Guaifenesin spherical crystal and preparation method thereof

Abstract

The invention belongs to the technical field of crystallization in the chemical engineering industry, and discloses a guaifenesin spherical crystal and a preparation method thereof.The preparation method comprises the following steps that guaifenesin and a potassium carbonate aqueous solution are heated and stirred till liquid-liquid phase separation occurs, guaifenesin liquid drops are evenly dispersed in the potassium carbonate aqueous solution, and the guaifenesin spherical crystal is obtained; obtaining a guaifenesin-potassium carbonate mixed aqueous solution; and cooling the guaifenesin-potassium carbonate mixed aqueous solution, continuously stirring until crystals appear, and sequentially filtering, washing and drying to obtain the guaifenesin spherical crystals. Through liquid-liquid phase separation and controllable crystallization processes, the prepared guaifenesin crystal is of a regular spherical structure, the particle surface is round and compact, and the flowability and bulk density of the product are greatly improved. The average particle size of the guaifenesin spherical crystal product is 390-933 [mu] m, the angle of repose is 25-27 degrees, and the tap density is 0.46-0.55 g / cm < 3 >.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical engineering industrial crystallization, and in particular to guaifenesin spherical crystals and a preparation method thereof. Background Art

[0002] Guaifenesin (CAS: 93-14-1), chemical name is 3-(2-methoxyphenoxy)propane-1,2-diol, structural formula is Alias ​​methyl phenyl ether, guaiacol glycerol ether, glyceryl guaiacol ester. Guaifenesin is a water-soluble drug with the English name Guaifenesin and the molecular formula C 10 H 14 O4, molecular weight 198.21. Guaifenesin irritates the gastric mucosa after oral administration, reflexively increasing bronchial secretions, thinning sputum, and acting as a disinfectant and antiseptic. Guaifenesin also has antitussive, antispasmodic, and anticonvulsant properties. It is used to treat productive coughs associated with chronic bronchitis, lung abscesses, bronchiectasis, and secondary asthma. It is often used in combination with other antitussive and antiasthmatic drugs when mucus is difficult to expectorate.

[0003] In industrial production, guaifenesin is mostly available in the form of tablets, syrups, and granules, and is also commonly used in a granular state with other drugs (such as antihistamines, antipyretic analgesics) to form compound preparations. For example, patent publication number CN106267220A discloses a loaded pill prepared from guaifenesin, dextromethorphan hydrobromide, and a filler, wherein guaifenesin is mixed with other ingredients in the form of powder particles, granulated, extruded, shot blasted, and dried to obtain micropills, which requires guaifenesin to have good fluidity and compressibility. However, current technical reports on guaifenesin are mostly about the synthesis process, and research on its product crystallization and refining process is relatively rare. A suitable recrystallization and refining process can significantly improve the product crystal habit, thereby increasing the tap density and fluidity of the product, ultimately affecting the subsequent use of guaifenesin.

[0004] Therefore, there is an urgent need to develop a method for preparing spherical crystals of guaifenesin that is efficient, green, has good fluidity, simple process, and controllable particle size. Summary of the Invention

[0005] The present invention aims to provide guaifenesin spherical crystals and a preparation method thereof. The spherical crystals prepared by the above method are round and compact, the crystallization process uses a single raw material, the process is simple, and it is green and environmentally friendly.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing spherical crystals of guaifenesin, comprising the following steps:

[0008] (1) heating and stirring guaifenesin and potassium carbonate aqueous solution until liquid-liquid phase separation occurs, so that guaifenesin droplets are uniformly dispersed in the potassium carbonate aqueous solution to obtain a guaifenesin-potassium carbonate mixed aqueous solution;

[0009] (2) Cooling the guaifenesin-potassium carbonate mixed aqueous solution and continuing to stir until crystals appear, followed by filtering, washing, and drying in sequence to obtain the guaifenesin spherical crystals.

[0010] Preferably, the concentration of guaifenesin in step (1) is 0.0045 to 0.06 g / g water, and the concentration of the potassium carbonate aqueous solution is 0.3 to 0.45 g / g water.

[0011] Preferably, the temperature of the mixing and heating in step (1) is 70-90°C.

[0012] Preferably, the cooling rate in step (2) is 40-45°C / 10min, and the temperature is lowered to 2-10°C.

[0013] Preferably, the stirring time in step (2) is 0.5 to 3 hours.

[0014] Preferably, the washing solvent in step (2) is water.

[0015] Preferably, the drying temperature in step (2) is 30-40° C., and the drying time is 12-24 hours.

