Preparation method of norvenlafaxine succinate crystal form I large-particle crystal

Abstract

The invention discloses a preparation method of a large-particle crystal of a desvenlafaxine succinate crystal form I, and belongs to the field of medicine crystallization. The preparation method of the large-particle crystal of the desvenlafaxine succinate crystal form I comprises the following steps: mixing desvenlafaxine succinate free alkali, succinic acid, acetone and purified water or mixing desvenlafaxine succinate monohydrate, acetone and purified water, stirring, heating, dissolving, cooling, filtering, washing, and drying to obtain the large-particle crystal of the desvenlafaxine succinate crystal form I. The invention further discloses a preparation method of the large-particle crystal of the desvenlafaxine succinate crystal form I. Adding a desvenlafaxine succinate crystal form I seed crystal 0.5-1 h after spontaneous crystallization and turbidity, and stirring at a constant temperature to grow the crystal; and continuously cooling and crystallizing, and separating out crystals, thereby obtaining the large-particle crystals of the desvenlafaxine succinate crystal form I. The crystal prepared by the method disclosed by the invention has higher crystal form I purity, is mainly uniform blocky large particles, is perfect in crystal growth, and is suitable for the production requirements of preparations, especially sustained release preparations.

Description

Technical Field

[0001] This invention belongs to the field of drug crystallization, specifically relating to a method for preparing large-particle crystals of desmectin succinate (Crystalline) of type I. Background Technology

[0002] Desvenlafaxine succinate is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It was first marketed in the United States in May 2008 for the treatment of major depressive disorder (MDD). Its monohydrate crystal form I is the formulation used, CAS: 386750-22-7. Its molecular structure is as follows: The crystal forms of desvenlafaxine succinate were first disclosed in patent CN1501909A in 2002, including crystal forms I, II, III, IV, and an amorphous form. Crystal form I is a monohydrate, stable at room temperature, and is prepared by recrystallization in an acetone-water system. The patent also reported formulations made using crystal form I.

[0003] In 2007, Matrix Lab. of India disclosed methods for preparing crystal forms A, B, and crystal forms I, II, and III in patent IN1519CHE2007. Crystal form I can be prepared in solvents such as acetone, acetone-xylene, and tetrahydrofuran. In 2008, TevaPharm. reported the screening of crystal forms I, II, III, IV, and amorphous crystal forms in patent WO2008112313A2. Dr. Reddy's Laboratories team disclosed the single-crystal structure of crystal form I in 2008 (Crystallogr., Sect. C, 2008, 64, o290–o292.) and the single-crystal structure of crystal form II in 2009 (CrystEngComm, 2009, 11, 989–992). Crystal forms I and II have similar structures, both belonging to the triclinic crystal system. Space group. Based on its single-crystal data, standard powder X-ray diffraction (PXRD) patterns for crystal forms I and II can be simulated, as shown in the attached figure. Figure 15 As shown, crystal form II has two unique peaks at 2θ = 13.2° and 14.4°, which can be used as characteristic peaks to distinguish it from crystal form I.

[0004] Other possible valid crystal forms include: an unnamed new crystal form (WO2008017886Al), V, F (CN101274897A), V, VI (IN175MUM2008), two unnamed new crystal forms (WO2008156748A2), Z (IN189MUM2010), Z1 (US8933123B2), etc.

[0005] Although the above literature reports various methods for preparing crystal form I, due to the similarity in structure between crystal form I and crystal form II, mixed crystals are easily formed in actual preparation processes, and there are no publicly available, reproducible, and practical methods for controlling crystal particle size. Generally, API registration tends to use a single stable crystal form. Furthermore, API crystal particle size is particularly important for the dissolution performance of the formulation, especially for sustained-release formulations, which typically require relatively uniform, large-particle API crystals. Summary of the Invention

