A process for the preparation of crystalline salts of troglitazone

Abstract

The present application relates to a kind of preparation methods of crystalline of succinic acid Crizotin, belong to the crystallization technical field of bulk drug. By the low molecular alcohol solution of succinic acid is added to the low molecular alcohol solution of Crizotin base, obtain suspension, then the low molecular ester solvent of 2-3 times the mass of succinic acid in first step is added to the suspension, gradient cooling is carried out, and the final D90 less than 10 microns small particle size succinic acid Crizotin crystal is obtained at the end point temperature. By the method, the two-step process of salification and refining is coupled into one step, the process efficiency is greatly improved, and the production cost is reduced. The process is stable, controllable, with good batch stability, low cost, and the molar yield can reach 90%-97%, suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of crystalline trelagliptin succinate, belonging to the technical field of crystallization of bulk drug. BACKGROUND

[0002] Trelagliptin succinate, chemical name: 2-[[6-[(3R)-3-amino-1-piperidyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrile succinate, CAS number: 1029877-94-8, molecular formula: C 18 H 20 FN5O2·C4H6O4, white or white-like granules. As a dipeptidyl peptidase IV (DPP-4) inhibitor, it can be used for the treatment of type II diabetes, and once a week can meet the requirements, greatly improving the quality of life of patients. Its structural formula is shown as formula I.

[0003]

[0004] Compared with traditional diabetes drugs, trelagliptin succinate has higher advantages once a week, reducing the burden of long-term medication for patients, especially the elderly. Trelagliptin succinate, once a week, is mainly due to the unique molecular structure of trelagliptin succinate, which makes it decompose slowly in the human body, so as to achieve the purpose of long-acting control of blood sugar.

[0005] It is well known that the particle size distribution of a solid compound will affect its flowability, dissolution rate and other indicators, so in the fields of pharmaceuticals, chemicals and the like, the particle size distribution indicators of products are often limited to ensure the quality stability of the products. Therefore, by reasonably controlling the particle size distribution of trelagliptin succinate, the dissolution rate thereof can be regulated, and then the release rate of the drug can be controlled, which can complement the particularity of its structure, and different period preparations can be prepared.

[0006] At present, enterprises at home and abroad generally use crushing and screening processes to control the particle size distribution of products. Due to the crushing equipment and screen aperture, the particle size distribution of products in batches is difficult to achieve uniform distribution and has large batch-to-batch differences, which cannot effectively meet the customized needs of downstream customers for the particle size of products. At present, there is no separation and purification preparation method for trelagliptin succinate products less than 10 microns.

[0007] As an important separation and purification technology, crystallization technology can realize effective control of compound crystal form, particle size and other indicators, and is widely used in chemical, food, pharmaceutical and other fields. However, the crystallization process is often used as a refining process in the preparation process of compounds, and is rarely coupled with the preparation process, and even multiple repeated refining processes are performed according to actual needs to meet the quality standards of products. At present, the refining process of succinic acid triglitazone in China still mostly adopts the method of heating, hot filtering and cooling crystallization, and the product quality is difficult to control. If the crystallization operation can be carried out at the same time as the reaction, not only the process preparation efficiency will be significantly improved, but also the process cost and material loss will be significantly reduced, which has great industrial application prospect.

[0008] Although the synthesis of succinic acid triglitazone is relatively simple, its preparation and separation process is still a relatively independent process. If the crystallization process can be effectively controlled at the same time as the reaction, not only the particle size customization demand can be realized in one step, but also the process energy consumption and production cost will be effectively reduced. Therefore, it is particularly necessary to develop a new crystallization preparation method of succinic acid triglitazone, which can realize product crystallization precipitation at the same time as the reaction, effectively control the particle size distribution, and has good batch reproducibility and easy industrial production. SUMMARY

[0009] The purpose of the application is to meet the demand for release behavior regulation of long-acting preparation succinic acid triglitazone, and to provide a preparation method of small particle size succinic acid triglitazone crystal, which can effectively realize the regulation of particle size distribution of succinic acid triglitazone at the same time as the reaction preparation.

