WO2019205021A1

WO2019205021A1 - Amorphous teneligliptin hydrobromide and preparation method thereof

Info

Publication number: WO2019205021A1
Application number: PCT/CN2018/084459
Authority: WO
Inventors: 张�杰; 王磊鑫; 陈勇; 罗忠华; 黄芳芳
Original assignee: 乳源东阳光药业有限公司; 广东东阳光药业有限公司
Priority date: 2018-04-25
Filing date: 2018-04-25
Publication date: 2019-10-31
Also published as: JP2021522332A

Abstract

Provided is an amorphous teneligliptin 2.5 hydrobromide and a preparation method thereof. The method includes: rotary evaporation of a teneligliptin 2.5 hydrobromide hydrate under a certain water bath temperature by using a rotary evaporator; or dissolving a teneligliptin 2.5 hydrobromide hydrate into a solvent, and spray-drying the solution by using a spray dyer; or freeze drying a teneligliptin 2.5 hydrobromide hydrate solution, to prepare the amorphous teneligliptin 2.5 hydrobromide. The method is simple, efficient, and economical, the quality of the intermediate can be controlled, and the method is suitable for industrial preparation. The prepared preparation product is stable.

Description

Amorphous form of tigeaglin hydrobromide and preparation method thereof

Technical field

The invention belongs to the technical field of organic and pharmaceutical synthesis, and particularly relates to an amorphous form of tigeaglin hydrobromide and a preparation method thereof.

Background technique

Tiglipstatin hydrobromide, English name: Teneligliptin Hydrobromide Hydrate, chemical name: 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5- Peptazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine 2.5 hydrobromide hydrate

Molecular formula: C ₂₂ H ₃ 0N ₆ OS·2.5HBr·xH ₂ O

Molecular weight: 628.86, the structural formula is as follows:

Formula (I) Original research company: Japan's Mitsubishi Tanabe Pharmaceutical Co., Ltd., listed in Japan in 2012, is suitable for the treatment of type 2 diabetes. Mechanism of action: DPP-IV inhibitor. CN101119991B reports a 1.0-2.0 hydrate crystal form of tiglistatin 2.5 hydrobromide salt, which has many impurities in the process of preparing its hydrate crystal form, and has a patent barrier.

Summary of the invention

The present invention overcomes the patent barrier problem existing in the prior art method for preparing ticagrelor 2.5 hydrobromide hydrate, and provides a method for preparing tigelastine 2.5 hydrobromide salt and a preparation method thereof. It is simple, efficient and economical, and the quality of the intermediate is controllable, which is suitable for industrial preparation. The amorphous form prepared by the invention has been successfully applied to the preparation product and has good stability.

The present invention provides an amorphous form of tiglietine 2.5 hydrobromide.

The technical feature of the present invention is that the crystal form of the crystal form is characterized by X-ray powder diffraction analyzer (PXRD) diffraction detection, and the result proves to be amorphous.

The characteristic of the thermogravimetric spectrum is detected by differential scanning calorimetry (DSC): the decomposition temperature is about 239.39 °C.

In some embodiments, the tigeraceine 2.5 hydrobromide amorphous has a moisture content of from 0 to 8%.

The invention provides a method for the amorphous form of tiglietine 2.5 hydrobromide, which is prepared by dissolving tiglietine 2.5 hydrobromide hydrate in a certain amount of solvent, using a rotary evaporator for rotary steaming, in a certain water bath. The mixture was steamed under reduced pressure at a temperature to finally obtain an amorphous form of tiglistatin 2.5 hydrobromide.

In some embodiments, the solvent is water, C ₁ -C ₅ alcohols or mixtures thereof.

In some embodiments, the solvent is water or an alcohol in C ₁ -C _5.

In some embodiments, the alcohol is, but not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol.

In some embodiments, the mass-to-volume ratio of the amount of ticastatin 2.5 hydrobromide hydrate to solvent is from about 1 g/100 ml to 1 g/1 ml.

In some embodiments, it is from about 1 g/10 ml to 1 g/20 ml.

In some embodiments, the water bath temperature is between about 20 ° C and 100 ° C.

In some embodiments it is between about 40 ° C and 60 ° C.

