CN113929683A - A method for improving the bulk density and fluidity of riboflavin crystals - Google Patents

Abstract

The invention provides a method for improving the bulk density and the flowability of riboflavin crystals, which comprises the following steps: (1) dissolving a riboflavin sample into a hydrochloric acid solution with the mass fraction of 27-31%, and carrying out solid-liquid separation to obtain a saturated solution; (2) adding the saturated solution obtained in the step (1) into a hydrochloric acid solution with the mass fraction of 1.4% -2.4%, mixing, cooling and growing crystals to obtain riboflavin crystals; the riboflavin product obtained by the method is rod-shaped, has good fluidity, the bulk density of the product reaches 0.50g/mL-0.88g/mL, and the single impurity content of the product is less than 0.2%.

Description

Method for improving bulk density and fluidity of riboflavin crystals

Technical Field

The invention belongs to the technical field of medical crystallization, and relates to a method for improving the bulk density and the flowability of riboflavin crystals.

Background

Riboflavin, alias vitamin B₂Is an important component of vitamin B group, the precursor of which is vitamin G and the molecular formula of which is C₁₇H₂₀N₄O₆Molecular weight 376.37,chemical name 7, 8-dimethyl-10 (1' -D-ribityl) -isoalloxazine, respectively.

Riboflavin exerts biological effects in vivo in the form of flavin coenzymes, and mainly takes part in various redox reactions in vivo in the form of flavin mononucleotide and flavin adenine dinucleotide. Lack of riboflavin can cause fatigue, hypodynamia and itching eyes with burning sensation, and the pathological changes of oral cavity and scrotum appear, which is called oral cavity reproductive system syndrome and is a common nutritional deficiency disease for residents in China. In addition, research shows that the riboflavin has the effects of promoting urination, preventing cancer, reducing blood pressure, improving cardiac function and the like. The American food nutrition Committee recommends that the daily intake dose of riboflavin for adults is 0.9-1.3 mg. It is not only widely used in clinical applications, but also, because it is non-toxic and yellow in color, it is often used in the food industry as a nutritional additive and a pigment. Riboflavin is one of the early vitamins entering the international market, more than two hundred clinical application, health care and anti-aging preparations are used at home and abroad, and the demand of the market for the riboflavin is continuously increased due to the rapid development of the food industry, the health care product industry and the nutritional additive industry.

Most of riboflavin crystals are needle-shaped at present, and due to the small bulk density and poor flow property, the processing property is poor, the processing difficulty is high, and the processing properties such as tabletting and the like are influenced finally. In the prior art, methods for separating and purifying riboflavin exist, for example, CN109851619A discloses a riboflavin purification process, which uses an acid dissolution method to perform crystallization to purify a riboflavin product, but the obtained riboflavin product has low bulk density, and metal powder, inorganic salt and a small-molecule reducing organic reagent are added as reducing agents in the process, so that the subsequent post-treatment problem exists. Patent CN110283175A discloses a preparation process of high-purity riboflavin, which comprises dissolving crude riboflavin in acid or alkali, taking filtrate, crystallizing and drying to obtain riboflavin product, but the problem of overdimension of impurity a and impurity D in riboflavin product is easily caused due to the alkali dissolution method used in the process. Patent CN1765897A discloses an extraction process of riboflavin fermentation broth, comprising the steps of pretreatment of fermentation broth, membrane filtration, acidification, oxidation and crystallization, and recovering riboflavin in the acidified mother liquor by a recovery process. The method has low riboflavin content and yield.

In view of the above, the application of riboflavin in the fields of medicine and the like is widened, and the application problem of riboflavin at present is overcome.

Therefore, it is of great importance to develop a high quality riboflavin product with high bulk density, good fluidity and high purity.

Disclosure of Invention

The invention aims to provide a method for improving the bulk density and the fluidity of riboflavin products, wherein the riboflavin products prepared by the preparation method are rod-shaped in crystal habit and good in fluidity, the bulk density of the products reaches 0.50-0.88g/mL, and the single impurity content of the products is less than 0.2%.

In order to achieve the purpose, the invention adopts the following technical scheme:

one of the objects of the present invention is to provide a method for increasing the bulk density and fluidity of riboflavin crystals, said method comprising the steps of:

(1) dissolving a riboflavin sample into a hydrochloric acid solution with the mass fraction of 27-31%, and carrying out solid-liquid separation to obtain a saturated solution;

(2) and (2) adding the saturated solution obtained in the step (1) into a hydrochloric acid solution with the mass fraction of 1.4% -2.4%, mixing, cooling and growing crystals to obtain riboflavin crystals.

