CN105384724A - A kind of crystal form of fluoride and preparation method thereof - Google Patents

Abstract

The invention provides a crystal form of a fluoro-material and a preparation method thereof, belonging to the field of pharmaceutical chemistry. The crystal form is a crystal form II or a crystal form IV, wherein the X-ray powder diffraction pattern of the crystal form II has peaks at about 20.04,20.85 and 21.86 degrees of 2 theta; form IV has an X-ray powder diffraction pattern with peaks at approximately 16.28,20.03,22.30, and 27.55 degrees 2 Θ. The crystal form II or the crystal form IV does not contain solvent or crystal water, has better solubility or stability, is beneficial to operation in storage, transfer and production processes, and is suitable for being prepared into medicinal salts or oral preparations.

Description

A kind of crystal form of fluoride and preparation method thereof

technical field

The invention relates to a new crystal form of an antidiabetic fluoride and a preparation method thereof, belonging to the field of medicinal chemistry.

Background technique

Trelagliptin (Trelagliptin) is a dipeptidyl peptidase IV (DPP-4) inhibitor once a week, which can selectively and continuously inhibit DPP-4 and control blood sugar levels; its structure is as follows (1 ) as shown:

Patent CN200780049086.5 discloses various crystal forms of trexagliptin succinate, and patent CN201310056368 discloses various crystal forms of trexagliptin free base and related information. Because drug polymorphism is a common phenomenon in drug research and development, it is an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, and bioavailability, and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug etc. have different effects; in order to obtain effective crystal forms that are beneficial to production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of drugs to obtain crystal forms that meet production requirements.

Contents of the invention

Summary of the invention

The first aspect of the present invention provides various new crystal forms of trexagliptin.

The second aspect of the present invention provides a preparation method of the trexagliptin crystal form.

The third aspect of the present invention provides the use of Trexagliptin crystal form for treating diabetes.

Definition of Terms

The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including but not limited to defined terms, term usage, described techniques, etc.), this application prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the CAS edition of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can be referred to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

The term "comprising" or "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

The term "crystal form" is used to describe the state of existence of solid compounds, and to describe the collection of various parameters of ions, atomic or molecular composition, symmetry properties and periodic arrangement within the crystal.

The term "substantially as shown" refers to a "crystalline form" that is substantially pure by at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks appear in the given X-ray powder diffraction pattern. When the content of a certain crystal form in the sample gradually decreases, some diffraction peaks belonging to the crystal form in the X-ray powder diffraction pattern may become less due to the detection sensitivity of the instrument.

The term "relative intensity" refers to the ratio of the intensity of other peaks to the intensity of the first intense peak when the intensity of the first intense peak in a group of diffraction peaks assigned to a certain crystal form is defined as 100%.

In the context of the present invention, 2Θ (also known as 2theta or diffraction peak) values in an X-ray powder diffraction pattern are in degrees (°).

When referring to a spectrum and/or data in a graph, the term "diffraction peak" refers to a feature that one skilled in the art would not attribute to background noise.

The X-ray powder diffraction peak of the crystal form, the 2θ of its X-ray powder diffraction pattern or the measurement of the diffraction peak have experimental errors, between one machine and another machine and between one sample and another sample , the measurement of 2θ or diffraction peaks of the X-ray powder diffraction pattern may be slightly different, and the value of the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units , so the values of the 2θ or diffraction peaks cannot be regarded as absolute.

The differential scanning calorimetry curve (DSC) of the crystal form has experimental error, and the position and peak value of the endothermic peak may vary slightly between one machine and another machine and between one sample and another sample. The difference, the experimental error or the value of the difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C, so the peak position or peak value of the DSC endothermic peak The value of is not to be regarded as absolute.

The thermogravimetric analysis curve (TGA) of the crystal form has experimental error, and between one machine and another machine and between one sample and another sample, the endothermic curve or the weight loss rate may be slightly different, the experiment The value of the error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, so the thermogravimetric analysis curve or its weight loss rate cannot be regarded as absolute.