[0016] The present invention also provides spherical guaifenesin crystals prepared by the preparation method.

[0017] The present invention has the following beneficial effects:

[0018] (1) The present invention uses liquid-liquid phase separation and controllable crystallization technology to produce guaifenesin crystals with a regular spherical structure and a rounded and compact particle surface, which significantly reduces the friction and agglomeration tendency between particles and greatly improves the fluidity and bulk density of the product.

[0019] (2) The preparation process of the present invention only requires mixing guaifenesin with an aqueous potassium carbonate solution, without the introduction of complex additives or organic solvents. The process is simple, environmentally friendly, and cost-controlled, meeting the requirements of the green chemical industry.

[0020] (3) The present invention can flexibly control the crystal particle size by adjusting the stirring rate to meet the specific requirements of particle size distribution in different formulation scenarios.

[0021] (4) The spherical crystals of guaifenesin obtained by the present invention have uniform physical and chemical properties, high tap density, and low angle of repose, which are significantly superior to traditional particle morphology. DETAILED DESCRIPTION

[0022] The present invention provides a method for preparing spherical crystals of guaifenesin, comprising the following steps:

[0023] (1) heating and stirring guaifenesin and potassium carbonate aqueous solution until liquid-liquid phase separation occurs, so that guaifenesin droplets are uniformly dispersed in the potassium carbonate aqueous solution to obtain a guaifenesin-potassium carbonate mixed aqueous solution;

[0024] (2) Cooling the guaifenesin-potassium carbonate mixed aqueous solution and continuing to stir until crystals appear, followed by filtering, washing, and drying in sequence to obtain the guaifenesin spherical crystals.

[0025] In the present invention, the concentration of the guaifenesin aqueous solution in step (1) is preferably 0.0045 to 0.06 g / g water, more preferably 0.015 to 0.05 g / g water, and even more preferably 0.036 to 0.045 g / g water.

[0026] In the present invention, the concentration of the potassium carbonate aqueous solution is preferably 0.3 to 0.45 g / g water, more preferably 0.32 to 0.43 g / g water, and even more preferably 0.35 to 0.4 g / g water.

[0027] In the present invention, the temperature of the mixing and heating in step (1) is preferably 70 to 90°C, more preferably 72 to 88°C, and even more preferably 75 to 85°C.

[0028] In the present invention, the cooling rate in step (2) is preferably 40-45°C / 10 min, more preferably 41-44°C / min, and even more preferably 42-43°C / min.

[0029] In the present invention, the temperature in step (2) is preferably lowered to 2-10°C, more preferably to 2-9°C, and even more preferably to 2-8°C.

[0030] In the present invention, the stirring time in step (2) is preferably 0.5 to 3 hours, more preferably 1 to 2.5 hours, and even more preferably 1.5 to 2 hours.

[0031] In the present invention, the washing solvent in step (2) is preferably water.

[0032] In the present invention, the drying temperature in step (2) is preferably 30-40°C, more preferably 32-38°C, and even more preferably 34-36°C.

[0033] In the present invention, the drying time is preferably 12 to 24 hours, more preferably 14 to 22 hours, and even more preferably 16 to 20 hours.

[0034] The present invention also provides spherical guaifenesin crystals prepared by the preparation method.

[0035] The technical solutions provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0036] Example 1

[0037] Guaifenesin and potassium carbonate were added to 300 g of water to maintain their concentrations at 0.0045 g / g water and 0.45 g / g water, respectively. The mixture was mixed and heated at 70° C. and stirred at a stirring rate of 100 rpm until liquid-liquid phase separation occurred, so that the guaifenesin droplets were uniformly dispersed in the potassium carbonate aqueous solution. The guaifenesin-potassium carbonate mixed aqueous solution was cooled to 5° C. at a cooling rate of 40° C. / 10 min and continued to be stirred at a stirring rate of 100 rpm for 0.5 h until crystals formed. The solution was then vacuum filtered, washed with water, and dried at 30° C. for 12 h to obtain spherical guaifenesin crystals.

[0038] The product obtained in this example is a stable crystal with rounded crystal particles and high fluidity. The average particle size of the spherical particle product is 390 μm, the angle of repose is 27°, and the tap density is 0.49 g / cm 3 .

[0039] Example 2:

[0040] Guaifenesin and potassium carbonate were added to 300 g of water, maintaining their concentrations at 0.06 g / g water and 0.3 g / g water, respectively. The mixture was mixed and heated at 70° C. and stirred at a stirring rate of 100 rpm until liquid-liquid phase separation occurred, so that the guaifenesin droplets were uniformly dispersed in the potassium carbonate aqueous solution. The guaifenesin-potassium carbonate mixed aqueous solution was cooled to 2° C. at a cooling rate of 40° C. / 10 min and continued to be stirred at a stirring rate of 100 rpm for 1 h until crystals formed. The solution was then vacuum filtered, washed with water, and dried at 35° C. for 24 h to obtain spherical guaifenesin crystals.