[0006] To overcome the difficulties in existing preparation processes, such as the easy formation of mixed crystals and the lack of a publicly available, reproducible, and practical method for controlling crystal particle size, this invention provides a method for preparing large-particle desvenlafaxine succinate crystals of crystal form I. Using this method, relatively large and uniform blocky desvenlafaxine succinate crystals can be obtained, and the product exhibits high purity of crystal form I.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing large-particle crystals of desmectin venlafaxine (Crystal Type I) includes the following steps: S1: Mix desvenlafaxine free base, succinic acid, acetone and purified water, or mix desvenlafaxine succinate monohydrate, acetone and purified water. Stir and heat to dissolve and clear the solution, then cool down. After spontaneous crystallization and turbidity (i.e. the system turns white visible to the naked eye), add desvenlafaxine succinate crystal type I seed crystals 0.5-1h and stir at a constant temperature to grow crystals. S2: Continue cooling to crystallize and separate the crystals to obtain large-particle crystals of desmectin venlafaxine type I.

[0008] Using desvenlafaxine monohydrate as raw material, there is no need to add succinic acid. Instead, convert it into free desvenlafaxine base and then feed it into the production process according to the above process parameters.

[0009] Unlike conventional crystallization processes where seed crystals are added before crystals precipitate from the solution, the seed crystals in this invention are added 0.5-1 hours after spontaneous crystallization and the solution becomes turbid. If seed crystals are added before crystallization, the crystal growth and cooling processes cannot be well controlled, resulting in mixed crystals of crystal types I and II, with uncontrollable size and an overall small particle size.

[0010] As a preferred embodiment, in S1, based on the mass of desvenlafaxine free base, 0.45-0.55 times the mass of succinic acid, 5.5-7.6 times the mass of acetone, and 1.5-3.5 times the mass of purified water are added.

[0011] As a more preferred embodiment, in S1, based on the mass of desvenlafaxine free base, 6 times the mass of acetone and 2.6 times the mass of purified water are added.

[0012] The method of this invention uses succinic acid added to desvenlafaxine free base, or directly uses desvenlafaxine succinate monohydrate as raw material, and adds 5.5-7.6 times the mass of acetone and 1.5-3.5 times the mass of purified water. The water content of the solvent is between 15% and 40%, which can better dissolve and crystallize the material and obtain relatively uniform crystal particles. More preferably, the water content is 30%, that is, about 6 times the mass of acetone and 2.6 times the mass of purified water are added.

[0013] Preferably, in S1, the temperature is raised to 50-60℃, then lowered to 35-45℃, and the cooling rate is ≤10℃ / h.

[0014] Preferably, in S1, the amount of the added succinic acid desvenlafaxine crystal type I seed crystal is 0.4% or more of the mass, based on the mass of the desvenlafaxine free base.

[0015] Preferably, in S1, the temperature for spontaneous crystallization and crystal growth is 35-45℃.

[0016] Preferably, in S1, the crystal growth time is ≥2h.

[0017] Preferably, in S2, the process of continuing to cool down and crystallize includes: cooling down to 15-25°C, stirring at a constant temperature for 1-2 hours, and then cooling down to 0-10°C and stirring at a constant temperature for 1-2 hours.

[0018] Preferably, in S2, during the continued cooling and crystallization process, the cooling rate is ≤10℃ / h.

[0019] In the method of this invention, the cooling rate should not be too fast. If the rate is too fast, crystal form II may be generated, and small particulate crystals may be formed. The cooling rate should preferably not exceed 10℃ / h, and the crystals should be stirred and grown at 15-25℃ and 0-10℃ for 2h each time to fully release the unsaturation.

[0020] Preferably, in step S2, the process of separating the crystals includes: after filtration, drying the separated solid by blowing or vacuum; the temperature of the blowing or vacuum drying is 40-50°C.

[0021] Both static drying with forced air or vacuum drying can achieve good results.

[0022] Preferably, in S2, the desmectin lafaxine crystal type I large particle crystal is a blocky crystal with a width of 100-300μm and a length of 240-700μm.

