Preparation method of monodisperse calcium carbonate microspheres

Abstract

The invention discloses a preparation method of monodisperse calcium carbonate microspheres, which comprises the following steps: S1) mixing a calcium source, ethanol and water to prepare a mixed solution; s2) adding carbonate into the mixed solution, and uniformly stirring at room temperature to prepare a precursor; s3) mixing an emulsifier and an organic solvent to prepare an oil phase solution, adding the precursor into the oil phase solution, stirring, mixing and heating to prepare a microsphere intermediate; s4) cleaning the microsphere intermediate with an organic solvent, and drying to obtain a composite microsphere; and S5) carrying out high-temperature calcination on the composite microspheres to prepare the monodisperse calcium carbonate microspheres. The monodisperse calcium carbonate microspheres prepared by controlling the HLB (Hydrophile-Lipophile Balance) value of the oil-phase solution prepared from the emulsifier and the organic solvent are controllable in particle size and more uniform.

Description

Technical Field

[0001] The invention relates to the technical field of microsphere preparation, and in particular to a method for preparing monodisperse calcium carbonate microspheres. Background Art

[0002] Calcium carbonate microspheres are a non-toxic and biocompatible material, which are often used in drug delivery research. They can not only load enough drugs and not react with them, but also fully release drugs under specific conditions to exert their efficacy, and at the same time meet the requirements of the carrier itself being non-toxic and stable in nature. In the prior art, the synthesis process of calcium carbonate microspheres prepared by the general precipitation method is relatively complicated, the morphology cannot be controlled, and if the particle size uniformity of the prepared calcium carbonate microspheres is not good and the specific surface area is insufficient, it will affect its drug loading and drug release, resulting in its use effect being affected.

[0003] Based on the above reasons, developing a new method for preparing monodisperse calcium carbonate microspheres that can be industrially produced is an urgent problem to be solved in current research. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing monodisperse calcium carbonate microspheres, wherein a precursor having a calcium source is used as a reaction unit, and the HLB value of the coating liquid is controlled within a range of 5.5-8.5 to obtain monodisperse calcium carbonate microspheres having controllable particle sizes and more uniformity.

[0005] To achieve the above object, the technical solution adopted by the present invention is: a method for preparing monodisperse calcium carbonate microspheres, comprising the following steps:

[0006] S1) mixing a calcium source, ethanol and water to prepare a mixed solution;

[0007] S2) adding carbonate to the mixed solution and stirring uniformly at room temperature to obtain a precursor;

[0008] S3) mixing an emulsifier and an organic solvent to obtain an oil phase solution, adding the precursor to the oil phase solution, stirring and mixing, and heating to obtain a microsphere intermediate;

[0009] S4) washing the microsphere intermediate with an organic solvent and drying to obtain composite microspheres;

[0010] S5) calcining the composite microspheres at high temperature to obtain monodisperse calcium carbonate microspheres.

[0011] As a further optimization, S1 further includes a protective agent, which is carboxymethyl cellulose.

[0012] As a further optimization, the calcium source in S1 is calcium chloride.

[0013] As a further optimization, the carbonate in S2 is one or more of potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate.

[0014] As a further optimization, the emulsifier in S3 is a mixture of Tween 80 and Span 80, and the mass ratio of the two is 1:(1-2); the organic solvent in S3 is liquid paraffin and / or petroleum ether.

[0015] As a further optimization, the HLB value of the oil phase solution in S3 is 5.5-8.5.

[0016] As a further optimization, the reaction conditions in S3 are: temperature 45-60°C, time 1-8h.

[0017] As a further optimization, the drying temperature in S4 is 80-100°C.

[0018] As a further optimization, the calcination temperature in S5 is 550-650°C, and the calcination time is 8-24h.

[0019] As a further optimization, the monodisperse calcium carbonate microspheres described in S5 have a particle size of 1-500 μm, a CV value of 2.5-3.2%, and a specific surface area of ​​200-400 m 2 / g.

[0020] Through the above steps and methods, the beneficial effects of the present invention are:

[0021] 1. The prepared precursor containing a calcium source can be used to form an oil-in-water microsphere intermediate through an emulsifier and an organic solvent to prepare an oil phase solution. The "core" of the microsphere intermediate is heat-treated to remove the outer coating liquid to form a composite microsphere, and the "cores" are combined with each other under high temperature to obtain calcium carbonate microspheres. The present invention controls the hydrophilic-lipophilic balance value of the surfactant by an oil-in-water method to prepare uniform calcium carbonate microspheres with different particle sizes. For example, Tween 80 and Span 80 are used for compounding, wherein Tween 80 The affinity balance value of is 15, and the affinity balance value of Span 80 is 4.3. The affinity balance value of the two after compounding can be in the range of 5.5-8.5, which can wrap the precursor well and avoid the disordered combination of the precursor leading to uneven particle size of the microspheres. Therefore, the above system is used to accurately calculate the amount of water phase feed, the type composition and amount of emulsifier, and the amount of oil phase, and the calcium carbonate microspheres with uniform particle size are obtained by controlling the reaction temperature, the pressure of the reaction system, and the reaction time. The size of the colloid particles can be controlled by the above raw material dosage and reaction conditions to control the particle size of the final calcium carbonate microspheres;

[0022] 2. The use of protective agent (carboxymethyl cellulose) can effectively adjust the dispersion system in the precursor, ensure the stability of the dispersion system through its suspending effect, ensure that the calcium source can be more evenly dispersed in the precursor, and help the microspheres form uniform particle size.

