A method for preparing metastable crystal form II of vanillin based on template regulation

Abstract

The present invention relates to a method for preparing a vanillin metastable crystal form II crystal based on template regulation, and the operation steps are as follows: first, a vanillin organic solution is prepared under stirring conditions, and then a template is added to the above solution according to a mass ratio to form a template suspension solution, and then water equal in volume to the organic solvent is added to the template suspension, and the stirring process is maintained until the vanillin crystals are precipitated, and then a cooling program is started, and the cooling rate is regulated to reach the terminal temperature, and a vanillin metastable crystal form II product is finally obtained by centrifugation and freeze drying. The vanillin metastable crystal form II prepared by the present invention has more performance improvement than the industrially produced vanillin stable crystal form I, has good solubility, large particle size, and a high yield, which can reach more than 90%, and a purity of more than 98%, and is more suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical engineering crystallization, and in particular to a method for preparing vanillin metastable crystal form II based on template regulation. Background Art

[0002] Vanillin (C8H8O3, 152.11 g / mol, CAS NO: 121-33-5), also known as vanillin, is an organic compound extracted from the rutaceous plant vanilla beans. It is usually a white or white-like crystalline powder, slightly sweet, slightly soluble in hot water and ethanol, and not easily soluble in cold water and vegetable oil. Vanillin has the aroma of vanilla beans and a strong milky aroma, and plays a role in flavor enhancement and fixation. It is widely used in cosmetics, tobacco, cakes, candies, baked food and other industries. It is one of the most produced synthetic spices in the world. The industrial production of vanillin has a history of more than 100 years. Vanillin can also be used as a plant growth promoter, bactericide, lubricant defoamer, etc. It is also an important intermediate for synthetic drugs and other spices. In addition, it can also be used as a polishing agent in the electroplating industry, a ripening agent in agriculture, a deodorant in rubber products, an anti-hardening agent in plastic products, and a pharmaceutical intermediate. Since vanillin itself has antibacterial effects, it can also be used as a pharmaceutical intermediate in the pharmaceutical industry, including in drugs for the treatment of skin diseases. However, most of the vanillin crystals currently prepared industrially are fibrous, with poor crystal fluidity and tableting properties, which is not conducive to the production and processing of downstream industrial tablets. Therefore, it is urgent to develop a new method for preparing vanillin crystals to regulate the appropriate crystal morphology and improve fluidity and tableting properties.

[0003] With the development of the pharmaceutical industry, a large number of researchers have realized that the solid form of a drug largely determines the therapeutic effect of the drug, so a large number of research and development work on the solid form of vanillin has been carried out. At present, a variety of solid forms of vanillin have been developed, including 4 anhydrous polymorphic structures (form I, form II, form III, and form IV). Among them, form I has the most thermodynamically stable structure, and the other forms are metastable forms, which are unstable at room temperature and easily transformed into form I. However, vanillin metastable form II has the highest water solubility, with a water solubility of up to 85 mg / L at 25°C, while the water solubility of stable form I is only 20 mg / L, which means that vanillin metastable form II is well absorbed by the human body as the final therapeutic drug, thereby bringing the best therapeutic effect. Therefore, it is necessary to develop a stable and controllable preparation method for vanillin metastable form II crystal products to avoid its transformation to stable form I at room temperature. However, the existing preparation methods for vanillin are all about its stable form I, and there is almost no stable and controllable preparation method for metastable form II.

[0004] In summary, the metastable form II of vanillin has better solubility than the stable form I, but it is unstable. It is difficult to prepare metastable form II in experiments. It is urgent to develop a new crystallization preparation method and use a template to regulate the crystallization of metastable form II, which is of great significance for the production of vanillin metastable form II in the pharmaceutical industry. Summary of the invention

[0005] The purpose of the present invention is to solve the defects of the prior art and provide a method for preparing the metastable form II crystal of vanillin based on template regulation.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] A method for preparing vanillin metastable crystal form II based on template regulation, the specific steps are as follows:

