阅读说明：本技术 一种均一片形结构的药用辅料硬脂富马酸钠及其制备方法 (Pharmaceutic adjuvant sodium stearyl fumarate with uniform sheet-shaped structure and preparation method thereof ) 是由 邵一丹 毕勇 武蛟 任利亭 鲍慧娟 邵云鹤 于 2021-09-10 设计创作，主要内容包括：本发明公开了一种均一片形结构的药用辅料硬脂富马酸钠及其制备方法,所述制备方法为将待处理的硬脂富马酸钠在乙醇中加热溶解,经过滤除杂后,加入晶种进行重结晶,该方法可结晶出粒径分布较窄,平均粒径在5～15μm的片形结构的硬脂富马酸钠,片形结构完整,均匀度好,纯度高达99.6％以上,长时间放置仍能保持粉末状态,不易结块。(The invention discloses a pharmaceutical adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure and a preparation method thereof, wherein the preparation method comprises the steps of heating and dissolving sodium stearyl fumarate to be treated in ethanol, filtering impurities, and adding seed crystals for recrystallization, the method can crystallize the sodium stearyl fumarate with the sheet-shaped structure, which has narrow particle size distribution and average particle size of 5-15 mu m, the sheet-shaped structure is complete, the uniformity is good, the purity is up to more than 99.6%, and the sodium stearyl fumarate can still keep a powder state after being placed for a long time and is not easy to agglomerate.)

1. A preparation method of a medicinal auxiliary material sodium stearyl fumarate with a uniform sheet-shaped structure is characterized in that sodium stearyl fumarate to be treated is heated and dissolved in ethanol, impurities are filtered out, and then seed crystals are added for recrystallization.

2. The preparation method according to claim 1, comprising in particular the steps of:

(1) heating and dissolving sodium stearyl fumarate to be treated in an ethanol solution, and filtering while the solution is hot;

(2) adding sodium stearyl fumarate seed crystals when the sodium stearyl fumarate solution is cooled to a metastable zone of 60-75 ℃;

(3) cooling the solution by using circulating water at the temperature of 10-50 ℃, recrystallizing sodium stearyl fumarate in the cooling process, continuously stirring for a period of time after complete recrystallization, and then filtering, drying and crushing to obtain the uniform sheet-shaped pharmaceutical adjuvant sodium stearyl fumarate.

3. The preparation method according to claim 2, wherein in the step (1), the volume concentration of the ethanol solution is 10-70%; the heating temperature is 70-90 ℃.

4. The preparation method according to claim 2, wherein in the step (1), the mass-to-volume ratio of the sodium stearyl fumarate to the ethanol solution is 1 g: 5-20 mL.

5. The preparation method according to claim 2, wherein the sodium stearyl fumarate seed crystal is obtained by dry grinding or wet grinding sodium stearyl fumarate to be treated, and the average particle size of the sodium stearyl fumarate seed crystal is 0.5-5 μm.

6. The preparation method according to claim 2, wherein the mass of the sodium stearyl fumarate seed crystal is 0.5-5% of the mass of the sodium stearyl fumarate to be treated.

7. The preparation method according to claim 2, wherein in the step (2), the temperature reduction speed is controlled to be 0.1-0.3 ℃/min.

8. The preparation method according to claim 2, wherein in the step (3), after the recrystallization is completed, the stirring is continued for 0.5 to 1.5 hours.

9. The method according to claim 2, wherein in the step (3), the filtration means is centrifugal filtration; the drying mode is vacuum drying, boiling drying or freeze drying; the crushing mode is hammer type crushing.

10. The pharmaceutical adjuvant sodium stearyl fumarate with a uniform sheet structure prepared by the preparation method of any one of claims 1 to 9, wherein the pharmaceutical adjuvant sodium stearyl fumarate is a sheet structure with an average particle size of 5-15 μm and is complete in sheet structure.