[0023] 3. The preparation process of the present invention is simple, the reaction conditions are easy to control, the particle size of the prepared calcium carbonate microspheres is controllable, the particle size is uniform, and the particle size range is 1-500um. DETAILED DESCRIPTION

[0024] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments.

[0025] Example 1

[0026] A method for preparing monodisperse calcium carbonate microspheres comprises the following steps:

[0027] S1) weighing 10 g of calcium chloride, dissolving it in 80 g of ethanol and 100 g of water, and stirring to obtain a mixed solution;

[0028] S2) adding 10 g of sodium carbonate and 12 g of sodium bicarbonate to the mixed solution, and stirring evenly at room temperature to obtain a precursor;

[0029] S3) In a 1L reactor, 0.6g Tween 80, 1g Span 80 and 200g liquid paraffin (wherein the HLB value of the oil phase = 5.6) were added, stirred at 40°C for 1h, and then the precursor prepared in step S2 was added, and stirred at 50°C for 2h to prepare a microsphere intermediate;

[0030] S4) washing the microsphere intermediate with ethanol three times and drying at 80° C. to obtain composite microspheres;

[0031] S5) The composite microspheres are calcined at 600° C. for 10 h to obtain monodisperse calcium carbonate microspheres.

[0032] The particle size and particle size distribution of the monodisperse calcium carbonate microspheres were measured by Beckman Counter: the particle size was 10 μm, the CV (coefficient of variation) value was 3.0%, and the specific surface area was 375 m 2 / g.

[0033] Example 2

[0034] A method for preparing monodisperse calcium carbonate microspheres comprises the following steps:

[0035] S1) weighing 10 g of calcium chloride, dissolving it in 80 g of ethanol and 100 g of water, and stirring to obtain a mixed solution;

[0036] S2) adding 10 g of sodium carbonate and 12 g of sodium bicarbonate to the mixed solution, and stirring evenly at room temperature to obtain a precursor;

[0037] S3) In a 1L reactor, add 1g Tween 80, 1g Span 80 and 200g liquid paraffin (wherein the HLB value of the oil phase = 6.0), stir at 40°C for 1h, then add the precursor prepared in step S2, stir at 50°C for 2h, to prepare a microsphere intermediate;

[0038] S4) washing the microsphere intermediate with ethanol three times and drying at 80° C. to obtain composite microspheres;

[0039] S5) The composite microspheres are calcined at 600° C. for 10 h to obtain monodisperse calcium carbonate microspheres.

[0040] The particle size and particle size distribution of the monodisperse calcium carbonate microspheres were measured by Beckman Counter: the particle size was 8 μm, the CV (coefficient of variation) value was 2.9%, and the specific surface area was 380 m 2 / g.

[0041] Example 3

[0042] A method for preparing monodisperse calcium carbonate microspheres comprises the following steps:

[0043] S1) weighing 10 g of calcium chloride and 3 g of carboxymethyl cellulose, dissolving them in 100 g of ethanol and 80 g of water, and stirring to obtain a mixed solution;

[0044] S2) adding 10 g of potassium carbonate and 14 g of potassium bicarbonate to the mixed solution, and stirring evenly at room temperature to obtain a precursor;

[0045] S3) In a 1L reactor, add 0.6g Tween 80, 1g Span 80 and 200g liquid paraffin (wherein the HLB value of the oil phase = 5.6), stir at 40°C for 1h, then add the precursor prepared in step S2, stir at 50°C for 2h to prepare a microsphere intermediate;

[0046] S4) washing the microsphere intermediate with ethanol three times and drying at 80° C. to obtain composite microspheres;

[0047] S5) The composite microspheres are calcined at 600° C. for 10 h to obtain monodisperse calcium carbonate microspheres with a porous structure.

[0048] The particle size and particle size distribution were determined by Beckman Counter: the particle size was 12 μm, the CV (coefficient of variation) was 2.7%, and the specific surface area was 400 m2 / g.