The invention provides a method for the amorphous form of tiglietine 2.5 hydrobromide, which is prepared by dissolving tiglietine 2.5 hydrobromide hydrate in a certain amount of solvent, spray drying the solution by a spray dryer, and setting a certain amount. Inlet air temperature, outlet air temperature, pumping rate, and peristaltic pump speed. Final spray drying gave an amorphous form of tiglistatin 2.5 hydrobromide salt.

In some embodiments, the solvent is water or an alcohol in C ₁ -C _5.

In some embodiments, the quantity by volume ratio of the amount of tiguletine 2.5 hydrobromide hydrate to solvent is from about 1 g/1000 ml to 1 g/1 ml.

In some embodiments, it is from about 1 g/10 ml to 1 g/20 ml.

In some embodiments, the inlet air temperature is between about 50 ° C and 300 ° C.

In some embodiments it is between about 140 °C and 170 °C.

In some embodiments, the outlet temperature is between about 50 ° C and 150 ° C.

In some embodiments it is from about 92 °C to 87 °C.

In some embodiments, the pumping rate is between 20% and 100%.

In some embodiments, the peristaltic pump has a rotational speed of 5% to 100%.

The present invention provides a method for the amorphous form of tiglietine 2.5 hydrobromide, which is prepared by dissolving tiguletine 2.5 hydrobromide hydrate in a certain amount of solvent, lyophilizing the solution, setting a certain freezing temperature, One drying temperature and one dry vacuum, and analytical drying temperature and analytical vacuum. Final freeze-drying gave an amorphous form of tiglistatin 2.5 hydrobromide.

In some embodiments, the solvent is water or an alcohol in C ₁ -C _5.

In some embodiments, the solvent is water.

In some embodiments, it is from about 1 g/10 ml to 1 g/20 ml.

In some embodiments, the freezing temperature is from about -50 ° C to the point of solidification of the solvent.

In some embodiments it is about -35 °C.

In some embodiments, the primary drying temperature is between -20 ° C and 20 ° C.

In some embodiments, the primary dry vacuum is from 0.2 mpar to 1 mpar. .

In some embodiments, the analytical drying temperature is from -5 °C to 20 °C.

In some embodiments, the analytical dry vacuum is from 0.05 mpar to 1 mpar.

The present invention provides the results of the influencing factors of tiguestatine 2.5 hydrobromide salt, the conditions are as follows (the hydrate given in the table refers to the hydrate crystal form (1.0-2.0H ₂ O) in the patent US2011282058A1):

Table 1: Experimental conditions and parameters

Table 2: Experimental results

The results showed that tigestatin 2.5 hydrobromide amorphous was unstable under high temperature (60 ° C) and high humidity (93%) conditions, and was easily converted into hydrate crystal form; in light (UV + light) and sealed dry conditions Under the amorphous type, no change occurred, indicating that the amorphous type is relatively stable under light conditions and sealed dry conditions. This amorphous type is recommended for storage at room temperature and under sealed dry conditions.

The invention provides the results of long-term stability determination of tigelastine 2.5 hydrobromide salt, and the conditions are as follows: a sample of the cisplatin hydrobromide (2.5HBr) amorphous drug substance is sealed in a PE bag, and then placed in an aluminum foil bag. The desiccant was added at the same time, and finally vacuum sealed, placed in a 25 ° C incubator to investigate the long-term stability.

Table 3. Stability results of tigeaglips hydrobromide under amorphous room temperature sealed dry conditions

Definition of Terms

In the context of the present invention, the ml is milliliters, min is minutes, g is grams, room temperature is 10 ° C to 30 ° C, and the English code in the instrumentation is the specific model of the device.

Instruction sheet

1 is an XRPD characterization spectrum of an amorphous crystalline form of ticagrelor 2.5 hydrobromide salt prepared in Example 1;

2 is an amorphous crystalline form DSC characterization chart of ticastatin 2.5 hydrobromide salt prepared in Example 1;

3 is a graph showing the amorphous TGA characterization of tiguletine 2.5 hydrobromide salt prepared in Example 1;

Figure 4 is an XRD spectrum of tigestatin 2.5 hydrobromide salt after 5 days of amorphous high temperature, light, sealed dry storage;

Figure 5 is a DSC chart of tigeglitin 2.5 hydrobromide salt after 5 days of amorphous high temperature, light, sealed dry storage;