In the context of the present invention, all numbers disclosed herein are approximations, whether or not the word "about" or "approximately" is used. The value of each number may vary by 1%, 2%, or 5%. When approximate is used to describe the 2θ (also known as 2theta or diffraction peak) value of an X-ray powder diffraction peak, approximately means that the 2θ value may have +/-0.2 units or +/-0.1 units or +/-0.05 unit difference.

"Room temperature" means a temperature between about 20°C to 35°C or about 23°C to 28°C or about 25°C.

The term "good solvent" can be a single solvent or a mixed solvent, which means that the solubility of Trexagliptin in the single solvent or mixed solvent is greater than 1g/L, or greater than 2g/L, or greater than 3g/L, or greater than 4g/L , or greater than 5g/L, or greater than 6g/L, or greater than 7g/L, or greater than 8g/L, or greater than 9g/L, or greater than 10g/L, or greater than 15g/L, or greater than 20g/L, or Greater than 30g/L, or greater than 40g/L, or greater than 50g/L, or greater than 60g/L, or greater than 70g/L, or greater than 80g/L, or greater than 100g/L. In some embodiments, the solubility of trexagliptin in a good solvent is larger than that of a poor solvent; in some embodiments, the difference between the solubility of trexagliptin in a good solvent and a poor solvent is about 10%, 20%, 30 %, 40%, 50%, 60%, 70%, 80% or 90%; in some embodiments, the solubility of the good solvent to trexagliptin is greater than that of the poor solvent, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

The term "poor solvent" refers to a solvent that promotes supersaturation or crystallization of a solution. In some embodiments, the solubility of Trexagliptin in a poor solvent is less than 0.001g/L, or less than 0.01g/L, or less than 0.1g/L, or less than 0.2g/L, or less than 0.3g/L, Or less than 0.4g/L, or less than 0.5g/L, or less than 0.6g/L, or less than 0.8g/L, or less than 1g/L, or less than 2g/L, or less than 3g/L, or less than 4g/L L, or less than 5g/L, or less than 6g/L, or less than 7g/L, or less than 8g/L, or less than 9g/L, or less than 10g/L.

Detailed description of the invention

In the first aspect, the inventors have developed crystalline form I, crystalline form II, crystalline form III and crystalline form IV of Trexagliptin through research.

The crystal form I of Trexagliptin has the following characteristics: in its X-ray powder diffraction pattern, there are peaks at the positions of 2θ at about 11.33, 17.07, 20.44, and 22.85 degrees.

In some embodiments, in the X-ray powder diffraction pattern of the crystal form I of Trexagliptin, one of the positions at 2θ of about 5.65, 11.33, 12.50, 17.07, 19.87, 20.44, 22.48, 22.85, 25.19, 27.51 degrees or many peaks.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form I is about 5.65, 11.33, 12.50, 16.80, 17.07, 19.40, 19.87, 20.44, 22.48, 22.85, 25.19, 25.50, 27.51 in 2θ , There are one or more peaks at the position of 31.95 degrees.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form I is about 5.65, 11.33, 12.50, 15.80, 16.80, 17.07, 19.40, 19.87, 20.44, 21.21, 22.48, 22.85, 25.19 in 2θ , There are peaks at one or more positions at 25.50, 27.51, 28.66, 29.02, 29.79, 31.95, and 33.95 degrees.

In some embodiments, the X-ray powder diffraction pattern of the crystal form I of Trexagliptin is as shown in Figure 1, wherein the relative intensity of the peak at about 22.85 degrees in 2θ is greater than 50%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

The crystalline form I of trexagliptin also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at about 160°C-175°C. In a specific embodiment, its differential scanning calorimetry curve (DSC) has an endothermic peak at about 165°C-175°C. In a specific embodiment, its differential scanning calorimetry curve (DSC) has an endothermic peak at about 165°C-170°C, and the peak value of the endothermic peak is about 167°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form I of Trexagliptin is shown in FIG. 2 . DSC of Form I revealed that it starts to decompose upon heating to about 190°C.

