Preparation method of cyclomandelate spherical crystal

Abstract

The invention belongs to the technical field of crystallization in chemical engineering industry, and provides a preparation method of a cyclomandelate spherical crystal, which comprises the following steps: mixing cyclomandelate and water, heating, and stirring until liquid-liquid phase separation occurs to obtain a cyclomandelate-water solution; cooling the cyclomandelate-water solution, and continuously stirring; and adding a surfactant into the cooled solution, mixing and stirring until crystals appear, and sequentially filtering, washing and drying to obtain the cyclomandelate spherical crystals. The preparation method provided by the invention effectively creates a spherical liquid drop environment for nucleation and growth of cyclomandelate, and is simple in process and high in efficiency. According to the invention, by adding the surfactant, the cyclomandelate liquid drops are stably and uniformly dispersed in water, so that coalescence among the cyclomandelate liquid drops is effectively prevented. The angle of repose of the obtained cyclomandelate spherical crystal ranges from 23 degrees to 28 degrees, and the tap density of the cyclomandelate spherical crystal ranges from 0.48 g / cm < 3 > to 0.53 g / cm < 3 >.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical engineering industrial crystallization, and particularly to a method for preparing spherical crystals of cyclandelate. Background Art

[0002] Cyclandelate (CAS: 456 - 59 - 7), with the chemical name of 3,3,5 - trimethylcyclohexyl mandelate, has the structural formula Also known as Angiomyl, Antithrombus Pills, it is an excellent vasodilator developed by Elan Corporation in Ireland. Cyclandelate is a fat - soluble vasodilator with a similar effect to papaverine. Its English name is Cyclandelate, and its molecular formula is C 17 H 24 O 3 with a molecular weight of 276.37. It is usually a white crystalline powder with a melting point of 55.0 - 56.5 °C. It is extremely soluble in ethanol or acetone and almost insoluble in water. Pharmacological studies have shown that cyclandelate can directly relax vascular smooth muscle, dilate blood vessels. Its vasodilatory effect has a certain specificity. It significantly dilates the blood vessels of the brain, kidneys, peripheral extremities and coronary arteries, increases blood flow, and promotes blood circulation. Its effect is slightly weaker than that of papaverine but more persistent. This product can take effect 10 - 15 minutes after oral administration and reaches its peak after 4 - 5 hours, and has basically no effect on respiration, blood pressure, heart rate, myocardial blood volume and myocardial oxygen consumption.

[0003] In industrial production, cyclandelate dry powder is directly mixed evenly and filled into capsules. The cyclandelate for medicinal use is an amorphous powder, which causes many problems, such as poor fluidity, product agglomeration, poor powder properties, and poor operability. Due to the high fluidity, bulk density, stability, particle uniformity and good anti - caking performance of spherical crystals, the preparation of spherical particles of cyclandelate has always been a research hotspot. However, current technologies related to cyclandelate are mostly synthetic process patents, and there is less research on the crystallization and refining process of its products. A suitable recrystallization and refining process can significantly improve the crystal habit of the product, thereby increasing the tapped density and fluidity of the product, and ultimately affecting the subsequent use process of cyclandelate.

[0004] Therefore, finding a method for preparing spherical crystals of cyclandelate that is highly efficient, green, has uniform particles, good fluidity and can be industrialized is still a difficult problem unsolved by the existing technology. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for preparing spherical crystals of cyclandelate by liquid - liquid phase separation. The spherical crystals prepared by using the above - mentioned method can improve the powder properties of the raw drug, enhance its fluidity, and the product particles are compact and do not agglomerate. The process is simple, green and environmentally friendly.

[0006] To achieve the above-mentioned invention object, the present invention provides the following technical solutions:

[0007] The present invention provides a preparation method of cyclandelate spherical crystals, comprising the following steps:

[0008] (1) Mix cyclandelate and water, heat and stir until liquid-liquid phase separation occurs to obtain a cyclandelate-aqueous solution;

[0009] (2) Cool down the cyclandelate-aqueous solution and continue stirring;

[0010] (3) Add a surfactant to the cooled solution, mix and stir until crystallization occurs, then filter, wash and dry in sequence to obtain the cyclandelate spherical crystals.