[0023] Therefore, the present invention has the following beneficial effects: Compared with the prior art, the preparation method of the present invention yields succinic acid desvenlafaxine crystal form I, which is mainly uniform blocky large particles with perfect crystal growth, suitable for the production needs of formulations, especially sustained-release formulations. Attached Figure Description

[0024] Figure 1 Micrograph of the dried crystal of desmectin venlafaxine I prepared in Example 1.

[0025] Figure 2 The image shows the PXRD pattern of the dried crystal of desmectin venlafaxine I obtained in Example 1.

[0026] Figure 3 Micrograph of the dried crystal of desmectin venlafaxine I prepared in Example 2.

[0027] Figure 4 The image shows the PXRD pattern of the dried crystal of desmectin venlafaxine I obtained in Example 2.

[0028] Figure 5 Micrograph of the dried crystal of desmectin venlafaxine I prepared in Example 3.

[0029] Figure 6 The image shows the PXRD pattern of the dried crystal of desmectin venlafaxine I obtained in Example 3.

[0030] Figure 7 Micrograph of the dried crystal of desmectin venlafaxine I obtained in Example 4.

[0031] Figure 8 The image shows the PXRD pattern of the dried crystal of desmectin venlafaxine I obtained in Example 4.

[0032] Figure 9 Micrograph of the dried crystal of desmectin lafaxine I prepared in Comparative Example 1.

[0033] Figure 10 The image shows the PXRD pattern of the dried crystal of desmectin lafaxine I prepared in Comparative Example 1.

[0034] Figure 11 Micrograph of the dried crystal of desmectin lafaxine I prepared in Comparative Example 2.

[0035] Figure 12 The image shows the PXRD pattern of the dried crystal of desmectin venlafaxine I prepared in Comparative Example 2.

[0036] Figure 13 Micrograph of the dried crystal of desmectin venlafaxine I prepared in Comparative Example 3.

[0037] Figure 14 The image shows the PXRD pattern of the dried crystal of desmectin venlafaxine I prepared in Comparative Example 3.

[0038] Figure 15 Standard PXRD patterns of crystal forms I and II simulated using single-crystal data.

[0039] Figure 16 The image shows the PXRD pattern of the seed crystal. Detailed Implementation

[0040] The present invention will be further described below through specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0041] General Implementation Examples A method for preparing large-particle crystals of desmectin venlafaxine (Crystal Type I) includes the following steps: S1: Mix desvenlafaxine free base, succinic acid, acetone and purified water, or mix desvenlafaxine succinate monohydrate, acetone and purified water. Stir and heat to dissolve and clear the solution, then cool down. After spontaneous crystallization and turbidity (i.e. the system turns white visible to the naked eye), add desvenlafaxine succinate crystal type I seed crystals 0.5-1h and stir at a constant temperature to grow crystals. S2: Continue cooling to crystallize and separate the crystals to obtain large-particle crystals of desmectin venlafaxine type I.

[0042] In the above preparation process, by adding desmectin lafaxine succinate seed crystals of type I during the crystallization process and by using a specific timing for seed crystal addition, it is helpful to obtain larger and more uniform bulk crystals and to make the product have higher purity of type I crystals.

[0043] In one specific implementation, in S1, whether using desvenlafaxine free base or desvenlafaxine monohydrate succinate, the mass of the desvenlafaxine free base is used as the basis, with 0.45-0.55 times the mass of succinic acid, 5.5-7.6 times the mass of acetone, and 1.5-3.5 times the mass of purified water added. That is, in the scheme using desvenlafaxine monohydrate succinate, the mass of the desvenlafaxine monohydrate succinate converted to the mass of the desvenlafaxine free base is used as the basis, with 0.45-0.55 times the mass of succinic acid, 5.5-7.6 times the mass of acetone, and 1.5-3.5 times the mass of purified water added.

[0044] Furthermore, in S1, based on the mass of desvenlafaxine free base, 6 times the mass of acetone and 2.6 times the mass of purified water were added.