[0008] S1. Prepare vanillin solution under stirring conditions:

[0009] Add the stable crystalline form of vanillin Ι to an organic solvent at a temperature of 30 to 60°C to a concentration of 0.5 to 1.0 mol / L; stir at a constant temperature for 10 to 30 minutes to completely dissolve the vanillin solid to obtain a vanillin solution;

[0010] S2. At a temperature of 30 to 60° C., add the template agent to the vanillin solution of step S1 according to a mass ratio, keep stirring, and form a template agent suspension, wherein the mass ratio of the template agent to the vanillin is 0.1 to 1:10;

[0011] S3, adding water of equal volume to the organic solvent to the template suspension solution obtained in step S2 at a temperature of 30 to 60° C., and maintaining stirring until vanillin crystals precipitate, for 1 to 3 hours;

[0012] S4, keep stirring, start the cooling program for the crystal suspension in step S3, set the end temperature to 10°C, and the cooling rate to 0.1-1°C / min;

[0013] S5, centrifuging the crystal suspension obtained in step S4, and freeze-drying the product to obtain a final vanillin spherical crystal product;

[0014] Furthermore, in step S1, the organic solvent is selected from any one of dimethyl sulfoxide, acetone, dioxane, acetonitrile and ethanol.

[0015] Furthermore, in step S2, the template is selected from any one of SBA-15 molecular sieve, ZSM-5 molecular sieve, and ZSM-11 molecular sieve.

[0016] Furthermore, in step S5, the freeze-drying conditions are -15 to -5°C, the vacuum degree is 0.02 to 0.08 MPa, and the drying time is 24 to 48 hours.

[0017] Further, in all steps, the stirring rate was 200-400 rpm.

[0018] The beneficial effects of the present invention are as follows: the template control method for the vanillin metastable crystal form II of the present invention is simple and easy to operate, and the prepared product has more improved performance than the industrially produced vanillin stable crystal form I, has good solubility, large particle size, and a very high yield that can reach more than 90%, and a purity that reaches more than 98%, which is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is the XRD diagram of the metastable form II of vanillin in a preferred embodiment of the present invention;

[0020] Figure 2 This is a DSC graph of the metastable form II of vanillin in a preferred embodiment of the present invention;

[0021] Figure 3 This is a microscope image of the metastable crystal form II of vanillin in a preferred embodiment of the present invention;

[0022] Figure 4 This is a solubility diagram of the metastable form II of vanillin in a preferred embodiment of the present invention. Implementation

[0023] A method for preparing vanillin metastable crystal form II based on template regulation, the specific steps are as follows:

[0024] S1. Prepare vanillin solution under stirring conditions:

[0025] Add the stable crystalline form of vanillin Ι to an organic solvent at a temperature of 30 to 60°C to a concentration of 0.5 to 1.0 mol / L; stir at a constant temperature for 10 to 30 minutes to completely dissolve the vanillin solid to obtain a vanillin solution;

[0026] S2. At a temperature of 30 to 60° C., add the template agent to the vanillin solution of step S1 according to a mass ratio, keep stirring, and form a template agent suspension, wherein the mass ratio of the template agent to the vanillin is 0.1 to 1:10;

[0027] S3, adding water of equal volume to the organic solvent to the template suspension solution obtained in step S2 at a temperature of 30 to 60° C., and maintaining stirring until vanillin crystals precipitate, for 1 to 3 hours;

[0028] S4, keep stirring, start the cooling program for the crystal suspension in step S3, set the end temperature to 10°C, and the cooling rate to 0.1-1°C / min;

[0029] S5, centrifuging the crystal suspension obtained in step S4, and freeze-drying the product to obtain a final vanillin spherical crystal product;

[0030] Furthermore, in step S1, the organic solvent is selected from any one of dimethyl sulfoxide, acetone, dioxane, acetonitrile and ethanol.

[0031] Furthermore, in step S2, the template is selected from any one of SBA-15 molecular sieve, ZSM-5 molecular sieve, and ZSM-11 molecular sieve.