Figure 6 is a TGA diagram of tigestatin 2.5 hydrobromide salt after 5 days of amorphous high temperature, light, sealed dry storage;

Figure 7 is an XRD spectrum of tiguestatine 2.5 hydrobromide salt after 10 days of amorphous high temperature, light, sealed dry storage;

Figure 8 is a DSC chart of tigeglitin 2.5 hydrobromide salt after 10 days of amorphous high temperature, light, sealed dry storage;

Figure 9 is a TGA diagram of tigeglitin 2.5 hydrobromide salt after 10 days of amorphous high temperature, light, sealed dry storage;

Figure 10 is an XRD spectrum of tiguestatine 2.5 hydrobromide salt after 15 days of amorphous high temperature, light, sealed dry storage;

Figure 11 is a DSC chart of tigeglitin 2.5 hydrobromide salt after 15 days of amorphous high temperature, light, sealed dry storage;

Figure 12 is a TGA diagram of tigestatin 2.5 hydrobromide salt after 15 days of amorphous high temperature, light, sealed dry storage.

detailed description

In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described in detail below by way of non-limiting embodiments.

The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.

The present invention can monitor the degree of reaction of the raw materials by TLC or HPLC, as monitored by HPLC, and the reaction is completed when the peak area is less than 1.0%.

Example 1 Preparation of tigelastine 2.5 hydrobromide amorphous form

Under a room temperature condition (25.0 ° C), 10.00 g of tiglidendine hydrobromide hydrate and 100 ml of water were added to a 250 ml flask, magnetically stirred at 200 rpm, and stirred for 30 minutes, and then completely dissolved. The mixture was subjected to rotary evaporation using a rotary evaporator IKA RV10, and steamed at 60 ° C in a water bath. After 2 hours of rotary evaporation, 9.70 g of a solid product was obtained, which was determined to be amorphous by analysis.

Example 2 Preparation of tigelastine 2.5 hydrobromide amorphous form

Under a room temperature condition (25.0 ° C), 10.00 g of tiglidendine hydrobromide hydrate and 100 ml of methanol were added to a 250 ml flask, and the mixture was stirred magnetically at 200 rpm, and stirred for 30 minutes, and then completely dissolved. The mixture was subjected to rotary evaporation using a rotary evaporator IKA RV10, and steamed at 50 ° C in a water bath. After 2 hours of rotary evaporation, 9.50 g of a solid product was obtained, which was determined to be amorphous by analysis.

Example 3 Preparation of tigelastine 2.5 hydrobromide amorphous form

Under a condition of 60.0 ° C, 8.00 g of tiglidendine hydrobromide hydrate and 160 ml of ethanol were added to a 250 ml flask, magnetically stirred at 200 rpm, and stirred for 30 minutes, and then completely dissolved. The mixture was subjected to rotary evaporation using a rotary evaporator IKA RV10, and steamed at 60 ° C in a water bath. After 2 hours of rotary evaporation, 7.85 g of a solid product was obtained, which was determined to be amorphous by analysis.

Example 4 Preparation of tigelastine 2.5 hydrobromide amorphous form

Under a room temperature condition (25.0 ° C), 30.00 g of tiglidendine hydrobromide hydrate and 300 ml of water were added to a 500 ml flask, magnetically stirred at 200 rpm, and stirred for 30 minutes, and then completely dissolved. The solution was spray dried using a spray dryer BUCHI Mini Spray Dryer (B-290) with the following parameters: inlet air temperature 170 ° C; outlet air temperature 92 ° C; pumping rate 100%; peristaltic pump speed 15%. Final spray drying gave 18.50 g of solid which was determined to be amorphous.

Example 5 Preparation of tigelastine 2.5 hydrobromide amorphous form

Under a condition of 60.0 ° C, 16.00 g of tiglidendine hydrobromide hydrate and 400 ml of ethanol were added to a 500 ml flask, magnetically stirred at 200 rpm, and stirred for 30 minutes, and then completely dissolved. The solution was spray dried using a spray dryer BUCHI Mini Spray Dryer (B-290) with the following parameters: inlet air temperature 140 ° C; outlet air temperature 87 ° C; pumping rate 100%; peristaltic pump speed 20%. Final spray drying gave 10.50 g of solid which was determined to be amorphous.