Technical Field

The invention belongs to the technical field of pharmaceutical adjuvant refining, and particularly relates to a pharmaceutical adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure and a preparation method thereof.

Background

Stearyl fumarate sodium (C)₂₂H₃₉NaO₄) Is an important auxiliary material and has wide application in the fields of food and medicine. The sodium stearyl fumarate is structurally formed by ester bond connection of stearic alcohol at a hydrophobic end and sodium fumarate at a hydrophilic end, has hydrophilicity, can be used as a lubricant for tablets and capsules, can improve disintegration and promote dissolution, has strong compatibility and stable property, and is an excellent substitute for magnesium stearate. The sodium stearyl fumarate can be absorbed by human body, and converted into stearyl alcohol and fumaric acid, wherein the stearyl alcohol and the stearic acid are further oxidized into stearic acid, and are main components of natural food, and are nontoxic and non-irritant; the latter is in turn a normal constituent of human tissue.

In the prior art, a refining method of sodium stearyl fumarate generally adopts the steps of firstly pulping and washing by using an organic solvent to remove residual soluble impurities in the sodium stearyl fumarate, and then crushing by using special equipment to control the particle size within a proper range. The method has the disadvantages of poor uniformity of particle size, wide particle size distribution range, serious damage to sheet-shaped structure, and easy caking after long-time storage, which causes inconvenience in the using process of the preparation.

Disclosure of Invention

In order to solve the technical problems, the invention provides a pharmaceutical adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure and a preparation method thereof.

The technical scheme adopted by the invention is as follows:

a process for preparing the sodium stearyl fumarate with uniform flaky structure includes such steps as heating the sodium stearyl fumarate to be treated in alcohol for dissolving, filtering, and adding crystal seed for recrystallizing.

The preparation method specifically comprises the following steps:

(1) heating and dissolving sodium stearyl fumarate to be treated in an ethanol solution, and filtering while the solution is hot;

(2) adding sodium stearyl fumarate seed crystals when the sodium stearyl fumarate solution is cooled to a metastable zone of 60-75 ℃;

(3) cooling the solution by using circulating water at the temperature of 10-50 ℃, recrystallizing sodium stearyl fumarate in the cooling process, continuously stirring for a period of time after complete recrystallization, and then filtering, drying and crushing to obtain the uniform sheet-shaped pharmaceutical adjuvant sodium stearyl fumarate.

In the step (1), the volume concentration of the ethanol solution is 10-70%, preferably 10-50%, and sodium stearyl fumarate is insoluble in absolute ethanol, but soluble in hot water, and can be completely dissolved in the ethanol solution with the concentration range at a certain heating temperature.

In the step (1), the heating temperature is 70-90 ℃, and preferably 75-85 ℃.

In the step (1), the mass-to-volume ratio of the sodium stearyl fumarate to the ethanol solution is 1 g: 5-20 mL, preferably 1 g: 5-10 mL.

In the step (2), the temperature is preferably reduced to 60 to 70 ℃.

In the step (2), the cooling speed is controlled to be 0.1-0.3 ℃/min; if the temperature reduction rate is too high, the solute can be precipitated in advance and cannot reach the metastable zone range, mixed crystals can be formed once the solute is precipitated in advance, and finally the crystallized material has the phenomenon of uneven size; if the cooling speed is too slow, the production efficiency is low.

The sodium stearyl fumarate seed crystal is obtained by dry grinding or wet grinding of sodium stearyl fumarate to be treated, and the average particle size of the sodium stearyl fumarate seed crystal is 0.5-5 mu m, preferably 1.5-4.5 mu m. With the control of the temperature, the sodium stearyl fumarate product obtained after recrystallization of the seed crystals with the particle sizes is uniform in particle size and complete in tablet shape.

The dry crushing is any one or more of a grinding method, a mechanical crushing method or a jet milling method.

The wet grinding is one or more of a homogenizing method, a homogenizing method or a shearing method.