[0032] Furthermore, in step S5, the freeze-drying conditions are -15 to -5°C, the vacuum degree is 0.02 to 0.08 MPa, and the drying time is 24 to 48 hours.

[0033] Further, in all steps, the stirring rate was 200-400 rpm.

[0034] The present application is described in detail below with reference to specific drawings and embodiments. Example

[0035] 1) Under stirring conditions, 1.5 g of vanillin stable crystalline form I (10 mmol) was added to a crystallizer containing 10 mL of dimethyl sulfoxide solvent at a temperature of 60 °C to make its concentration 1.0 mol / L; the vanillin stable crystalline form I was completely dissolved by stirring at a constant temperature for 30 minutes to obtain a vanillin solution at a stirring rate of 400 rpm;

[0036] 2) At 60 °C, add the template (SBA-15 molecular sieve) to the above vanillin solution, the mass ratio of SBA-15 molecular sieve to vanillin is 1:10, and keep stirring to form an SBA-15 molecular sieve suspension at a stirring rate of 400 rpm;

[0037] 3) At 60°C, add water of equal volume to dimethyl sulfoxide to the SBA-15 molecular sieve suspension obtained in step 2) above, and keep stirring until vanillin crystals precipitate, the time is 3 hours, and the stirring rate is 400 rpm;

[0038] 4) Keep stirring and start the cooling program for the crystal suspension in step 3), set the end temperature to 10°C and the cooling rate to 1°C / min;

[0039] 5) centrifuging the vanillin crystal suspension obtained in step 4), and freeze-drying the product to obtain the final vanillin metastable crystal form II product, wherein the drying conditions are -15°C, vacuum degree 0.02 MPa, and 24 hours;

[0040] The mass yield of the crystallization process is 91.5%, the product purity is 98.6%, the solubility is as high as 85 mg / L, and the particle size reaches 500 microns. The XRD, DSC, microscopy and solubility results of the obtained product are as follows: Figure 1 , 2 , 3, and 4. Example

[0041] 1) Under stirring conditions, 1.2 g of vanillin stable crystalline form I (10 mmol) was added to a crystallizer containing 10 mL of dimethyl sulfoxide solvent at a temperature of 50 °C to make its concentration 0.8 mol / L; the vanillin stable crystalline form I was completely dissolved by stirring at a constant temperature for 20 minutes to obtain a vanillin solution at a stirring rate of 300 rpm;

[0042] 2) At a temperature of 50 °C, a template (ZSM-11 molecular sieve) was added to the above vanillin solution, the mass ratio of ZSM-11 molecular sieve to vanillin was 1:50, and stirring was maintained to form a ZSM-11 molecular sieve suspension at a stirring rate of 300 rpm;

[0043] 3) At 50°C, add water of equal volume to acetone to the ZSM-11 molecular sieve suspension obtained in step 2) above, and keep stirring until vanillin crystals precipitate, the time is 2 hours, and the stirring rate is 300 rpm;

[0044] 4) Keep stirring and start the cooling program for the crystal suspension in step 3), set the end temperature to 10°C and the cooling rate to 0.5°C / min;

[0045] 5) centrifuging the vanillin crystal suspension obtained in step 4), and freeze-drying the product to obtain the final vanillin metastable crystal form II product, wherein the drying conditions are -10°C, vacuum degree 0.08 MPa, and 36 hours;

[0046] The mass yield of the crystallization process was 91.1%, the product purity was 98.2%, the solubility was as high as 86 mg / L, the particle size reached 550 μm, and the XRD, DSC, microscopy and solubility results of the obtained product were as follows: Figure 1 , 2 , 3, and 4. Example

[0047] 1) Under stirring conditions, 0.75 g of vanillin stable crystalline form I (10 mmol) was added to a crystallizer containing 10 mL of dimethyl sulfoxide solvent at a temperature of 40 °C to make its concentration 0.5 mol / L; the vanillin stable crystalline form I was completely dissolved by stirring at a constant temperature for 10 minutes to obtain a vanillin solution at a stirring rate of 200 rpm;