[0010] The technical scheme of the application is as follows:

[0011] A preparation method of small particle size succinic acid triglitazone crystal, comprising the following steps:

[0012] Step 1: Dissolve succinic acid in low molecular alcohol, the liquid-solid ratio is 5-8:1 (mass ratio), continuously stir and dissolve at 45-55℃ for 30 min, filter, transfer the filtrate to a crystallizer and incubate at 45-55℃ for 30-45 min.

[0013] Step 2: Uniformly add 2.5-2.8 times of the mass of succinic acid in step 1 to the solution of step 1 to obtain a suspension.

[0014] Step 3: Incubate the solution at 35-45℃ for 40-50 min to obtain a suspension.

[0015] Step 4: Continue to uniformly add 2-3 times of the mass of succinic acid in step 1 to the suspension in step 3 to obtain a suspension.

[0016] Fifth step: cooling the system obtained in the fourth step to 5-20℃ at a cooling rate of 5-10 min / ℃, and keeping the temperature constant for 60-90 min at the end of the cooling.

[0017] Sixth step: filtering, washing the filter cake with a low molecular ester solvent, and finally drying the product to obtain the crystalline product of the succinic acid trglitazone.

[0018] The small particle size crystalline product of the succinic acid trglitazone according to the present application refers to the crystalline product of the succinic acid trglitazone with a D90 of less than 10 microns.

[0019] The low molecular alcohol solvent in the first step of the present application is a mixed solvent of one or more of methanol, ethanol, isopropyl alcohol and n-propanol.

[0020] The low molecular alcohol solution of the trglitazone free base in the second step of the present application is a mixed solution of the trglitazone free base and one or more of methanol, ethanol, isopropyl alcohol and n-propanol, wherein the mass ratio of the trglitazone free base to the low molecular alcohol solvent is 1:4-6.

[0021] The low molecular ester solvent in the fourth step of the present application is one of ethyl acetate, butyl acetate and isopropyl acetate.

[0022] The drying condition according to the present application is vacuum drying, the vacuum degree is 0.06-0.1 Mpa, and the drying temperature is 50-60℃.

[0023] The yield range of the present application is 90-97%.

[0024] The amount of the first addition of the small molecule ester is a key process parameter, if the amount exceeds 3 times, a large amount of crystal particles will spontaneously precipitate, and agglomeration is likely to occur, and the particle size distribution cannot be effectively controlled; if the amount is less than 2 times, the supersaturation degree is too low, and a small particle size crystal product with sufficient yield cannot be obtained.

[0025] Beneficial effects: the present application provides a crystalline preparation method of the succinic acid trglitazone with a D90 of less than 10 microns, the two steps of salt formation and purification are coupled into one step, the process efficiency is greatly improved, and the production cost is reduced. The process is stable, controllable, has good batch-to-batch stability, low cost, and the molar yield can reach 90-97%, and is suitable for industrial production. At the same time, the process can stably obtain products with different particle sizes, the crystal shape is complete, the particle size distribution curve is normal unimodal, the fluidity is good, and the product is easy to disperse, and can be directly used for the preparation of different shelf-life preparations. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 : PXRD pattern of the succinic acid trglitazone obtained in Example 1;

[0027] Figure 2 DSC pattern of succinate trogitaπine obtained in Example 1;

[0028] Figure 3 Particle size distribution pattern of succinate trogitaπine obtained in Example 1;

[0029] Figure 4 Particle size distribution pattern of succinate trogitaπine obtained in Comparative Example 1;

[0030] Figure 5 Particle size distribution pattern of succinate trogitaπine obtained in Comparative Example 2. DETAILED DESCRIPTION Example 1