The trexagliptin crystal form I is non-hygroscopic, does not contain crystallization solvent or crystal water, and is non-solvate or non-hydrate. In some embodiments, the thermogravimetric analysis curve (TGA) of trexagliptin crystal form I is shown in FIG. 3 .

The crystal form II of Trexagliptin has the following characteristics: in its X-ray powder diffraction pattern, there are peaks at the positions of 2θ at about 20.04, 20.85, and 21.86 degrees.

In some embodiments, in the X-ray powder diffraction pattern of the crystal form II of Trexagliptin, there are peak.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form II is about 5.48, 10.98, 12.86, 16.55, 16.87, 18.79, 20.04, 20.85, 21.86, 23.15, 25.80, 28.04, 30.41 in 2θ There are peaks at one or more positions of degrees.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form II is about 5.48, 10.98, 12.86, 13.74, 13.93, 16.55, 16.87, 17.76, 18.79, 20.04, 20.85, 21.86, 23.15 in 2θ , There are peaks at one or more positions at 25.80, 28.04, 28.98, 30.41, and 33.93 degrees.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form II is about 5.48, 10.98, 11.51, 12.86, 13.74, 13.93, 15.05, 16.55, 16.87, 17.10, 17.76, 18.79, 20.04 in 2θ , 20.85, 21.86, 22.15, 22.42, 23.15, 23.74, 25.80, 28.04, 28.98, 30.41, 33.93 degrees have peaks at one or more positions.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form II of Trexagliptin is shown in Figure 4, wherein the relative intensity of the peak at about 20.85 degrees in 2θ is greater than 50%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

The crystalline form II of Trexagliptin can be transformed into the crystalline form IV upon heating. The DSC of Form II is shown in Figure 5, suggesting that it transforms into Form IV at 145°C-150°C.

The trexagliptin crystal form II is non-hygroscopic, does not contain crystallization solvent or crystal water, and is non-solvate or non-hydrate. In some embodiments, the thermogravimetric analysis curve (TGA) of trexagliptin crystal form II is shown in FIG. 6 .

In the crystal form III of Trexagliptin, there are peaks in the X-ray powder diffraction pattern at positions of 2θ of approximately 4.80, 9.62, 19.09, 20.44, 23.03, 24.25, 29.20, and 31.77 degrees.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form III is about 4.80, 9.62, 19.09, 20.44, 22.31, 23.03, 24.25, 25.14, 25.79, 27.32, 29.20, 31.77, 34.22 in 2θ There is a peak at the position of degree.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form III is about 4.80, 9.62, 19.09, 20.44, 22.31, 22.53, 23.03, 24.25, 25.14, 25.79, 27.32, 27.72, 29.20 in 2θ , There are peaks at one or more positions of 29.59, 31.77, 34.22, and 36.17 degrees.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form III is about 4.80, 9.62, 14.47, 15.71, 17.04, 17.55, 18.39, 19.09, 19.39, 20.44, 20.81, 21.01, 22.31 in 2θ , 22.53, 23.03, 24.25, 25.14, 25.79, 27.32, 27.72, 29.20, 29.59, 31.77, 34.22, 36.17 degrees have peaks at one or more positions.

In some embodiments, the X-ray powder diffraction pattern of trexagliptin crystal form III is shown in Figure 7, wherein the relative intensity of the peak at 2θ of about 9.62 degrees is greater than 90%, or greater than 99%.

Form III is a metastable crystal form. If the crystalline form III sample is sealed and stored at room temperature, the crystalline form will not change; however, it will be transformed into crystalline form I or crystalline form II under certain conditions. After a sample of Form III was vacuum-dried at 50° C. for 1 hour, it was found to transform into Form II. The crystal form III sample obtained by crystallization from acetone and water was placed in the air, and the crystal form was transformed into the crystal form II. The crystalline form III sample obtained by crystallization from ethanol and water was placed in the air, and the crystalline form was transformed into crystalline form I.