[0048] 2) At 40 °C, add the template (ZSM-5 molecular sieve) to the above vanillin solution, the mass ratio of ZSM-5 molecular sieve to vanillin is 1:100, and keep stirring to form a ZSM-5 molecular sieve suspension at a stirring rate of 200 rpm;

[0049] 3) At 40°C, add water of equal volume to that of dioxane to the ZSM-5 molecular sieve suspension obtained in step 2) above, and keep stirring until vanillin crystals precipitate, for 1 hour, at a stirring rate of 200 rpm;

[0050] 4) Keep stirring and start the cooling program for the crystal suspension in step 3), set the end temperature to 10°C and the cooling rate to 1°C / min;

[0051] 5) centrifuging the vanillin crystal suspension obtained in step 4), and freeze-drying the product to obtain the final vanillin metastable crystal form II product, wherein the drying conditions are -5°C, vacuum degree 0.08 MPa, and 48 hours;

[0052] The mass yield of the crystallization process was 90.8%, the product purity was 98.3%, the solubility was as high as 85 mg / L, the particle size reached 550 μm, and the XRD, DSC, microscopy and solubility results of the obtained product were as follows: Figure 1 , 2 , 3, and 4. Example

[0053] 1) Under stirring conditions, 0.9 g of vanillin stable crystalline form I (10 mmol) was added to a crystallizer containing 10 mL of ethanol solvent at a temperature of 30 °C to make its concentration 0.6 mol / L; the vanillin stable crystalline form I was completely dissolved by stirring at a constant temperature for 10 minutes to obtain a vanillin solution at a stirring rate of 200 rpm;

[0054] 2) At 30 °C, add the template (SBA-15 molecular sieve) to the above vanillin solution, the mass ratio of SBA-15 molecular sieve to vanillin is 1:100, and keep stirring to form an SBA-15 molecular sieve suspension at a stirring rate of 200 rpm;

[0055] 3) At 30°C, add water of equal volume to ethanol to the SBA-15 molecular sieve suspension obtained in step 2) above, and keep stirring until vanillin crystals precipitate, the time is 1 hour, and the stirring rate is 200 rpm;

[0056] 4) Keep stirring and start the cooling program for the crystal suspension in step 3), set the end temperature to 10°C and the cooling rate to 0.5°C / min;

[0057] 5) centrifuging the vanillin crystal suspension obtained in step 4), and freeze-drying the product to obtain the final vanillin metastable crystal form II product, wherein the drying conditions are -10°C, vacuum degree 0.08 MPa, and 48 hours;

[0058] The mass yield of the crystallization process is 91.7%, the product purity is 98.5%, the solubility is as high as 85 mg / L, and the particle size reaches 530 microns. The XRD, DSC, microscopy and solubility results of the obtained product are as follows: Figure 1 , 2 , 3, and 4. Example

[0059] 1) Under stirring conditions, 1.5 g of vanillin stable crystalline form I (10 mmol) was added to a crystallizer containing 10 mL of acetonitrile solvent at a temperature of 40 °C to make its concentration 1 mol / L; the vanillin stable crystalline form I was completely dissolved by stirring at a constant temperature for 20 minutes to obtain a vanillin solution at a stirring rate of 300 rpm;

[0060] 2) At a temperature of 40 °C, a template (ZSM-11 molecular sieve) was added to the above vanillin solution, the mass ratio of ZSM-11 molecular sieve to vanillin was 1:50, and stirring was maintained to form a ZSM-11 molecular sieve suspension at a stirring rate of 300 rpm;

[0061] 3) At 40°C, add water of equal volume to acetonitrile to the ZSM-11 molecular sieve suspension obtained in step 2) above, and keep stirring until vanillin crystals precipitate, the time is 3 hours, and the stirring rate is 300 rpm;

[0062] 4) Keep stirring and start the cooling program for the crystal suspension in step 3), set the end temperature to 10°C and the cooling rate to 1°C / min;

[0063] 5) centrifuging the vanillin crystal suspension obtained in step 4), and freeze-drying the product to obtain the final vanillin metastable crystal form II product, wherein the drying conditions are -15°C, vacuum degree 0.08 MPa, and 36 hours;

[0064] The mass yield of the crystallization process is 91.2%, the product purity is 98.3%, the solubility is as high as 85 mg / L, and the particle size reaches 540 microns. The XRD, DSC, microscopy and solubility results of the obtained product are as follows: Figure 1 , 2 , 3, and 4.