The sodium stearyl fumarate seed crystal is preferably prepared by wet pulverization, and is more preferably prepared by a homogenization method.

The homogenizing method comprises the following steps: mixing sodium stearyl fumarate to be treated according to a feed-liquid ratio of 1: 5 adding the mixture into 10-70% ethanol for homogenizing for 10-30 min to obtain the sodium stearyl fumarate seed crystal with the average grain size of 0.5-5 mu m.

The mass of the sodium stearyl fumarate seed crystal is 0.5-5% of that of the sodium stearyl fumarate to be treated, and preferably 0.5-2%.

In the step (3), preferably, the temperature of the solution is reduced by circulating water at 15-45 ℃. And slowly cooling the solution by circulating water at a specific temperature to maintain the constant rate of crystal precipitation, so as to ensure the size and uniformity of crystals and obtain the sodium stearyl fumarate with a uniform sheet-shaped structure. If the temperature of the circulating water is too high during recrystallization, normal crystallization cannot be realized, and if the temperature of the circulating water is too low, crystallization is too fast, so that more mixed crystal products are produced, and the particle size of the product is not uniform.

And (3) adding sodium stearyl fumarate seed crystals, and slowly stirring at a rotation speed of 45r/min to keep the crystal precipitation rate constant, so as to ensure the size and uniformity of crystals.

And (3) after the recrystallization is completed, continuously stirring for 0.5-1.5 h at the stirring speed of 60r/min, so that the solution after the recrystallization is completed is naturally cooled to room temperature and then filtered.

In the step (3), the filtration mode is centrifugal filtration; the drying mode is vacuum drying, boiling drying or freeze drying; the crushing mode is hammer type crushing, and the crushing mode can break up the materials under the condition of not damaging the original particle form.

The pharmaceutical adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure, which is prepared by the preparation method disclosed by the invention, is a sheet-shaped structure with an average particle size of 5-15 micrometers, and the sheet-shaped structure is complete.

According to the preparation method of the pharmaceutical adjuvant sodium stearyl fumarate with the uniform sheet-shaped structure, provided by the invention, an ethanol solution is heated to dissolve sodium stearyl fumarate, the sodium stearyl fumarate is filtered when the sodium stearyl fumarate is hot, insoluble impurities in the sodium stearyl fumarate can be removed after the sodium stearyl fumarate is filtered when the sodium stearyl fumarate is hot, sodium stearyl fumarate seed crystals with specific particle sizes are added after the filtered sodium stearyl fumarate solution is cooled to a metastable zone, the solution is cooled by circulating water at the temperature of 10-50 ℃, and the sodium stearyl fumarate is recrystallized in the cooling process, so that the soluble impurities in the sodium stearyl fumarate can be removed after recrystallization. According to the invention, through the accurate control of each process parameter in the process, the particle size distribution of the sodium stearyl fumarate after recrystallization is controlled to be narrow, the average particle size is 5-15 mu m, the sodium stearyl fumarate with a uniform sheet-shaped structure is obtained, and the sheet-shaped structure is complete.

Compared with the prior art, the method disclosed by the invention is simple to operate, special crushing equipment and sieving equipment are not required, the obtained sodium stearyl fumarate is of a sheet structure with the average particle size of 5-15 microns, the particle size range is narrower, the sheet structure is complete, the uniformity is better, the sodium stearyl fumarate is not easy to agglomerate after being placed for a long time, and the preparation production is convenient.

Drawings

FIG. 1 is a scanning electron micrograph of sodium stearyl fumarate to be treated;

FIG. 2 is a scanning electron micrograph of sodium stearyl fumarate prepared according to example 1;

FIG. 3 is a scanning electron micrograph of sodium stearyl fumarate prepared according to comparative example 1;

FIG. 4 is a scanning electron micrograph of sodium stearyl fumarate prepared according to comparative example 2;

FIG. 5 is a scanning electron micrograph of sodium stearyl fumarate prepared according to comparative example 3;

FIG. 6 is a scanning electron micrograph of sodium stearyl fumarate prepared according to comparative example 4;

FIG. 7 is a scanning electron micrograph of sodium stearyl fumarate prepared according to comparative example 5.