Example 6 Preparation of tigelastine 2.5 hydrobromide amorphous form

Under a room temperature condition (25.0 ° C), 10.00 g of tiglidendine hydrobromide hydrate and 100 ml of water were added to a 500 ml flat-bottomed flask, magnetically stirred at 200 rpm, and stirred for 30 min to completely dissolve. The solution was freeze-dried using a freeze dryer LYO-0.5. The specific parameters were as follows: -35 ° C freezing for 360 min; a dry vacuum of 0.30 mbar, heating to -10 ° C for 600 min, warming to 0 ° C for 600 min, heating to 5.0 ° C It was continued for 780 min; the dry vacuum was analyzed to 0.10 mbar, and the temperature was raised to 20 ° C for 480 min. Final freeze-drying gave 9.80 g of solid which was determined to be amorphous.

In summary, the method for preparing an amorphous crystalline form of tiglietine 2.5 hydrobromide hydrate provided by the present invention has the advantages of simplicity, high efficiency, economy, and the like.

Instrument parameters and test conditions of the present invention

Instrument information:

1) X-ray powder diffraction analyzer (PXRD)--PANalytical

2) Differential Scanning Calorimeter (DSC)--TA Q2000

3) Thermogravimetric Analyzer (TGA)--TA Q500

4) Magnetic stirrer - OragonLab MS-Pro

5) Rotary evaporator - IKA RV10

6) Spray dryer - BUCHI Mini Spray Dryer (B-290)

7) Freeze dryer - LYO-0.5

testing method:

1) PXRD method

2) DSC and TGA methods

The parameters of the DSC method are as follows:

30-300 ° C, 10 ° C / min; N 2 (50 mL / min)

The TGA method parameters are as follows:

30-300 ° C, 10 ° C / min; N 2 (60 mL / min)

The method of the present invention has been described by the preferred embodiments, and it is obvious that those skilled in the art can make modifications and/or changes and combinations of the methods and applications described herein to implement and apply the present technology. . Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.

Claims

An amorphous form of tiglietine 2.5 hydrobromide salt.
The ticagreline 2.5 hydrobromide amorphous form according to claim 1, wherein the DSC decomposition temperature is 239.39 °C.
The ticagrelor 2.5 hydrobromide amorphous form according to claim 1, characterized in that the amorphous moisture content is from 0 to 8%.
An amorphous method for preparing tiglietine 2.5 hydrobromide salt according to claim 1, characterized in that tiglietine 2.5 hydrobromide hydrate is dissolved in a certain amount of solvent to form a solution Then, using a rotary evaporator to spin under a certain water bath temperature, to obtain an amorphous form of tiglistatin 2.5 hydrobromide salt; or spray drying the solution by a spray dryer, at a certain inlet air temperature, air temperature At the pumping rate and the peristaltic pump speed, the final spray drying results in an amorphous form of tiglietine 2.5 hydrobromide salt; or the solution is freeze-dried at a certain freezing temperature, a drying temperature and a dry vacuum, and The amorphous temperature and the analytical vacuum were analyzed, and finally freeze-dried to obtain an amorphous form of tiglistatin 2.5 hydrobromide.
The method of claim 4 wherein said solvent is water, a C 1 -C 5 alcohol or a mixture thereof.
The method according to claim 5, wherein the alcohol solvent is at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.
The method according to claim 4, wherein the amount of the tigestatin 2.5 hydrobromide hydrate to the solvent is from 1 g/100 ml to 1 g/1 ml.
The method of claim 4 wherein said pumping rate is between 20% and 100%.
The method of claim 4 wherein said peristaltic pump rotational speed is between 5% and 100%.
The method of claim 4 wherein said water bath temperature is from 20 ° C to 100 ° C.
The method of claim 4 wherein said inlet air temperature is between 50 ° C and 300 ° C.
The method of claim 4 wherein said outlet temperature is between 50 ° C and 150 ° C.
The method of claim 4 wherein said freezing temperature is from -50 ° C to 20 ° C.
The method according to claim 4, wherein said primary drying temperature is -20 ° C to 20 ° C.
The method of claim 4 wherein said primary drying vacuum is from 0.2 mpar to 1 mpar.
The method of claim 4 wherein said analytical drying temperature is from -5 ° C to 20 ° C.
The method of claim 4 wherein said analytical dry vacuum is from 0.05 mpar to 1 mpar.