[0011] Preferably, in the step (1), the mixing temperature is 60-95°C.

[0012] Preferably, in the step (1), the concentration of the cyclandelate-aqueous solution is 0.02-0.1 g / mL.

[0013] Preferably, in the step (2), the cooling rate is 40-45°C / 10 min, and the temperature is cooled down to 5-25°C.

[0014] Preferably, in the step (3), the surfactant is one of sodium stearate, sodium hexametaphosphate, sodium dodecylbenzenesulfonate and sodium dodecyl sulfate.

[0015] Preferably, in the step (3), the addition amount of the surfactant is 0.05-0.1% of the mass fraction of the cyclandelate-aqueous solution.

[0016] Preferably, in the step (3), the stirring time is 0.5-3 h.

[0017] Preferably, in the step (3), the washing solvent is water;

[0018] In the step (3), the drying temperature is 30-40°C, and the drying time is 12-24 h.

[0019] The present invention has the following beneficial effects:

[0020] 1. The preparation method of the present invention effectively creates a spherical droplet environment for the nucleation and growth of cyclandelate, and the process is simple and efficient.

[0021] 2. By adding a surfactant, the present invention enables the cyclandelate droplets to be stably and uniformly dispersed in water, effectively preventing the coalescence between the cyclandelate droplets, thereby preparing spherical particles with non-coalescence and good fluidity.

[0022] 3. The spherical products obtained by the present invention have excellent filling properties, compression formability, and stability, and can be directly used for tabletting or capsule filling, greatly reducing the industrial cost.

[0023] 4. Only water is used as the solvent throughout the process of the present invention. The raw materials are single, environmentally friendly, the process is simple, industrialization can be achieved, and the economic input is low. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 XRD powder diffraction pattern of the spherical crystals of cyclandelate in Example 1;

[0025] Figure 2 SEM image of the spherical crystals of cyclandelate in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides a method for preparing spherical crystals of cyclandelate, comprising the following steps:

[0027] (1) Mix cyclandelate and water, heat and stir until liquid-liquid phase separation occurs to obtain a cyclandelate-aqueous solution;

[0028] (2) Cool the cyclandelate-aqueous solution and continue stirring;

[0029] (3) Add a surfactant to the cooled solution, mix and stir until crystallization occurs, and then filter, wash and dry in sequence to obtain the spherical crystals of cyclandelate.

[0030] In the present invention, the mixing temperature in step (1) is preferably 60-95 °C, more preferably 65-90 °C, and even more preferably 70-85 °C.

[0031] In the present invention, the concentration of the cyclandelate-aqueous solution in step (1) is preferably 0.02-0.1 g / mL, more preferably 0.03-0.09 g / mL, and even more preferably 0.04-0.08 g / mL.

[0032] In the present invention, the cooling rate in step (2) is preferably 40-45 °C / 10 min, more preferably 41-44 °C / 10 min, and even more preferably 42-43 °C / min;

[0033] In the present invention, the cooling is preferably to 5-25 °C, more preferably 7-23 °C, and even more preferably 10-20 °C.

[0034] In the present invention, the surfactant in step (3) is preferably one of sodium stearate, sodium hexametaphosphate, sodium dodecylbenzenesulfonate and sodium dodecyl sulfate.

[0035] In the present invention, the addition amount of the surfactant in the step (3) is preferably 0.05-0.1% of the mass fraction of cyclandelate-aqueous solution, more preferably 0.06-0.09%, and still more preferably 0.07-0.08%.

[0036] In the present invention, the stirring time in the step (3) is preferably 0.5-3 h, more preferably 1-2.5 h, and still more preferably 1.5-2 h.

[0037] In the present invention, after adding the surfactant, the stirred crystals aggregate into compact spheres, and then are sequentially filtered, washed and dried to obtain the spherical crystals of cyclandelate.