Detailed Description

The present invention will be described in detail with reference to examples.

The raw materials and reagents used in the present invention are commercially available.

Example 1

A preparation method of a pharmaceutic adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure comprises the following steps:

1) 1000mL of 40% ethanol solution and 100g of sodium stearyl fumarate to be treated are added into a reaction vessel, and the mixture is heated at 85 ℃ until the sodium stearyl fumarate is completely dissolved; the scanning electron microscope image of the sodium stearyl fumarate to be treated is shown in fig. 1, and the sodium stearyl fumarate is in a sheet structure with different sizes, and the integrity of the sheet structure is poor;

2) filtering the sodium stearyl fumarate solution obtained in the step 1) with a filter bag while the solution is hot, adding the filtered solution into another reaction vessel, and slowly cooling to 70 ℃ at a speed of 0.15 ℃/min;

3) taking 1g of sodium stearyl fumarate to be treated, adding 5mL of ethanol, homogenizing for 20min, and performing wet detection to obtain sodium stearyl fumarate seed crystals with average particle size of 2.3 μm; adding the mixture into the step 2), slowly stirring at a stirring speed of 45r/min, cooling the reaction container by circulating water at 45 ℃ until crystallization is complete, and stirring for 1h at normal temperature for 60 r/min;

4) centrifuging, filtering, vacuum drying at 65 deg.C for 5 hr, and pulverizing the dried material in hammer mill to obtain 93.3g sodium stearyl fumarate with yield of 92.38% and content of 100.3% by gas phase detection.

The SEM image of the sodium stearyl fumarate as the medicinal adjuvant with a uniform plate-shaped structure prepared in the example is shown in FIG. 1, and as can be seen from the SEM image, the sodium stearyl fumarate has a plate-shaped structure with a small particle size, and the plate-shaped structure is complete and uniform.

Example 2

A preparation method of a pharmaceutic adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure comprises the following steps:

1) 1000mL of 30% ethanol solution and 100g of sodium stearyl fumarate to be treated are added into a reaction vessel, and the mixture is heated at 80 ℃ until the sodium stearyl fumarate is completely dissolved;

2) filtering the sodium stearyl fumarate solution obtained in the step 1) with a filter bag while the solution is hot, adding the filtered solution into another reaction vessel, and slowly cooling to 65 ℃ at a speed of 0.2 ℃/min;

3) taking 1.5g of sodium stearyl fumarate to be treated, adding 7.5mL of ethanol, homogenizing for 10min, and performing wet detection to obtain sodium stearyl fumarate seed crystals with average particle size of 4.4 μm; adding the mixture into the step 2), slowly stirring at a stirring speed of 45r/min, cooling the reaction container by circulating water at 40 ℃ until crystallization is complete, and stirring for 1h at normal temperature for 60 r/min;

4) centrifuging, filtering, vacuum drying at 68 deg.C for 5 hr, and pulverizing the dried material in hammer mill to obtain 91.8g sodium stearyl fumarate with yield of 90.44% and content of 99.6% by gas phase detection.

Example 3

A preparation method of a pharmaceutic adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure comprises the following steps:

1) 1000mL of 20% ethanol solution and 100g of sodium stearyl fumarate to be treated are added into a reaction vessel, and the mixture is heated at 80 ℃ until the sodium stearyl fumarate is completely dissolved;

2) filtering the sodium stearyl fumarate solution obtained in the step 1) with a filter bag while the solution is hot, adding the filtered solution into another reaction vessel, and slowly cooling to 68 ℃ at a speed of 0.15 ℃/min;

3) taking 2.5g of sodium stearyl fumarate to be treated, adding 12.5mL of ethanol, homogenizing for 25min, and performing wet detection to obtain sodium stearyl fumarate seed crystals with average particle size of 2.1 μm; adding the mixture into the step 2), slowly stirring at a stirring speed of 45r/min, cooling the reaction container by circulating water at 35 ℃ until crystallization is complete, and stirring for 1h at normal temperature for 60 r/min;

4) centrifuging, filtering, vacuum drying at 70 deg.C for 5 hr, and pulverizing the dried material in hammer mill to obtain sodium stearyl fumarate 92.3g with yield of 90.05% and content of 99.6% by gas phase detection.