The crystal form IV of trexagliptin has the following characteristics: in its X-ray powder diffraction pattern, there are peaks at the positions of 2θ at about 16.28, 20.03, 22.30, and 27.55 degrees.

In some embodiments, in the X-ray powder diffraction pattern of the crystal form IV of Trexagliptin, there are peak.

In some embodiments, in the X-ray powder diffraction pattern of the crystalline form IV of Trexagliptin, the 2θ is about 11.63, 15.71, 16.28, 17.50, 18.83, 20.03, 20.81, 22.30, 22.99, 23.45, 27.55 degrees. One or more peaks.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form IV is about 5.79, 11.63, 11.84, 12.56, 15.71, 16.28, 17.50, 18.83, 20.03, 20.81, 22.30, 22.99, 23.45 in 2θ , There are peaks at one or more positions of 27.55, 27.81 degrees.

In some embodiments, the X-ray powder diffraction pattern of Trexagliptin Form IV is about 5.79, 11.63, 11.84, 12.56, 13.77, 15.71, 16.28, 16.84, 17.50, 18.83, 19.27, 20.03, 20.81 in 2θ , There are peaks at one or more positions at 22.30, 22.99, 23.45, 24.68, 25.07, 27.55, 27.81, 28.80, 33.07, 33.73 degrees.

In some embodiments, the X-ray powder diffraction pattern of trexagliptin crystal form IV is shown in Figure 8, wherein the relative intensity of the peak at 2θ of about 22.30 degrees is greater than 50%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

The crystalline form IV of trexagliptin also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at about 160°C-175°C. In a specific embodiment, its differential scanning calorimetry curve (DSC) has an endothermic peak at about 165°C-170°C. In a specific embodiment, its differential scanning calorimetry curve (DSC) has an endothermic peak at about 165°C-170°C, and the peak value of the endothermic peak is about 167°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form I of Trexagliptin is shown in FIG. 9 .

The trexagliptin crystalline form IV is a powder with good fluidity, non-hygroscopic, does not contain crystallization solvent or water of crystallization, and is non-solvate or non-hydrate. In some embodiments, the thermogravimetric analysis curve (TGA) of trexagliptin crystal form IV is shown in FIG. 10 .

Crystalline form IV can be produced by heating transformation of crystal form II at high temperature.

The crystalline form I of trexagliptin is a powder with good appearance and fluidity, and has good performance in terms of solubility, stability, fluidity, etc., which is beneficial to storage, transfer, and operation in the production process, and is suitable for the preparation of into its medicinal salt or oral preparations.

The crystalline form II of trexagliptin is a powder with good fluidity, has good performance in terms of solubility and fluidity, is beneficial to storage, transfer, and operation in the production process, and is suitable for preparation into pharmaceutically acceptable salts or Oral preparations.

The trexagliptin crystalline form IV has good properties in terms of stability, fluidity, etc., is beneficial to storage, transfer, and operation in the production process, and is suitable for preparation into pharmaceutically acceptable salts or oral preparations thereof.

In a second aspect, the present invention provides a method for preparing trexagliptin crystal form I or crystal form II.

A method for preparing trexagliptin crystalline form I comprises: dissolving trexagliptin in a good solvent, then placing in air, volatilizing the solvent at room temperature or evaporating the solvent to dryness under reduced pressure to precipitate crystals, collecting the crystals to obtain the crystal form I. The good solvent is one or more of methanol, ethanol, isopropanol, dichloromethane, acetone, ethyl acetate, isopropyl acetate, and acetonitrile.

A method for preparing trexagliptin crystal form I comprises: dissolving trexagliptin in an ester solvent, then adding a poor solvent to precipitate crystals, collecting the crystals, and removing the solvent to obtain crystal form I. The ester solvent is one or more of ethyl acetate and isopropyl acetate; the poor solvent is one or more of n-hexane, n-pentane, cyclohexane and n-heptane.