[0049] Example 4

[0050] A method for preparing monodisperse calcium carbonate microspheres comprises the following steps:

[0051] S1) weighing 10 g of calcium chloride and 3 g of carboxymethyl cellulose, dissolving them in 100 g of ethanol and 80 g of water, and stirring to obtain a mixed solution;

[0052] S2) adding 10 g of potassium carbonate and 14 g of potassium bicarbonate to the mixed solution, and stirring evenly at room temperature to obtain a precursor;

[0053] S3) In a 1L reactor, add 1g Tween 80, 1g Span 80 and 200g liquid paraffin (wherein the HLB value of the oil phase = 6.0), stir at 40°C for 1h, then add the precursor prepared in step S2, stir at 50°C for 2h to prepare a microsphere intermediate;

[0054] S4) washing the microsphere intermediate with ethanol three times and drying at 80° C. to obtain composite microspheres;

[0055] S5) The composite microspheres are calcined at 600° C. for 10 h to obtain monodisperse calcium carbonate microspheres with a porous structure.

[0056] The particle size and particle size distribution were determined by Beckman Counter: the particle size was 10 μm, the CV (coefficient of variation) was 2.6%, and the specific surface area was 400 m 2 / g.

[0057] Comparative Example 1

[0058] A method for preparing monodisperse calcium carbonate microspheres comprises the following steps:

[0059] S1) weighing 10 g of calcium chloride, dissolving it in 80 g of ethanol and 100 g of water, and stirring to obtain a mixed solution;

[0060] S2) adding 10 g of sodium carbonate and 12 g of sodium bicarbonate to the mixed solution, and stirring evenly at room temperature to obtain a precursor;

[0061] S3) In a 1L reactor, add 2g of Tween 80, 1g of Span 80 and 200g of liquid paraffin (wherein the HLB value of the oil phase is 8.8), stir at 40°C for 1h, then add the precursor prepared in step S2, stir at 50°C for 2h, to prepare a microsphere intermediate;

[0062] S4) washing the microsphere intermediate with ethanol three times and drying at 80° C. to obtain composite microspheres;

[0063] S5) The composite microspheres are calcined at 600° C. for 10 h to obtain monodisperse calcium carbonate microspheres.

[0064] The particle size and particle size distribution of the monodisperse calcium carbonate microspheres were measured by Beckman Counter: the particle size was 10 μm, the CV (coefficient of variation) value was 3.8%, and the specific surface area was 380 m 2 / g.

[0065] It can be seen from the data of Examples 1 to 4 and Comparative Example 1 that by controlling the HLB value of the coating liquid (after compounding Tween 80 and Span 80) within 5.5-8.5, the obtained monodisperse calcium carbonate microspheres can have a better CV value, and the addition of a protective agent can further ensure the uniformity of the particle size of the obtained monodisperse calcium carbonate microspheres. Therefore, by controlling the type, composition and amount of the emulsifier, the amount of the oil phase, and by controlling the reaction temperature, the pressure of the reaction system and the reaction time, calcium carbonate microspheres with uniform particle size can be obtained, and the size of the microsphere particles can be controlled.

[0066] The specific embodiments described herein are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the appended claims.

Claims

1. A method for preparing monodisperse calcium carbonate microspheres, characterized in that: The steps include: S1) mixing a calcium source, ethanol and water to prepare a mixed solution; S2) adding carbonate to the mixed solution and stirring uniformly at room temperature to obtain a precursor; S3) mixing an emulsifier and an organic solvent to obtain an oil phase solution, adding the precursor to the oil phase solution, stirring and mixing, and heating to obtain a microsphere intermediate; S4) washing the microsphere intermediate with an organic solvent and drying to obtain composite microspheres; S5) calcining the composite microspheres at high temperature to obtain monodisperse calcium carbonate microspheres.

2. The method for preparing monodisperse calcium carbonate microspheres according to claim 1, wherein S1 further comprises a protective agent, which is carboxymethyl cellulose.

3. The method for preparing monodisperse calcium carbonate microspheres according to claim 1 or 2, characterized in that: The calcium source in S1 is calcium chloride.

4. The method for preparing monodisperse calcium carbonate microspheres according to claim 1, characterized in that: The carbonate in S2 is one or more of potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate.

5. The method for preparing monodisperse calcium carbonate microspheres according to claim 1, characterized in that: The emulsifier in S3 is a mixture of Tween 80 and Span 80, and the mass ratio of the two is 1:(1-2); the organic solvent in S3 is liquid paraffin and / or petroleum ether.

6. The method for preparing monodisperse calcium carbonate microspheres according to claim 1 or 5, characterized in that: The HLB value of the oil phase solution in S3 is 5.5-8.

5.

7. The method for preparing monodisperse calcium carbonate microspheres according to claim 1, characterized in that: The reaction conditions in S3 are: temperature 45-60°C, time 1-8h.

8. The method for preparing monodisperse calcium carbonate microspheres according to claim 1, characterized in that: The drying temperature in S4 is 80-100°C.

9. The method for preparing monodisperse calcium carbonate microspheres according to claim 1, characterized in that: The calcination temperature in S5 is 550-650°C, and the calcination time is 8-24h.

10. The method for preparing monodisperse calcium carbonate microspheres according to claim 1, characterized in that: The monodisperse calcium carbonate microspheres described in S5 have a particle size of 1-500 μm, a CV value of 2.5-3.2%, and a specific surface area of ​​200-400 m 2 / g.