[0038] In the present invention, the washing solvent is preferably water.

[0039] In the present invention, the drying temperature in the step (3) is preferably 30-40 °C, more preferably 32-38 °C, and still more preferably 34-36 °C.

[0040] In the present invention, the drying time is preferably 12-24 h, more preferably 14-22 h, and still more preferably 16-20 h.

[0041] In the present invention, due to the low melting point of cyclandelate and its low solubility in water, at 60-95 °C, a cyclandelate-aqueous solution with a concentration of 0.02-0.1 g / mL can undergo liquid-liquid phase separation (i.e., cyclandelate and water form a layered phenomenon under static conditions). There is currently no public report on the design method of liquid-liquid phase separation systems. Therefore, at present, the phase separation conditions of cyclandelate need to be explored individually, and its laws can be gradually mastered based on a large number of experimental explorations and experience accumulations. And based on the liquid-liquid phase separation interval, a mixing granulation process is constructed by designing a temperature curve. Then, by applying stirring at an appropriate rate and adding an appropriate amount of surfactant, cyclandelate is stably and uniformly dispersed in water in the form of droplets, providing a droplet microenvironment for the crystallization of cyclandelate. Under rapid cooling conditions, the cyclandelate droplets quickly crystallize and aggregate into spheres, and finally a spherical cyclandelate product with compact particles is obtained.

[0042] 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 protection scope of the present invention.

[0043] Example 1

[0044] Mix and heat amydricum and water at 80 °C, and stir until liquid-liquid phase separation occurs and the amydricum droplets are dispersed in water to obtain 120 mL of an amydricum-aqueous solution with a concentration of 0.024 g / mL. Cool the amydricum-aqueous solution to 5 °C at a rate of 40 °C / 10 min, and continue to stir evenly at a rate of 200 rpm; add 0.08% (based on the mass of the amydricum-aqueous solution) of sodium dodecyl sulfate at this temperature, mix and stir for 0.5 h until crystallization occurs, make the crystals coalesce into compact particles, successively perform vacuum filtration, wash with water, and dry at 30 °C for 12 h to obtain the amydricum spherical crystals.

[0045] The product obtained in this example was detected by an X-ray diffractometer, as Figure 1 shown.

[0046] From Figure 1 it can be seen that the product prepared in this example is a stable crystal; the average particle size of the spherical particles is 2697 μm, the angle of repose is 28°, and the tapped density is 0.53 g / cm 3 .

[0047] The amydricum spherical crystal product obtained in this example was scanned by a scanning electron microscope, as Figure 2 shown.

[0048] From Figure 2 it can be seen that the crystal morphology of the product obtained in this example has been greatly improved.

[0049] Example 2

[0050] Mix and heat amydricum and water at 80 °C, and stir until liquid-liquid phase separation occurs and the amydricum droplets are dispersed in water to obtain 120 mL of an amydricum-aqueous solution with a concentration of 0.024 g / mL. Cool the amydricum-aqueous solution to 5 °C at a rate of 40 °C / 10 min, and continue to stir evenly at a rate of 300 rpm; add 0.08% (based on the mass of the amydricum-aqueous solution) of sodium hexametaphosphate at this temperature, mix and stir for 0.5 h until crystallization occurs, make the crystals coalesce into compact particles, successively perform vacuum filtration, wash with water, and dry at 30 °C for 12 h to obtain the amydricum spherical crystals.

[0051] Using the same test method as in Example 1 for the amydricum spherical crystals obtained in this example, it can be known that the average particle diameter of the obtained spherical crystals is 1690 μm, the angle of repose is 24°, and the tapped density is 0.50 g / cm 3 .