[0041] The product obtained in this example is a stable crystal with rounded crystal particles and high fluidity. The average particle size of the spherical particle product is 933 μm, the angle of repose is 25°, and the tap density is 0.46 g / cm 3 .

[0042] Example 3

[0043] Guaifenesin and potassium carbonate were added to 300 g of water to maintain their concentrations at 0.06 g / g water and 0.3 g / g water, respectively. The mixture was mixed and heated at 70° C. and stirred at 150 rpm until liquid-liquid phase separation occurred, thereby uniformly dispersing the guaifenesin droplets in the potassium carbonate aqueous solution. The guaifenesin-potassium carbonate mixed aqueous solution was cooled to 2° C. at a cooling rate of 45° C. / 10 min and continued to be stirred at 150 rpm for 1 h until crystals formed. The mixture was then vacuum filtered, washed with water, and dried at 40° C. for 18 h to obtain spherical guaifenesin crystals.

[0044] The product obtained in this example is a stable crystal with rounded crystal particles and high fluidity. The average particle size of the spherical particle product is 569 μm, the angle of repose is 26°, and the tap density is 0.50 g / cm 3 .

[0045] Example 4

[0046] Guaifenesin and potassium carbonate were added to 300 g of water to maintain their concentrations at 0.045 g / g water and 0.45 g / g water, respectively. The mixture was mixed and heated at 80° C. and stirred at 150 rpm until liquid-liquid phase separation occurred, thereby uniformly dispersing the guaifenesin droplets in the potassium carbonate aqueous solution. The guaifenesin-potassium carbonate mixed aqueous solution was cooled to 10° C. at a cooling rate of 45° C. / 10 min and continued to be stirred at 150 rpm for 3 h until crystals formed. The solution was then vacuum filtered, washed with water, and dried at 40° C. for 18 h to obtain spherical guaifenesin crystals.

[0047] The product obtained in this example is a stable crystal with rounded crystal particles and high fluidity. The average particle size of the spherical particle product is 524 μm, the angle of repose is 27°, and the tap density is 0.47 g / cm 3 .

[0048] Example 5

[0049] Guaifenesin and potassium carbonate were added to 300 g of water, maintaining their concentrations at 0.045 g / g water and 0.45 g / g water, respectively. The mixture was mixed and heated at 90° C. and stirred at a stirring rate of 100 rpm until liquid-liquid phase separation occurred, so that the guaifenesin droplets were uniformly dispersed in the potassium carbonate aqueous solution. The guaifenesin-potassium carbonate mixed aqueous solution was cooled to 5° C. at a cooling rate of 42° C. / 10 min and continued to be stirred at a stirring rate of 200 rpm for 2.5 h until crystals formed. The solution was then vacuum filtered, washed with water, and dried at 30° C. for 20 h to obtain spherical guaifenesin crystals.

[0050] The product obtained in this example is a stable crystal with rounded crystal particles and high fluidity. The average particle size of the spherical particle product is 485 μm, the angle of repose is 26°, and the tap density is 0.52 g / cm 3 .

[0051] Example 6

[0052] Guaifenesin and potassium carbonate were added to 300 g of water, maintaining their concentrations at 0.015 g / g water and 0.3 g / g water, respectively. The mixture was heated and mixed at 90° C. and stirred at 200 rpm until liquid-liquid phase separation occurred, thereby uniformly dispersing the guaifenesin droplets in the potassium carbonate aqueous solution. The guaifenesin-potassium carbonate mixed aqueous solution was cooled to 5° C. at a cooling rate of 43° C. / 10 min and stirred at 200 rpm for 2 h until crystals formed. The solution was then vacuum filtered, washed with water, and dried at 35° C. for 12 h to obtain spherical guaifenesin crystals.

[0053] The product obtained in this example is a stable crystal with rounded crystal particles and high fluidity. The average particle size of the spherical particle product is 455 μm, the angle of repose is 25°, and the tap density is 0.55 g / cm 3 .