[0031] Put 100 g of succinic acid into 500 g of methanol, and stir to dissolve at 45 °C for 30 min; filter while hot; transfer the filtrate into a crystallizer and stir at 45 °C for 30 min. Then add 250 g of a methanol solution of trogitaπine free base (trogitaπine:methanol = 1:4, mass ratio) into the crystallizer at a constant rate, and control the addition time to be 30 min. Then keep the temperature at 35 °C for 40 min, and then add 200 g of ethyl acetate into the crystallizer at a constant rate, and control the addition time to be 30 min, and then keep the temperature constant for 30 min; then cool the system to 5 °C at a rate of 10 min / °C, and keep the temperature at 5 °C for 90 min. Filter, and rinse the filter cake with ethyl acetate, and dry at 50 °C under vacuum for 5 h, with a vacuum degree of 0.1 MPa. The PXRD pattern of the succinate trogitaπine crystal product obtained is shown in Figure 1 , the DSC pattern is shown in Figure 2 , the particle size distribution curve obtained by Malvern particle size analyzer is a normal unimodal curve (as shown in Figure 3 ), D90 is 8.556 μm, the HPLC purity is 99.97%, and the product yield is 93.2%. Example 2

[0032] Put 100 g succinic acid into 800 ethanol, stir to dissolve at 50 °C for 40 min; filter while hot; move the filtrate into a crystallizer and stir at 50 °C for 45 min. Then add 280 g of the ethanol solution of the free base of trelagliptin (trelagliptin: ethanol = 1:6, mass ratio) into the crystallizer at a constant rate, with the flow rate controlled at 30 min. Then keep the temperature at 45 °C for 50 min, and then add 300 g of butyl acetate into the crystallizer, with the flow rate controlled at 45 min, and then keep the temperature at 45 °C for 45 min; then lower the temperature to 10 °C at a rate of 5 min / °C, and keep the temperature at 10 °C for 60 min. Filter, and rinse the filter cake with butyl acetate, and dry at 55 °C under vacuum for 4 h, with the vacuum degree being 0.08 MPa. The obtained trelagliptin succinate crystal product has a uniform particle size distribution, the particle size distribution curve obtained by a Malvern particle size analyzer is a normal unimodal curve, D90 is 6.970 μm, the HPLC purity is 99.95%, and the product yield is 95.2%. Example 3

[0033] Put 100 g succinic acid into 800 isopropyl alcohol, stir to dissolve at 50 °C for 40 min; filter while hot; move the filtrate into a crystallizer and stir at 50 °C for 45 min. Then add 280 g of the isopropyl alcohol solution of the free base of trelagliptin (trelagliptin: isopropyl alcohol = 1:6, mass ratio) into the crystallizer at a constant rate, with the flow rate controlled at 30 min. Then keep the temperature at 45 °C for 50 min, and then add 300 g of isopropyl acetate into the crystallizer, with the flow rate controlled at 45 min, and then keep the temperature at 45 °C for 45 min; then lower the temperature to 10 °C at a rate of 5 min / °C, and keep the temperature at 10 °C for 60 min. Filter, and rinse the filter cake with butyl acetate, and dry at 55 °C under vacuum for 4 h, with the vacuum degree being 0.08 MPa. The obtained trelagliptin succinate crystal product has a uniform particle size distribution, the particle size distribution curve obtained by a Malvern particle size analyzer is a normal unimodal curve, D90 is 8.790 μm, the HPLC purity is 99.93%, and the product yield is 94.7%. Example 4

[0034] The succinic acid was dissolved in 800 g of n-propanol at 50 °C for 40 min, and then filtered while hot. The filtrate was transferred into a crystallizer and stirred at 50 °C for 45 min. Then, 280 g of a solution of the free base of trelagliptin in n-propanol (trelagliptin : n-propanol = 1 : 6, mass ratio) was added to the crystallizer at a constant rate over 30 min. The temperature was then maintained at 45 °C for 50 min, and then 300 g of butyl acetate was added to the crystallizer at a constant rate over 45 min, and the temperature was then maintained at 45 °C for another 45 min. The temperature was then decreased to 10 °C at a rate of 5 min / °C, and the temperature was maintained at 10 °C for 60 min. The product was filtered, and the filter cake was washed with butyl acetate. The product was dried at 55 °C under vacuum for 4 h at a vacuum degree of 0.08 MPa. The obtained trelagliptin succinate crystal product had a uniform particle size distribution, and the particle size distribution curve obtained by a Malvern particle size analyzer was a normal unimodal curve, with a D90 of 7.750 μm. The purity of the product was 99.94% by HPLC, and the yield of the product was 95.1%. Example 5