Example 4

A preparation method of a pharmaceutic adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure comprises the following steps:

1) 1000mL of 15% ethanol solution and 100g of sodium stearyl fumarate to be treated are added into a reaction vessel, and the mixture is heated at 82 ℃ until the sodium stearyl fumarate is completely dissolved;

2) filtering the sodium stearyl fumarate solution obtained in the step 1) with a filter bag while the solution is hot, adding the filtered solution into another reaction vessel, and slowly cooling to 68 ℃ at a speed of 0.2 ℃/min;

3) taking 4g of sodium stearyl fumarate to be treated, adding 20mL of ethanol, homogenizing for 20min, and performing wet detection to obtain sodium stearyl fumarate seed crystals with the average particle size of 2.4 mu m; adding the mixture into the step 2), slowly stirring at a stirring speed of 45r/min, cooling the reaction container by circulating water at 35 ℃ until crystallization is complete, and stirring for 1h at normal temperature for 60 r/min;

4) centrifuging, filtering, vacuum drying at 70 deg.C for 5 hr, and pulverizing the dried material in hammer mill to obtain 96.8g sodium stearyl fumarate with yield of 93.08%, and content of 100.1% by gas phase detection.

Example 5

A preparation method of a pharmaceutic adjuvant sodium stearyl fumarate with a uniform sheet-shaped structure comprises the following steps:

1) 1000mL of 50% ethanol solution and 100g of sodium stearyl fumarate to be treated are added into a reaction vessel, and the mixture is heated at 80 ℃ until the sodium stearyl fumarate is completely dissolved;

2) filtering the sodium stearyl fumarate solution obtained in the step 1) with a filter bag while the solution is hot, adding the filtered solution into another reaction vessel, and slowly cooling to 70 ℃ at a speed of 0.15 ℃/min;

3) taking 2g of sodium stearyl fumarate to be treated, adding 10mL of ethanol, homogenizing for 30min, and performing wet detection to obtain sodium stearyl fumarate seed crystals with the average particle size of 2.0 mu m; adding the mixture into the step 2), slowly stirring at a stirring speed of 45r/min, cooling the reaction container by circulating water at 35 ℃ until crystallization is complete, and stirring for 1h at normal temperature for 60 r/min;

4) centrifuging, filtering, vacuum drying at 65 deg.C for 5 hr, and pulverizing the dried material in hammer mill to obtain 89.8g sodium stearyl fumarate with yield of 88.04% and content of 99.8% by gas phase detection.

Comparative example 1

Otherwise, as in example 1, except that the 40% ethanol solution obtained in step (1) was replaced with an equal volume of purified water, 89.3g of sodium stearyl fumarate was obtained with a yield of 88.42%, and its content was 99.5% by gas phase assay.

The SEM image of the sodium stearyl fumarate prepared by the comparative example is shown in FIG. 3, and it can be seen from the SEM image that the particle sizes are different, and the flake structures are incomplete.

Comparative example 2

Otherwise, the same as example 1, except that the temperature of the sodium stearyl fumarate solution in the step (2) is reduced to 55 ℃, and then sodium stearyl fumarate seed crystals are added, at this time, a large amount of solute is precipitated in advance. 91.7g of sodium stearyl fumarate was obtained with a yield of 90.79%, the content of which was 100.9% by gas phase detection.