[0065] In the above Examples 1 to 5, the vanillin metastable crystal form II product was prepared, and the X-ray powder diffraction pattern of the product had characteristic peaks at diffraction angles 2θ=10.5±0.1, 11.1±0.1, 11.9±0.1, 12.7±0.1, 13.8±0.1, 14.9±0.1, 16.2±0.1, and 21.7±0.1 degrees, as shown in FIG. Figure 1 shown.

[0066] In the above-mentioned Examples 1 to 5, the vanillin metastable crystal form II product was prepared. The DSC graph of the product had a phase inversion peak and a melting peak at temperatures T = 78.8 ± 0.5 ° C and 82.5 ± 0.5 ° C, respectively. Figure 2 shown.

[0067] In the above examples 1 to 5, the vanillin metastable crystal form II product was prepared. The microscopic image of the product showed that the average particle size was 550 μm. Figure 3 shown.

[0068] In the above examples 1 to 5, the vanillin metastable crystal form II product was prepared, and the solubility of the product was as high as 85 mg / L. Figure 4 shown.

[0069] In summary, the template control method for the metastable crystal form II of vanillin of the present invention is simple and easy to operate, and the prepared product has more improved performance than the industrially produced stable crystal form I of vanillin, has good solubility, large particle size, and a very high yield that can reach more than 90%, and a purity that reaches more than 98%, which is more suitable for industrial production.

[0070] The present invention discloses and proposes a method for preparing a metastable crystal form II product of vanillin based on template regulation. Those skilled in the art can refer to the content of this article and appropriately change the raw materials, process parameters and other links to achieve the method and product of the present invention. The method and product of the present invention have been described through preferred embodiments. It is obvious that relevant technical personnel can modify or appropriately change and combine the method and product of this article without departing from the content, spirit and scope of the present invention to achieve the technology of the present invention. It should be particularly 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 spirit, scope and content of the present invention.

Claims

1. A method for preparing metastable form II crystal of vanillin based on template regulation, characterized in that: The specific steps are as follows: S1. Prepare vanillin solution under stirring conditions: Add the stable crystalline form of vanillin Ι to an organic solvent at a temperature of 30 to 60°C to a concentration of 0.5 to 1.0 mol / L; stir at a constant temperature for 10 to 30 minutes to completely dissolve the vanillin solid to obtain a vanillin solution; S2. At a temperature of 30 to 60° C., add the template agent to the vanillin solution of step S1 according to a mass ratio, keep stirring, and form a template agent suspension, wherein the mass ratio of the template agent to the vanillin is 0.1 to 1:10; S3, adding water of equal volume to the organic solvent to the template suspension solution obtained in step S2 at a temperature of 30 to 60° C., and maintaining stirring until vanillin crystals precipitate, for 1 to 3 hours; S4, keep stirring, start the cooling program for the crystal suspension in step S3, set the end temperature to 10°C, and the cooling rate to 0.1-1°C / min; S5, centrifuging the crystal suspension obtained in step S4, and freeze-drying the product to obtain a final vanillin spherical crystal product; In step S1, the organic solvent is selected from any one of dimethyl sulfoxide, acetone, dioxane, acetonitrile, and ethanol; In step S2, the template is selected from any one of SBA-15 molecular sieve, ZSM-5 molecular sieve, and ZSM-11 molecular sieve; In step S5, the freeze-drying conditions are -15 to -5°C, the vacuum degree is 0.02 to 0.08 MPa, and the drying time is 24 to 48 hours; In all steps, the stirring rate was 200-400 rpm.

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