[0045] Based on the mass of desvenlafaxine free base, when acetone is 5.5-7.6 times its mass and purified water is 1.5-3.5 times its mass, the water content of the solvent is 15%-40%, which can effectively dissolve and crystallize the crystals and obtain relatively uniform crystal particles. When acetone is 6 times its mass and purified water is 2.6 times its mass, the water content is 30%, which achieves the best dissolution and crystallization effect and results in more uniform crystal particles.

[0046] In one specific implementation, in S1, the temperature is raised to 50-60℃ and then lowered to 35-45℃, with a cooling rate ≤10℃ / h.

[0047] When the cooling rate is less than or equal to 10℃ / h, no crystal form II or small crystal particles will be produced. Furthermore, stirring and crystallizing at 15-25℃ and 0-10℃ for 2 hours can fully release the unsaturation.

[0048] In one specific implementation, in S1, whether using desvenlafaxine free base or desvenlafaxine succinate monohydrate, the amount of desvenlafaxine succinate crystal type I seed crystal added is 0.4% or more by mass, based on the mass of the desvenlafaxine free base.

[0049] In one specific implementation, in S1, the temperature for spontaneous crystallization and crystal growth is 35-45℃.

[0050] The optimal temperature range for spontaneous crystallization and seeding is 35-45℃. Within this temperature range, the solution has a relatively high supersaturation, which is beneficial for the diffusion and adhesion of solute molecules to the crystal surface. Simultaneously, a suitable temperature maintains the stability of the solution and the integrity of the crystal morphology, preventing excessively high temperatures from leading to excessive solubility and reduced crystal growth, or excessively low temperatures from slowing molecular motion and crystal growth.

[0051] In one specific implementation, in S1, the crystal growth time is ≥2h.

[0052] In one specific implementation, in S2, the process of continuing to cool down and crystallize includes: cooling down to 15-25°C, stirring at a constant temperature for 1-2 hours, and then cooling down to 0-10°C and stirring at a constant temperature for 1-2 hours.

[0053] In one specific implementation, during S2, the cooling rate is ≤10℃ / h during the continued cooling and crystallization process.

[0054] In the method of this invention, the cooling rate should not be too fast. If the rate is too fast, crystal form II may be generated, and small particulate crystals may be formed. Therefore, this invention controls the cooling rate to no more than 10℃ / h, and cools to 15-25℃ and stirs to grow crystals for 1-2 hours, and then continues to cool to 0-10℃ and stirs to grow crystals for 1-2 hours to fully release the unsaturation.

[0055] In one specific implementation, in S2, the process of separating the crystals includes: after filtration, drying the separated solid by blowing or vacuum; the temperature of the blowing or vacuum drying is 40-50℃.

[0056] In one specific embodiment, in S2, the desmectin lafaxine succinate crystal type I large particle crystal is a large particle block crystal type I crystal with a width of 100-300μm and a length of 240-700μm.

[0057] The size of API crystal particles is particularly important for the dissolution performance of formulations, especially for sustained-release formulations, which generally require relatively uniform large-particle API crystals. The desvenlafaxine succinate crystal type I prepared by this invention is a large-particle block crystal type I with a width of 100-300μm and a length of 240-700μm. The particles are uniform, have good dissolution performance, and have perfect crystal growth, which is suitable for the production needs of formulations, especially sustained-release formulations. Specific Implementation The present invention will now be described through specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention, and the scope of protection of the present invention is defined by the appended claims and any equivalents thereof.

[0059] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Unless otherwise specified, the raw materials and equipment used in this invention are conventional in the art and can be obtained through conventional commercial means; unless otherwise specified, the methods used in this invention are conventional methods in the art.

[0060] Example 1 A method for preparing large-particle crystals of desmectin venlafaxine (Crystal Type I) includes the following steps: S1: Add 50g of venlafaxine succinic acid monohydrate, 210.7g of acetone, and 84g of purified water. Stir and heat to dissolve completely. After dissolving, cool to 40℃ at a rate of 10℃ / h. At 40℃, spontaneous crystallization occurs, and the mixture slowly becomes cloudy (i.e., the system visibly turns white). Maintain this temperature for 0.5h. Then add succinic acid seed crystals of venlafaxine type I (PXRD pattern as shown). Figure 16 (As shown) 0.2g, stirred at constant temperature, and cultured for 3 hours.