The SEM image of sodium stearyl fumarate prepared in this comparative example is shown in fig. 4, from which it can be seen that although its platelet structure is intact, the particle size is large and the uniformity is poor.

Comparative example 3

Otherwise as in example 1 except that the seed crystals in step (2) were directly seeded with sodium stearyl fumarate having an average size of 12.64. mu.m without homogenization treatment. 89.3g of sodium stearyl fumarate was obtained in 88.42% yield, the content of which was 99.8% by gas phase detection.

The SEM image of the sodium stearyl fumarate prepared by the comparative example is shown in FIG. 5, and it can be seen from the SEM image that the particle size is too large and varied, and the flake structure is incomplete.

Comparative example 4

The same procedure as in example 1 was repeated except that in step (2), the temperature was lowered to 70 ℃ at a rate of 1 ℃/min. During the temperature reduction process, a part of solute is separated out; in contrast, in examples 1-5, no solute was precipitated from the solution prior to seeding.

This comparative example produced 87.8g of sodium stearyl fumarate having a yield of 86.93% and a content of 100.4% as determined in the vapour phase.

The SEM image of the sodium stearyl fumarate prepared by the comparative example is shown in FIG. 6, and the sodium stearyl fumarate has more mixed crystals, uneven particle size and poorer integrity.

Comparative example 5

The rest is the same as example 1, except that in step (3), the temperature of the reaction vessel is reduced by circulating water at 5 ℃. 93.1g of sodium stearyl fumarate was obtained in 92.17% yield, and its content was 99.7% by gas phase detection.

The SEM image of the sodium stearyl fumarate prepared by the comparative example is shown in FIG. 7, and the sodium stearyl fumarate has more mixed crystals, uneven particle size and poorer integrity.

The results of testing the sodium stearyl fumarate to be treated and the pharmaceutical excipients with uniform platelet structure prepared in the above examples and comparative examples are shown in tables 1 and 2.

TABLE 1

TABLE 2

As can be seen from fig. 1 in conjunction with table 1, the sodium stearyl fumarate prepared in example 1 had a particle size of 90% or less at a ratio of 13.76 μm or less; the sodium stearyl fumarate prepared in example 2 has a particle size of 90% to 15.98 μm; the sodium stearyl fumarate prepared in example 3 had a particle size of 11.88 μm or less and a proportion of 90%; the sodium stearyl fumarate prepared in example 4 had a particle size of 90% to 10.01 μm or less; 90% of the sodium stearyl fumarate prepared in example 5, which had a particle size of 16.16 μm or less; therefore, the sodium stearyl fumarate prepared in each embodiment of the invention has small particle size, high uniformity, narrow particle size distribution range and large specific surface area.

As can be seen from fig. 3 to 7 in conjunction with table 2, sodium stearyl fumarate prepared in comparative example 1 had a particle size of 11.34 μm or less of 90% by weight, but had poor uniformity of particle size, a wide particle size distribution range, and non-uniformity in tablet form; the sodium stearyl fumarate prepared in the comparative example 2 is large in particle size, poor in uniformity and wide in particle size distribution range; the sodium stearyl fumarate prepared in the comparative example 3 is poor in particle size uniformity and low in specific surface area; the sodium stearyl fumarate prepared in the comparative example 4 is large in particle size, poor in uniformity and wide in particle size distribution range; the sodium stearyl fumarate prepared in comparative example 5 had poor uniformity of particle size and a wide range of particle size distribution.

According to the detection, the sodium stearyl fumarate prepared by the method disclosed by the invention has the advantages that the sheet structure is complete, the particle size and the specific surface area are controllable, the impurities are few, and the product quality is obviously improved.

The above detailed description of a pharmaceutical adjuvant sodium stearyl fumarate of uniform lamellar structure and the process for its preparation, with reference to the examples, is illustrative and not restrictive, and several examples are set forth according to the limits of the invention, and therefore variations and modifications which do not depart from the general concept of the invention are intended to be within the scope of the invention.