[0035] The succinic acid was dissolved in 800 g of n-propanol at 50 °C for 40 min, and then filtered while hot. The filtrate was transferred into a crystallizer and stirred at 50 °C for 45 min. Then, 280 g of a solution of the free base of trelagliptin in n-propanol (trelagliptin : n-propanol = 1 : 6, mass ratio) was added to the crystallizer at a constant rate over 30 min. The temperature was then maintained at 45 °C for 50 min, and then 300 g of butyl acetate was added to the crystallizer at a constant rate over 45 min, and the temperature was then maintained at 45 °C for another 45 min. The temperature was then decreased to 10 °C at a rate of 5 min / °C, and the temperature was maintained at 10 °C for 60 min. The product was filtered, and the filter cake was washed with butyl acetate. The product was dried at 55 °C under vacuum for 4 h at a vacuum degree of 0.08 MPa. The obtained trelagliptin succinate crystal product had a uniform particle size distribution, and the particle size distribution curve obtained by a Malvern particle size analyzer was a normal unimodal curve, with a D90 of 7.750 μm. The purity of the product was 99.94% by HPLC, and the yield of the product was 95.1%.

[0036] Comparative Example 1: The amount of ethyl acetate was more than 3 times the amount of succinic acid

[0037] Put 100 g succinic acid into 600 g methanol, stir and dissolve at 45 °C for 30 min; filter while hot; move the filtrate into a crystallizer and stir at 45 °C for 30 min. Then add 270 g of a methanol solution of tirzepatide free base (tirzepatide free base: methanol = 1:5, mass ratio) into the crystallizer at a uniform rate, with the addition time controlled at 30 min. Then keep the temperature at 35 °C for 40 min, and then add 350 g of ethyl acetate (5 °C, 3.5 times the mass of succinic acid) into the crystallizer at a uniform rate, with the addition time controlled at 45 min, and then keep the temperature constant for 45 min; then lower the temperature to 10 °C at a rate of 5 min / °C, and keep the temperature at 10 °C for 60 min. Filter, and rinse the filter cake with butyl acetate, and dry at 55 °C under vacuum for 4 h, with the vacuum degree being 0.08 MPa. The particle size distribution curve of the obtained tirzepatide succinate crystal product is bimodal (as shown in Figure 4 FIG. 1), the D90 is 139.969 μm, the HPLC purity is 99.5%, and the product yield is 98%.

[0038] This comparative example is consistent with the conditions of Example 1, except that the amount of ethyl acetate added for the first time exceeds the range of the aforementioned key process parameters. The particle size distribution of the product is bimodal, because the amount of ethyl acetate added is too much, the supersaturation is too large, the process is out of control, small crystals are spontaneously precipitated, and crystal agglomeration easily occurs, resulting in a large particle size. As can be seen from this comparative example, if the amount of ethyl acetate added exceeds the range of the aforementioned key process parameters, the D90 of the product will become large, and the particle size distribution will appear bimodal.

[0039] Comparative Example 2: The amount of ethyl acetate added is less than 2 times the mass of succinic acid

[0040] Put 100 g succinic acid into 800 g ethanol, stir and dissolve at 50 °C for 40 min; filter while hot; move the filtrate into a crystallizer and stir at 50 °C for 45 min. Then add 280 g of an ethanol solution of tirzepatide free base (tirzepatide: ethanol = 1:6, mass ratio) into the crystallizer at a uniform rate, with the addition time controlled at 30 min. Then keep the temperature at 45 °C for 50 min, and then add 150 g of butyl acetate (10 °C, 1.5 times the mass of succinic acid) into the crystallizer at a uniform rate, with the addition time controlled at 45 min, and then keep the temperature constant for 45 min; then lower the temperature to 10 °C at a rate of 5 min / °C, and keep the temperature at 10 °C for 60 min. Filter, and rinse the filter cake with butyl acetate, and dry at 55 °C under vacuum for 4 h, with the vacuum degree being 0.08 MPa. The particle size distribution curve of the obtained tirzepatide succinate crystal product is bimodal (as shown in Figure 5 FIG. 2), the D90 of the particles is 64.417 μm, the HPLC purity is 99.05%, and the product yield is 87%.