[0052] Example 3

[0053] Mix and heat cyclandelate and water at 80 °C, and stir until liquid-liquid phase separation occurs and the cyclandelate droplets are dispersed in water to obtain 120 mL of a cyclandelate-aqueous solution with a concentration of 0.024 g / mL. Cool the cyclandelate-aqueous solution to 5 °C at a rate of 40 °C / 10 min, and continue to stir evenly at a rate of 400 rpm; add 0.08% sodium dodecyl sulfate (based on the mass of the cyclandelate-aqueous solution) at this temperature, mix and stir for 0.5 h until crystallization occurs, and make the crystals coalesce into compact particles. Then, successively perform vacuum filtration, wash with water, and dry at 30 °C for 12 h to obtain the cyclandelate spherical crystals.

[0054] Using the same test method as in Example 1 for the cyclandelate spherical crystals obtained in this example, it can be known that the average particle size of the obtained spherical crystals is 2697 μm, the angle of repose is 23°, and the tapped density is 0.48 g / cm 3 .

[0055] By comparing Examples 1, 2, and 3, it can be seen that with the increase in the stirring rate during the crystallization process, the size of the finally obtained spherical particles gradually decreases. This is because a high stirring rate will provide a greater agglomeration resistance, making it more difficult for the crystals to agglomerate with each other, thus obtaining smaller spherical particles.

[0056] Example 4

[0057] Mix and heat cyclandelate and water at 80 °C, and stir until liquid-liquid phase separation occurs and the cyclandelate droplets are dispersed in water to obtain 120 mL of a cyclandelate-aqueous solution with a concentration of 0.024 g / mL. Cool the cyclandelate-aqueous solution to 15 °C at a rate of 40 °C / 10 min, and continue to stir evenly at a rate of 300 rpm; add 0.08% sodium dodecylbenzenesulfonate (based on the mass of the cyclandelate-aqueous solution) at this temperature, mix and stir for 1.5 h until crystallization occurs, and make the crystals coalesce into compact particles. Then, successively perform vacuum filtration, wash with water, and dry at 40 °C for 24 h to obtain the cyclandelate spherical crystals.

[0058] Example 5

[0059] Mix cyclandelate and water, heat the mixture at 80 °C, stir until liquid-liquid phase separation occurs and the cyclandelate droplets are dispersed in water to obtain 120 mL of a cyclandelate-aqueous solution with a concentration of 0.024 g / mL. Cool the cyclandelate-aqueous solution to 25 °C at a rate of 40 °C / 10 min and continue to stir evenly at a rate of 300 rpm; add 0.08% sodium dodecylbenzenesulfonate (based on the mass of the cyclandelate-aqueous solution) at this temperature, mix and stir for 3 h until crystallization occurs, make the crystals coalesce into compact particles, and sequentially perform vacuum filtration, wash with water, and dry at 40 °C for 24 h to obtain the cyclandelate spherical crystals.

[0060] From the comparison of Examples 1, 4, and 5, it can be seen that the lower the quenching temperature, the higher the sphericity of the product particles and the better the dispersibility. This is because at a lower crystallization temperature, the nucleation process of cyclandelate has a higher driving force, resulting in rapid nucleation and coalescence of the crystals into spheres; however, at a higher crystallization temperature, the nucleation rate of cyclandelate is lower, and the crystals cannot coalesce into spheres quickly, resulting in a lower sphericity of the product particles or even non-spherical particles.

[0061] Example 6

[0062] Mix cyclandelate and water, heat the mixture at 60 °C, stir until liquid-liquid phase separation occurs and the cyclandelate droplets are dispersed in water to obtain 120 mL of a cyclandelate-aqueous solution with a concentration of 0.02 g / mL. Cool the cyclandelate-aqueous solution to 5 °C at a rate of 40 °C / 10 min and continue to stir evenly at a rate of 200 rpm; add 0.05% sodium stearate (based on the mass of the cyclandelate-aqueous solution) at this temperature, mix and stir for 0.5 h until crystallization occurs, make the crystals coalesce into compact particles, and sequentially perform vacuum filtration, wash with water, and dry at 30 °C for 12 h to obtain the cyclandelate spherical crystals.