Crystal form I can also be prepared by stirring and beating crystal form II in a solvent. A method for preparing trexagliptin crystal form I comprises: mixing crystal form II trexagliptin with isopropyl ether, water, petroleum ether, n-hexane, cyclohexane, one or more solvents in n-heptane Mix to form a mixed solution containing solid insoluble matter, and then stir and beat the mixed solution at room temperature for 24-36 hours to collect crystals to obtain Form I.

A method for preparing trexagliptin crystal form II comprises: dissolving trexagliptin in methyl ethyl ketone, then placing the solvent in the air to evaporate the solvent at room temperature, or evaporating the solvent under reduced pressure, or adding a poor solvent, and then separating out crystals, and the crystals were collected to obtain Form II. The poor solvent is one or more of n-hexane, n-pentane, cyclohexane and n-heptane.

In some embodiments, trexagliptin is dissolved in methyl ethyl ketone, and then placed in air to evaporate the solvent at room temperature, and crystals are precipitated, and the crystals are collected to obtain Form II.

In some embodiments, trexagliptin is dissolved in butanone, and then the solvent is evaporated to dryness at 45°C under reduced pressure to precipitate crystals, and the crystals are collected to obtain Form II.

In some embodiments, trexagliptin is dissolved in methyl ethyl ketone, and then one or more solvents in n-pentane, cyclohexane, and n-heptane are added; crystals are precipitated, crystals are collected, and solvent is removed to obtain crystals Type II.

In the third aspect, the application of Trexagliptin crystalline form I, crystalline form II, crystalline form III and crystalline form IV in the preparation of medicines for treating diabetes is provided. The crystalline form I, crystalline form II, or crystalline form IV can be used to prepare medicines for treating diabetes.

The Trexagliptin crystal form I and/or crystal form II can be mixed with pharmaceutically acceptable adjuvants such as microcrystalline cellulose, sodium hydroxymethylcellulose, magnesium stearate, etc. to prepare a pharmaceutical composition; The pharmaceutical composition can be made into dosage forms such as tablets and capsules.

Description of drawings

Fig. 1 shows the X-ray powder diffraction pattern of trexagliptin crystal form I.

Figure 2 shows the differential scanning thermal curve (DSC) of trexagliptin crystal form I.

Figure 3 shows the thermogravimetric analysis (TGA) of Trexagliptin crystal form I.

Figure 4 shows the X-ray powder diffraction pattern of trexagliptin crystal form II.

Fig. 5 shows the differential scanning thermal curve (DSC) of Trexagliptin crystal form II.

Figure 6 shows the thermogravimetric analysis (TGA) of trexagliptin crystal form II.

Fig. 7 shows the X-ray powder diffraction pattern of trexagliptin crystal form III.

Figure 8 shows the X-ray powder diffraction pattern of trexagliptin crystal form IV.

Fig. 9 shows the differential scanning thermal curve (DSC) of Trexagliptin crystal form IV.

Figure 10 shows the thermogravimetric analysis (TGA) of trexagliptin crystal form IV.

detailed description

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

In the present invention, g means gram, mL means milliliter, L means liter, and h means hour.

Instrument parameters

All analyzes below were performed at room temperature unless otherwise specified in the parameters.

X-ray powder diffraction (XRPD)

X-ray powder diffraction (XRPD) analysis was performed using an x'celerator detector with a 2Θ range of 120°. Real-time data were collected at 0.01672θ resolution starting at 3° 2θ using Cu-Kα radiation. The tube voltage and amperage were set to 45 kV and 40 mA, respectively. The anti-scatter slit was set at 6.6 mm and the divergence slit at 1 degree. Take an appropriate amount of crystal form sample and place it in the circular groove of the zero-background sample holder, press lightly with a clean glass slide to obtain a flat plane, and fix the zero-background sample holder. On the sampling device, the samples are injected sequentially. Instrument calibration was performed using silicon reference standards. In the X-ray powder diffraction diagram, the ordinate is the diffraction intensity expressed in counts, and the abscissa is the diffraction angle 2θ expressed in degrees (°).

Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry (DSC) was performed using a TA Instruments Differential Scanning Calorimeter Q2000. Place the sample in an aluminum DSC pan and accurately record the weight. The disc is covered with a lid and then crimped. The sample cell was equilibrated at 25°C and heated to a final temperature of 200°C at a rate of 10°C/min under a nitrogen purge. Indium metal was used as the calibration standard. In the DSC diagram, the abscissa represents the temperature (Temperature, °C), and the ordinate represents the heat flow (HeatFlow, W/g) released by the substance per unit mass.

Thermogravimetric Analysis (TGA)

TGA data were acquired on TA InstrumentsQ500. Calibrate the temperature of the instrument using a certified nickel. Typically 8-12 mg of sample is loaded onto a pre-weighed platinum crucible and heated from room temperature to 300 °C at 10 °C/min. A nitrogen purge of 60 mL/min was maintained over the sample. In the TGA diagram, the abscissa represents temperature (Temperature, °C), and the ordinate represents the percentage of weight loss (Weight (%)).

Embodiment 1 prepares crystal form I

Take 50mg of trexagliptin and put it into a 20mL headspace bottle, add 5mL of methanol, heat to dissolve, and filter the filtrate to stand in the air and slowly volatilize at room temperature to obtain crystals; detected by X-ray powder diffraction, it is crystal form I .

Embodiment 2 prepares crystal form I

Take 50mg of trexagliptin and put it into a 20mL headspace bottle, add 5mL of acetone, heat to dissolve, filter the filtrate through the filter membrane and let it stand in the air and slowly volatilize at room temperature to obtain crystals; detected by X-ray powder diffraction, it is crystal form I .

Embodiment 3 prepares crystal form I

Take 50mg of trexagliptin and put it into a 20mL headspace bottle, add 3mL of acetone and 3mL of dichloromethane, heat to dissolve, and filter the filtrate to stand in the air and slowly volatilize at room temperature to obtain crystals; use X-ray powder diffraction to detect , is crystal form I.

Embodiment 4 prepares crystal form I

Take 50 mg of the crystal form II troxagliptin solid and put it into a 20 mL headspace bottle, add 5 mL of isopropyl ether to form a mixed solution containing the solid, and stir the mixed solution at room temperature for 30 hours; collect the solid, X-ray powder diffraction , DSC, TGA and other detections, it is crystal form I.

Embodiment 5 prepares crystal form I

Take 100 mg of trexagliptin solid and put it into a 50 mL single-necked bottle, add 10 mL of dichloromethane, heat to dissolve, and stir for 10 minutes. The solution was distilled to dryness at 45°C under reduced pressure, and the solid was collected. The solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form I.

Embodiment 6 prepares crystal form I

Take 100 mg of trexagliptin solid and put it into a 50 mL single-necked bottle, add 10 mL of ethyl acetate, heat to dissolve, and stir for 10 minutes. The solution was distilled to dryness at 45°C under reduced pressure, and the solid was collected. The solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form I.

Example 7 Preparation of Form I

Take 100 mg of trexagliptin solid and put it into a 50 mL single-necked bottle, add 6 mL of ethyl acetate and 4 mL of acetonitrile, heat to dissolve, and stir for 10 minutes. The solution was distilled to dryness at 45°C under reduced pressure, and the solid was collected. The solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form I.

Example 8 Preparation of Form I

Take 100 mg of trexagliptin solid and put it into a 50 mL single-necked bottle, add 10 mL of ethyl acetate, and heat to dissolve at 50°C. Add 20 mL of n-hexane, stir and cool down to room temperature for crystallization. The collected solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form I.