[0041] The comparative example is consistent with the conditions of example 2, only the amount of butyl acetate added exceeds the range of the aforementioned key process parameters. The product particle size is normally distributed, and the number of large particle size range particles is large, and the yield is low. The reason is that the amount of butyl acetate added is too small, and the supersaturation is low, and the crystal is mainly grown. It can be seen from the comparative example that the cooling rate exceeds the range of the aforementioned key process parameters, which will cause the overall particle size to become large, and the crushing process needs to be increased to meet the downstream requirements.

[0042] Test example Dissolution test

[0043] In the present application, the dissolution determination adopts the dissolution determination method (Appendix XC) of the second method (paddle method) device of the second part of the Chinese Pharmacopoeia 2010 edition, with 900 mL of degassed pH 6.8 phosphate buffer as the dissolution medium, the rotation speed is 50 rpm, and the temperature is 37°C. Sample 5 ml at the specified time (while supplementing the same amount of medium), filter, and determine the peak area by high performance liquid chromatography, calculate the concentration of succinic acid triglyceride in the dissolution medium, and calculate the cumulative dissolution.

[0044] Among them, the reference preparation is the marketed drug purchased, and the tablet core components include triglyceride succinate, mannitol, microcrystalline cellulose, sodium croscarmellose, hydroxypropyl cellulose and sodium stearate fumarate. The succinic acid triglyceride obtained by the examples and comparative examples of the present application is made into tablets according to the following method, and the dissolution test is determined.

[0045] The succinic acid triglyceride, sodium croscarmellose, hydroxypropyl cellulose, mannitol and microcrystalline cellulose obtained by the examples and comparative examples of the present application are mixed uniformly, dry granulation is carried out through a dry granulator, and dry granules are obtained; the dry granules and sodium stearate fumarate are mixed uniformly, and tablets are compressed.

[0046]

[0047] As can be seen from the above table, the dissolution effect of the succinic acid triglyceride tablets obtained by the present application is equivalent to that of the marketed product; the dissolution effect of the tablets obtained by comparative example 1 and comparative example 2 is poor.

Claims

1. A method for preparing small-particle succinate trelagliptin crystals, characterized in that: Step 1: Add the succinic acid low molecular weight alcohol solution to the treglitazone free base low molecular weight alcohol solution to obtain a suspension. The low molecular weight alcohol solvent is a mixture of one or more alcohol solvents selected from methanol, ethanol, isopropanol, and n-propanol. Step 2: Add 2 to 3 times the mass of succinic acid from Step 1 to the suspension for 30 to 45 minutes, and maintain the temperature for crystal growth for 30 to 60 minutes. The low molecular weight ester solvent is one of ethyl acetate, butyl acetate, or isopropyl acetate. Step 3: Cool the system obtained in step 2 to 5~20℃ at a rate of 5~10 min / ℃, and maintain the temperature at the end of cooling for 60~90 min to grow crystals. Step 4: Filter and dry to obtain small-particle succinate trelagliptin crystals.

2. The preparation method according to claim 1, characterized in that... Small-particle trogliptin succinate crystals refer to trogliptin succinate crystals with a D90 of less than 10 micrometers.

3. The preparation method according to claim 1, characterized in that... The preparation of the succinic acid low molecular weight alcohol solution in the first step involves dissolving succinic acid in low molecular weight alcohol, heating and stirring to dissolve, filtering, and the filtrate is the solution.

4. The preparation method according to claim 3, characterized in that... The mass ratio of succinic acid to low molecular weight alcohol is 1:5~8.

5. The preparation method according to claim 3, characterized in that... Heating temperature: 45~55℃.

6. The preparation method according to claim 1, characterized in that... In the first step, the mass ratio of the low molecular weight alcohol solution of treglitin free base to succinic acid is 2.5~2.8:

1.

7. The preparation method according to claim 6, characterized in that... The mass ratio of treglitazone free base to low molecular weight alcohol is 1:4-6.

8. The preparation method according to claim 1, characterized in that... The drying conditions are vacuum drying, with a vacuum degree of 0.06~0.1Mpa and a drying temperature of 50~60℃.

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