[0063] Example 7

[0064] Mix cyclandelate and water, heat the mixture at 95 °C, stir until liquid-liquid phase separation occurs and the cyclandelate droplets are dispersed in water to obtain 120 mL of a cyclandelate-aqueous solution with a concentration of 0.1 g / mL. Cool the cyclandelate-aqueous solution to 25 °C at a rate of 45 °C / 10 min and continue to stir evenly at a rate of 400 rpm; add 0.1% sodium dodecyl sulfate (based on the mass of the cyclandelate-aqueous solution) at this temperature, mix and stir for 3 h until crystallization occurs, make the crystals coalesce into compact particles, and sequentially perform vacuum filtration, wash with water, and dry at 40 °C for 24 h to obtain the cyclandelate spherical crystals.

[0065] Example 8

[0066] Mix cyclandelate and water, heat and stir them at 75 °C until liquid-liquid phase separation occurs and the cyclandelate droplets are dispersed in water, obtaining 120 mL of a cyclandelate-aqueous solution with a concentration of 0.024 g / mL. Cool the cyclandelate-aqueous solution to 15 °C at a rate of 42 °C / 10 min, and continue to stir evenly at a rate of 300 rpm; add 0.08% sodium stearate (based on the mass of the cyclandelate-aqueous solution) at this temperature, mix and stir for 2 h until crystallization occurs, make the crystals coalesce into compact particles, successively carry out vacuum filtration, wash with water, and dry at 35 °C for 20 h, then the cyclandelate spherical crystals are obtained.

[0067] As can be seen from the above examples, the present invention provides a method for preparing cyclandelate spherical crystals, comprising the following steps: mix cyclandelate and water, heat and stir until liquid-liquid phase separation occurs to obtain a cyclandelate-aqueous solution; cool the cyclandelate-aqueous solution and continue to stir; add a surfactant to the cooled solution, mix and stir until crystallization occurs, and then successively filter, wash and dry to obtain the cyclandelate spherical crystals. The preparation method of the present invention effectively creates a spherical droplet environment for the nucleation and growth of cyclandelate, with a simple process and high efficiency. By adding a surfactant, the cyclandelate droplets are stably and uniformly dispersed in water, effectively preventing the coalescence between the cyclandelate droplets, thereby preparing spherical particles with non-coalescence and good fluidity. The spherical product obtained by the invention has excellent filling properties, compression formability and stability, and can be directly tableted or filled into capsules, greatly reducing the industrial cost. Only water is used as a solvent throughout the process of the invention, with a single raw material, being green and environmentally friendly, having a simple process, being capable of realizing industrialization and having a low economic input. The angle of repose of the cyclandelate spherical crystals prepared by the present invention is between 23° and 28°, and the tapped density is 0.48 - 0.53 g / cm 3 。

[0068] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing spherical crystals of cyclomandelate, characterized in that: It includes the following steps: (1) mixing cyclomandelate and water, heating and stirring until liquid-liquid phase separation occurs to obtain a cyclomandelate-water solution; (2) cooling the cyclomandelate-water solution and continuing to stir; (3) adding a surfactant to the cooled solution, mixing and stirring until crystals appear, and then filtering, washing and drying in sequence to obtain the cyclomandelate spherical crystals.

2. The preparation method according to claim 1, characterized in that: The mixing temperature in step (1) is 60-95°C.

3. The preparation method according to claim 1, characterized in that: The concentration of the cyclomandelate-water solution in the step (1) is 0.02-0.1 g / mL.

4. The preparation method according to claim 1, characterized in that: The cooling rate in step (2) is 40-45°C / 10min, and the temperature is reduced to 5-25°C.

5. The preparation method according to claim 1, characterized in that: The surfactant in step (3) is one of sodium stearate, sodium hexametaphosphate, sodium dodecylbenzene sulfonate and sodium dodecyl sulfate.

6. The preparation method according to claim 1, characterized in that: The amount of surfactant added in step (3) is 0.05 to 0.1% of the mass fraction of the cyclomandelate-water solution.

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

8. The preparation method according to claim 1, characterized in that: The washing solvent in step (3) is water; The drying temperature in step (3) is 30 to 40° C., and the drying time is 12 to 24 hours.

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