[0061] S2: Cool to 20℃ at a rate of 10℃ / h, stir at constant temperature for 1h; continue cooling to 5℃ at a rate of 10℃ / h, stir at constant temperature for 1h, filter, dry at 42℃ overnight, to obtain 41.0g of desmectin lafaxine crystal type I dry product, yield 82.0%.

[0062] The micrographs of the crystal particles obtained in this embodiment are shown in the appendix. Figure 1 The PXRD pattern is attached. Figure 2 .

[0063] Example 2 A method for preparing large-particle crystals of desmectin venlafaxine (Crystal Type I) includes the following steps: S1: Add 330g of desvenlafaxine free base (equivalent to 500g of succinate monohydrate), 161g of succinic acid, 2107g of acetone, and 840g of water. Stir and heat to 59.5℃ to dissolve completely. After dissolving, cool to 40℃ at a rate of 10℃ / h. At 40℃, spontaneous crystallization will occur, and the mixture will slowly become cloudy (i.e., the system will turn white visibly). Maintain this temperature for 0.5h. Then add 2g of desvenlafaxine succinic acid crystal type I seed crystals, stir at a constant temperature, and allow the crystals to grow for 4h.

[0064] S2: Cool to 20℃ at a rate of 10℃ / h, stir at constant temperature for 1h; continue cooling to 5℃ at a rate of 10℃ / h, stir at constant temperature for 1h, filter, dry at 42℃ overnight, to obtain 345g of dried desmectin succinate crystal type I, yield 69.0%.

[0065] The micrographs of the crystal particles obtained in this embodiment are shown in the appendix. Figure 3 The PXRD pattern is attached. Figure 4 .

[0066] Example 3 A method for preparing large-particle crystals of desmectin venlafaxine (Crystal Type I) includes the following steps: S1: Add 50g of desvenlafaxine succinic acid monohydrate, 250g of acetone, and 115g of purified water. Stir and heat to dissolve completely. After dissolving, cool to 35℃ at a rate of 8℃ / h. At 35℃, spontaneous crystallization will occur, and the mixture will slowly become cloudy (i.e., the system will turn white visibly). Maintain this temperature for 1 hour. Then add 0.2g of desvenlafaxine succinic acid crystal type I seed crystals, stir at a constant temperature, and allow the crystals to grow for 2 hours.

[0067] S2: Cool to 20°C at a rate of 8°C / h, stir at constant temperature for 2 hours; continue cooling to 5°C at a rate of 8°C / h, stir at constant temperature for 2 hours, filter, dry in a forced-air environment at 42°C overnight, to obtain 35.3 g of desmectin lafaxine crystal form I dry product, yield 70.6%.

[0068] The micrographs of the crystal particles obtained in this embodiment are shown in the appendix. Figure 5 The PXRD pattern is attached. Figure 6 .

[0069] Example 4 A method for preparing large-particle crystals of desmectin venlafaxine (Crystal Type I) includes the following steps: S1: Add 50g of desvenlafaxine succinic acid monohydrate, 190g of acetone, and 60g of purified water. Stir and heat to dissolve completely. After dissolving, cool to 45℃ at a rate of 8℃ / h. At 45℃, spontaneous crystallization will occur, and the mixture will slowly become cloudy (i.e., the system will turn white visibly). Maintain this temperature for 1 hour. Then add 0.2g of desvenlafaxine succinic acid crystal type I seed crystals, stir at a constant temperature, and allow the crystals to grow for 2 hours.

[0070] S2: Cool to 20°C at a rate of 8°C / h, stir at constant temperature for 1.5h; continue cooling to 5°C at a rate of 8°C / h, stir at constant temperature for 2h, filter, dry at 42°C overnight, to obtain 44.6g of desvenlafaxine succinate crystal type I dry product, yield 89.2%.