Example 9 Preparation of Form I

Take 100 mg of trexagliptin solid and put it into a 50 mL single-necked bottle, add 8 mL of isopropyl acetate, and heat to dissolve at 50°C. Add 20 mL of n-heptane, stir and cool down to room temperature for crystallization. The collected solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form I.

Example 10 Preparation of Form II

Take 50 mg of trexagliptin solid and put it into a 20 mL headspace bottle, add 5 mL of methyl ethyl ketone, heat to dissolve, filter the filtrate through a filter membrane, and let the filtrate stand in the air at room temperature and slowly evaporate to dryness. The obtained solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form II.

Example 11 Preparation of Form II

Take 100 mg of trexagliptin solid and put it into a 50 mL single-necked bottle, add 10 mL of methyl ethyl ketone, heat to dissolve, and stir for 10 minutes. Then the butanone solution was distilled to dryness at 45°C under reduced pressure; the solid was collected and detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form II.

Example 12 Preparation of Form II

Take 100 mg of trexagliptin solid and put it into a 50 mL single-necked bottle, add 2 mL of acetone, stir, and heat to dissolve at 50°C. Add 20 mL of n-heptane, drop to -5°C for crystallization. The collected solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form II.

Example 13 Preparation of Form II

Take 100 mg of trexagliptin solid and put it into a 50 mL single-necked bottle, add 2 mL of acetone, stir, and heat to dissolve at 50°C. Add 20 mL of cyclohexane, drop to -5°C for crystallization. The collected solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form II.

Example 14 Preparation of Form III

Take 100mg of trexagliptin solid into a 50mL single-necked bottle, add 4mL of acetone aqueous solution (volume ratio 1:1) to dissolve, stir at room temperature to evaporate the solvent, collect the solid, and use X-ray powder diffraction, DSC, TGA, etc. It was detected as crystal form III.

After placing the obtained crystal form III sample in the air at room temperature for 4 hours, X-ray powder diffraction detection revealed that the crystal form was transformed into crystal form II.

Example 15 Preparation of Form IV

Take 100 mg of Trexagliptin crystal form II solid, put it into a crystallization dish, and heat at 150° C. for 2 hours. The collected solid was detected by X-ray powder diffraction, DSC, TGA, etc., and it was crystal form IV.

Embodiment 16 hygroscopicity test

According to the current guiding principles of the hygroscopicity test in the Chinese Pharmacopoeia, experiments were designed to investigate the hygroscopicity of various crystal forms, and the results are shown in Table 1 below:

Table 1: Investigation results of hygroscopicity of crystal forms

The results show that crystal form I, crystal form II and crystal form IV have slight hygroscopicity, and crystal form I and crystal form IV have relatively low hygroscopicity.

Embodiment 17 solubility test

Experimental method: Pre-weigh the test tube and stirrer, accurately weigh the samples of each crystal form, add to the bottle, add water dropwise, stir in the same way, stop adding water until the solid is completely dissolved. Complete dissolution was considered when no particles were visible to the eye. After dissolution, weigh the total weight of the test tube, stirring bar, and aqueous solution, calculate the weight of the added water, and then calculate the solubility; the density of water is calculated as 1.0g/mL. The solubility of each crystal form sample in water at 25°C was tested respectively.

Experimental results:

temperature crystal form Solubility 25°C Form I 3.52mg/mL 25°C Form II 3.57mg/mL 25°C Form IV 2.65mg/mL

Embodiment 18 stability investigation

According to the guidelines for the stability test of raw materials and pharmaceutical preparations in Appendix XIXC of the Chinese Pharmacopoeia 2010 edition, samples of crystalline form I, crystalline form II, and crystalline form IV were sealed and packaged in double-layer PE bags for accelerated experiments.

Storage conditions: 40℃±2℃, relative humidity: 75%±5%, constant temperature and humidity chamber; and

30℃±2℃, relative humidity: 65%±5% constant temperature and humidity chamber;

Storage time: 1 month; on the 3rd, 15th, and 30th day, detect DSC, X-ray powder diffraction, and HPLC to detect related substances and contents.

