of ethylene glycol to water is 5:1~20: 1; In the mixture of acetone and water, the volume ratio of acetone to water is ≥ 40:1; in the mixture of acetonitrile and water, the volume ratio of acetonitrile to water is ≥ 400: 1.

6. The method according to claim 5, characterized in that the sitagliptin phosphate solid suspension is at - 10°C to 50°C, preferably 4°C to 35°C, and more preferably 4°C to 35°C. Sitagliptin phosphate is directly obtained by dispersing sitagliptin phosphate in the solvent at room temperature; the sitagliptin phosphate in the sitagliptin acid solid suspension is derived from the amorphous, amorphous, and crystalline form of sitagliptin phosphate. objects and any combination thereof.

7. The method according to claim 5, characterized in that the sitagliptin phosphate solid suspension is at -10°C~50°C, preferably at 4°C~35°C, and more preferably at room temperature. It is obtained by reacting phosphoric acid or phosphoric acid solution and sitagliptin free base solution; Preferably, it is obtained by direct reaction by dropping phosphoric acid or phosphoric acid solution into sitagliptin free base solution; wherein, the sitagliptin phosphate solid suspension The solvent of the liquid is selected from a mixture of alkanol and water, a mixture of ethylene glycol and water, a mixture of acetone and water, or a mixture of acetonitrile and water.

8. The method according to claim 7, characterized in that the molar ratio of pure phosphoric acid to sitagliptin free base in the phosphoric acid or phosphoric acid solution is 1 to 3:1, preferably 1 to 1.5:1.

9. The method according to any one of claims 1 to 8, characterized in that, in the sitagliptin phosphate solid suspension, the ratio of sitagliptin phosphate to solvent is 5 mg to 500 mg: 1 mL; preferably The ratio is 50mg ~200mg:lmL.

10. The method according to claim 9, characterized in that seed crystals of sitagliptin phosphate crystalless form I are added to the sitagliptin phosphate solid suspension.

11. The method according to claim 10, characterized in that, in the sitagliptin phosphate solid suspension, the molar amount of the crystalline seed crystal of sitagliptin phosphate anhydrous form I is sitagliptin phosphate. 1%~10% of the molar amount; preferably 1%~3%.

12. The method according to claim 11, characterized in that the stirring and crystallization time is 6 to 48 hours, preferably 10 to 24 hours.

13. The method according to claim 12, characterized in that the drying temperature is 40°C~60°C.

14. A pharmaceutical composition containing a therapeutically effective amount of sitagliptin phosphate crystalline form I prepared according to the method of any one of claims 1 to 13 and one or more pharmaceutically acceptable excipients.