[0054] Example 7

[0055] Guaifenesin and potassium carbonate were added to 300 g of water, maintaining their concentrations at 0.036 g / g water and 0.3 g / g water, respectively. The mixture was mixed and heated at 90° C. and stirred at a stirring rate of 100 rpm until liquid-liquid phase separation occurred, so that the guaifenesin droplets were uniformly dispersed in the potassium carbonate aqueous solution. The guaifenesin-potassium carbonate mixed aqueous solution was cooled to 2° C. at a cooling rate of 40° C. / 10 min and continued to be stirred at a stirring rate of 100 rpm for 0.5 h until crystals formed. The solution was then vacuum filtered, washed with water, and dried at 35° C. for 12 h to obtain spherical guaifenesin crystals.

[0056] The product obtained in this example is a stable crystal with rounded crystal particles and high fluidity. The average particle size of the spherical particle product is 690 μm, the angle of repose is 25°, and the tap density is 0.48 g / cm 3 .

[0057] Example 8

[0058] Guaifenesin and potassium carbonate were added to 300 g of water, maintaining their concentrations at 0.036 g / g water and 0.3 g / g water, respectively. The mixture was mixed and heated at 80° C. and stirred at a stirring rate of 100 rpm until liquid-liquid phase separation occurred, so that the guaifenesin droplets were uniformly dispersed in the potassium carbonate aqueous solution. The guaifenesin-potassium carbonate mixed aqueous solution was cooled to 5° C. at a cooling rate of 42° C. / 10 min and continued to be stirred at a stirring rate of 100 rpm for 0.5 h until crystals formed. The solution was then vacuum filtered, washed with water, and dried at 40° C. for 20 h to obtain spherical guaifenesin crystals.

[0059] The product obtained in this example is a stable crystal with rounded crystal particles and high fluidity. The average particle size of the spherical particle product is 712 μm, the angle of repose is 26°, and the tap density is 0.47 g / cm 3 .

[0060] As can be seen from the above examples, the present invention provides spherical guaifenesin crystals and a method for preparing the same, comprising the following steps: heating and stirring an aqueous guaifenesin solution and an aqueous potassium carbonate solution until liquid-liquid phase separation occurs, so that guaifenesin droplets are evenly dispersed in the potassium carbonate solution to obtain a guaifenesin-potassium carbonate mixed aqueous solution; cooling the guaifenesin-potassium carbonate mixed aqueous solution and continuing to stir until crystals form, followed by filtering, washing, and drying to obtain the guaifenesin spherical crystals. The present invention utilizes a liquid-liquid phase separation and controlled crystallization process to produce guaifenesin crystals with a regular spherical structure and a rounded, compact particle surface, significantly reducing interparticle friction and agglomeration tendency, and significantly improving the product's fluidity and bulk density. The preparation process of the present invention only requires mixing guaifenesin with an aqueous potassium carbonate solution, without the need for complex additives or organic solvents. The process is simple, environmentally friendly, and cost-effective, meeting the requirements of the green chemical industry. The present invention can flexibly control the crystal size by adjusting the stirring rate to meet the specific requirements of particle size distribution for different formulation scenarios. The spherical crystals of guaifenesin obtained by the present invention have uniform physical and chemical properties, an average particle size of 390 to 933 μm, an angle of repose between 25° and 27°, and a tap density of 0.46 to 0.55 g / cm 3 .

[0061] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing spherical crystals of guaifenesin, characterized in that: It includes the following steps: (1) heating and stirring guaifenesin and potassium carbonate aqueous solution until liquid-liquid phase separation occurs, so that guaifenesin droplets are uniformly dispersed in the potassium carbonate aqueous solution to obtain a guaifenesin-potassium carbonate mixed aqueous solution; (2) Cooling the guaifenesin-potassium carbonate mixed aqueous solution and continuing to stir until crystals appear, followed by filtering, washing, and drying in sequence to obtain the guaifenesin spherical crystals.

2. The preparation method according to claim 1, characterized in that The concentration of guaifenesin in step (1) is 0.0045 to 0.06 g / g water, and the concentration of the potassium carbonate aqueous solution is 0.3 to 0.45 g / g water.

3. The preparation method according to claim 1, characterized in that The temperature of the mixing and heating in step (1) is 70-90°C.

4. The preparation method according to claim 1, characterized in that In the step (2), the cooling rate is 40-45°C / 10min, and the temperature is lowered to 2-10°C.

5. The preparation method according to claim 1, characterized in that The stirring time in step (2) is 0.5 to 3 hours.

6. The preparation method according to claim 1, characterized in that The washing solvent in step (2) is water.

7. The preparation method according to claim 1, characterized in that The drying temperature in step (2) is 30-40° C., and the drying time is 12-24 hours.

8. Spherical guaifenesin crystals prepared by the preparation method according to any one of claims 1 to 7.