Test results: DSC and X-ray powder diffraction test showed that the crystal form of the crystal form I, crystal form II and crystal form IV samples did not change after being placed for 1 month; HPLC test found that the related substances and content of each sample did not change more than 0.05% ,No significant changes.

The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims (6)

1. the crystal form II of bent Ge Lieting, or form IV, wherein, be approximately 20.04 at 2 θ, 20.85 in the X-ray powder diffraction pattern of described crystal form II, there is peak the position of 21.86 degree; Be approximately 16.28 at 2 θ, 20.03,22.30 in the X-ray powder diffraction pattern of described form IV, there is peak the position of 27.55 degree.

2. crystal form II according to claim 1, be approximately 10.98 at 2 θ, 16.87,20.04,20.85,21.86,25.80,28.04 in its X-ray powder diffraction pattern, there is peak the position of 30.41 degree; Or be approximately 5.48 at 2 θ, 10.98,12.86,16.55,16.87,18.79,20.04,20.85,21.86,23.15,25.80,28.04 in its X-ray powder diffraction pattern, there is peak the position of 30.41 degree; Or be approximately 5.48 at 2 θ, 10.98,12.86,13.74,13.93,16.55,16.87,17.76,18.79,20.04,20.85,21.86,23.15,25.80,28.04,28.98,30.41 in its X-ray powder diffraction pattern, there is peak the position of 33.93 degree; Or be approximately 5.48 at 2 θ, 10.98,11.51,12.86 in its X-ray powder diffraction pattern, 13.74,13.93,15.05,16.55,16.87,17.10,17.76,18.79,20.04,20.85,21.86,22.15,22.42,23.15,23.74,25.80, there is peak the position of 28.04,28.98,30.41,33.93 degree; Or its X-ray powder diffraction pattern as shown in Figure 4, wherein, the relative intensity being approximately the peak of 20.85 degree at 2 θ is greater than 50%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.

3. form IV according to claim 1, is approximately 4.80 at 2 θ, 9.62,19.09 in its X-ray powder diffraction pattern, 20.44,23.03,24.25,29.20, there is peak the position of 31.77 degree, or is approximately 4.80 at 2 θ, 9.62,19.09 in its X-ray powder diffraction pattern, 20.44,22.31,23.03,24.25,25.14,25.79,27.32,29.20,31.77, there is peak the position of 34.22 degree; Or be approximately 4.80 at 2 θ, 9.62,19.09,20.44,22.31,22.53,23.03,24.25,25.14,25.79,27.32,27.72,29.20,29.59,31.77,34.22 in its X-ray powder diffraction pattern, there is peak the position of 36.17 degree; Or be approximately 4.80 at 2 θ, 9.62,14.47,15.71,17.04 in its X-ray powder diffraction pattern, 17.55,18.39,19.09,19.39,20.44,20.81,21.01,22.31,22.53,23.03,24.25,25.14,25.79,27.32,27.72,29.20, there is peak the position of 29.59,31.77,34.22,36.17 degree; Or its X-ray powder diffraction pattern as shown in Figure 7, wherein, the relative intensity being approximately the peak of 9.62 degree at 2 θ is greater than 50%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.

4. form IV according to claim 3, its differential scanning calorimetric curve has endotherm(ic)peak at about 165 DEG C of-170 DEG C of places.

5. prepare a method for crystal form II described in claim 2, comprising: bent Ge Lieting is dissolved in butanone, be then placed in air at room temperature solvent flashing, or evaporated under reduced pressure solvent, or add poor solvent, then crystallize out, collect crystal and obtain crystal form II; Described poor solvent is Skellysolve A, hexanaphthene, one or more in normal heptane.

6. prepare a method for form IV described in claim 3, comprising: within 2 hours, change crystal form II according to claim 2 into form IV 150 DEG C of heating.