[0071] The micrographs of the crystal particles obtained in this embodiment are shown in the appendix. Figure 7 The PXRD pattern is attached. Figure 8 .

[0072] Analysis of experimental results: Microscopic images show that the desmectin succinate crystals obtained in Examples 1-4 are large, blocky particles with relatively uniform size and well-developed growth. The width is between 100-300 μm and the length is between 240-700 μm. PXRD patterns show that the desmectin succinate crystals obtained in Examples 1-4 are all crystal form I crystals and do not contain crystal form II crystals.

[0073] Comparative Example 1 (seedlings added before crystallization and natural cooling) The only difference between this comparative example and Example 1 is that in this comparative example, seed crystals are added before crystallization, and the cooling rate is not controlled; natural cooling is used. Specifically, this comparative example prepares desvenlafaxine succinate crystals through the following steps: S1: Add 50g of desvenlafaxine succinic acid monohydrate, 216.4g of acetone, and 86.3g of water. Stir and heat to dissolve. After dissolving, cool to 47°C. Add 0.21g of desvenlafaxine succinic acid crystal type I seed crystal. Cool naturally to 20°C (about 1 hour) and maintain the temperature for 1 hour.

[0074] S2: Cool to 5℃ and hold at that temperature for 1 hour, filter, and vacuum dry at 42℃ for 1.5 hours to obtain 38.2 g of desvenlafaxine succinate crystals (dry product), yield 76.4%.

[0075] The crystal particles obtained in this comparative example are of uneven size; their micrographs are shown in the appendix. Figure 9 The crystals prepared in this comparative example are mixed crystals of type I and type II, and their PXRD patterns are shown in the appendix. Figure 10 .

[0076] Comparative Example 2 (seed crystals added before crystallization) The only difference between this comparative example and Example 1 is that seed crystals were added before crystallization in this comparative example. Specifically, this comparative example prepared desvenlafaxine succinate crystals through the following steps: S1: Add 50g of desvenlafaxine succinic acid monohydrate, 210.7g of acetone, and 84g of water. Stir and heat to dissolve completely. After dissolving, cool to 47°C at a rate of 10°C / h. Add 2.0g of desvenlafaxine succinic acid crystal type I seed crystal. Continue to cool to 40°C at a rate of 10°C / h. Stir at a constant temperature for 3.5h.

[0077] S2: Cool to 20℃ at a rate of 10℃ / h, stir at constant temperature for 1h; continue cooling to 5℃ at a rate of 10℃ / h, stir at constant temperature for 1h, filter, dry at 42℃ overnight, to obtain 41.4g of desvenlafaxine succinate crystals, yield 82.8%.

[0078] The crystal particles obtained in this comparative example are long rods of uneven size, and their micrographs are shown in the appendix. Figure 11 The crystal form obtained in this comparative example is a mixed crystal of type I and trace amounts of type II, and its PXRD pattern is shown in the appendix. Figure 12 .

[0079] Comparative Example 3 (Rapid Cooling) The only difference between this comparative example and Example 1 is that the cooling rate before and after adding the seed crystals was accelerated in this comparative example. Specifically, this comparative example prepared desvenlafaxine succinate crystals through the following steps: S1: Add 50g of desvenlafaxine succinic acid monohydrate, 210.7g of acetone, and 84g of purified water. Stir and heat to dissolve completely. After dissolving, cool to 40℃ at a rate of 30℃ / h. At 40℃, spontaneous crystallization will occur, and the mixture will slowly become cloudy (i.e., the system will turn white visibly). Maintain this temperature for 0.5h. Then add 0.2g of desvenlafaxine succinic acid crystal type I seed crystals, stir at a constant temperature, and allow the crystals to grow for 3h.

[0080] S2: Cool to 5℃ at a rate of 30℃ / h, stir at constant temperature for 1h, filter, and dry overnight at 42℃ to obtain 41.5g of desvenlafaxine succinate crystals (yield 83.0%).

[0081] The crystal particles obtained in this comparative example are irregularly sized long rods and fine crystals resulting from rapid cooling; their micrographs are shown in the appendix. Figure 13 The crystals prepared in this comparative example are mixed crystals of type I and trace amounts of type II, and their PXRD patterns are shown in the appendix. Figure 14 .

[0082] Analysis of Experimental Results: Microscopic images show that the succinic acid desvenlafaxine crystals obtained in Comparative Examples 1-3 are uneven in size, with many small, elongated rod-shaped crystals less than 50 μm in width. PXRD patterns indicate that the succinic acid desvenlafaxine crystals obtained in Comparative Examples 1-3 are mixed crystals of crystal form I and trace amounts of crystal form II. These results suggest that the timing of adding crystal form I seeds and the cooling rate during crystallization both affect the final crystal size and form. Adding seeds before crystallization and poorly controlled cooling rates during crystallization both result in the inability to obtain large, bulky crystals, and the low purity of crystal form I crystals in the product.

[0083] The above description is merely a general embodiment of the present invention and is not intended to limit the invention. Modifications, equivalent substitutions, and optimizations made within the spirit and principles of the present invention should all be considered within the scope of protection of the present invention. The scope of protection claimed by the present invention is determined by the claims.

Claims

1. A method for preparing large-particle crystals of desmectic acid venlafaxine (Crystal Type I), characterized in that, Includes the following steps: S1: Mix desvenlafaxine free base, succinic acid, acetone and purified water, or mix desvenlafaxine succinate monohydrate, acetone and purified water, stir and heat to dissolve and clear, then cool down. After spontaneous crystallization and turbidity, add desvenlafaxine succinate crystal type I seed crystals 0.5-1 h, and stir at a constant temperature to grow crystals. S2: Continue cooling to crystallize and separate the crystals to obtain large-particle crystals of desmectin venlafaxine type I.

2. The method for preparing large-particle crystals of desmectic acid venlafaxine type I according to claim 1, characterized in that, In S1, based on the mass of desvenlafaxine free base, add 0.45-0.55 times the mass of succinic acid, 5.5-7.6 times the mass of acetone, and 1.5-3.5 times the mass of purified water.

3. The method for preparing large-particle crystals of desmectic acid crystalline form I according to claim 1 or 2, characterized in that, In S1, based on the mass of desvenlafaxine free base, add 6 times the mass of acetone and 2.6 times the mass of purified water.

4. The method for preparing large-particle crystals of desmectic acid crystalline form I according to claim 1, characterized in that, In S1, the temperature is raised to 50-60℃ and then lowered to 35-45℃, with a cooling rate ≤10℃ / h.

5. The method for preparing large-particle crystals of desmectic acid venlafaxine type I according to claim 1, characterized in that, In S1, based on the mass of the desvenlafaxine free base, the amount of desvenlafaxine succinate crystal type I seed crystal added is 0.4% or more by mass.

6. The method for preparing large-particle crystals of desmectic acid crystalline form I according to claim 1, characterized in that, In S1, the temperature for spontaneous crystallization and crystal growth is 35-45℃.

7. The method for preparing large-particle crystals of desmectic acid crystalline form I according to claim 1 or 6, characterized in that, In S1, the crystal growth time is ≥2 h.

8. The method for preparing large-particle crystals of desmectic acid crystalline form I according to claim 1, characterized in that, In S2, the process of continuing to cool down and crystallize includes: cooling down to 15-25℃, stirring at a constant temperature for 1-2 hours, then cooling down to 0-10℃ and stirring at a constant temperature for 1-2 hours.

9. The method for preparing large-particle crystals of desmectic acid crystalline form I according to claim 1 or 8, characterized in that, In S2, during the continued cooling and crystallization process, the cooling rate is ≤10℃ / h.

10. The method for preparing large-particle crystals of desmectic acid crystalline form I according to claim 1, characterized in that, In S2, the desmectin lafaxine crystal type I large particle crystal is a blocky crystal with a width of 100-300 μm and a length of 240-700 μm.

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