Preferably, the riboflavin sample in the step (1) is riboflavin crude product or purified riboflavin crude product.

Preferably, the preparation method of the purified crude riboflavin comprises the following steps: dissolving the crude riboflavin product into a hydrochloric acid solution with the mass fraction of 1.4-7.5%, or dissolving the crude riboflavin product in water and suspending for 4-5h at the temperature of 80-90 ℃.

Preferably, the riboflavin sample in step (1) has a dissolution temperature of 30-50 ℃.

Preferably, the solid-liquid separation method in the step (1) is filtration.

Preferably, the saturated solution in the step (2) is added dropwise at a rate of 0.5-1 mL/min.

Preferably, the mixing temperature in step (2) is 60-80 ℃.

Preferably, the volume ratio of the saturated solution in the step (2) to the hydrochloric acid solution with the mass fraction of 1.4% -2.4% is (0.16-0.19) to 1.

Preferably, the cooling temperature in step (2) is 5-40 ℃.

Preferably, the cooling rate of step (2) is not less than 5 mL/min.

Preferably, the time for growing the crystals in the step (2) is 0-2 h.

Preferably, the step (2) further comprises: and sequentially washing, carrying out solid-liquid separation and drying on the product obtained after cooling.

Preferably, the solid-liquid separation mode is filtration.

Preferably, the drying is carried out under normal pressure, the drying temperature is 60-90 ℃, and the drying time is 12-24 h.

As a preferred technical scheme of the invention, the method comprises the following steps:

(1) putting the riboflavin crude product or the purified riboflavin crude product into hydrochloric acid solution with the mass fraction of 27-31%, dissolving at 30-50 ℃, and filtering to obtain riboflavin filtrate;

(2) heating the riboflavin filtrate obtained in the step (1) to 60-80 ℃, and dropwise adding the riboflavin filtrate into a hydrochloric acid solution with the mass fraction of 1.4% -2.4% at the dropwise adding rate of 0.5-1mL/min to obtain a quenching front liquid;

(3) cooling the pre-quenching liquid obtained in the step (2) to 5-40 ℃ at a quenching rate of not less than 5mL/min to precipitate crystals, and growing the crystals for 0-2h to obtain a mixture;

(4) and (4) filtering the mixture obtained in the step (3), and drying at 60-90 ℃ for 12-24h under normal pressure to obtain riboflavin crystals.

The second object of the present invention is to obtain riboflavin crystals prepared by the process according to the first object.

Preferably, the bulk density of the riboflavin crystals is 0.50-0.88g/mL, and the product impurity is less than 0.2%.

The third object of the present invention is to provide a riboflavin crystal according to the second object for use in the preparation of a medicament or a dietary supplement.

Compared with the prior art, the invention has the following beneficial effects:

the riboflavin product prepared by the method provided by the invention is rod-shaped in crystal habit and good in fluidity, the bulk density of the product reaches 0.50-0.88g/mL, and the single impurity content of the product is less than 0.2%.

Drawings

FIG. 1 is a microscopic image of riboflavin obtained in example 1;

FIG. 2 is a PXRD spectrum of riboflavin prepared in example 1;

FIG. 3 is a TG plot of riboflavin prepared in example 1;

FIG. 4 is a DSC of riboflavin obtained in example 1.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

Example 1

A2.4% hydrochloric acid solution was prepared, and 240mL of the solution was added to a main stirred crystallizer and incubated at 60 ℃. Weighing 10g of crude raw material of the unpurified riboflavin, dissolving the crude raw material in 50mL of hydrochloric acid solution with the mass fraction of 31% at 50 ℃, suspending for 30min, adding 45mL of supernatant into a crystallizer, stirring with a main stirrer for series connection and heat preservation, dropping the saturated solution into an anti-solvent in a positive direction, allowing the solution to be used, directly pouring the dropped solution into the crystallizer at 5 ℃, growing the crystal for 2h after the crystal is generated, and after the completion, washing, drying and waiting for performance detection.

FIG. 1 is a micrograph of riboflavin obtained in example 1 (type: OLYMPUS, BX53, Japan), and it can be seen from FIG. 1 that the crystals of the product had a rod shape.

FIG. 2 is an XRD pattern (model D/MAX-2500, Japan) of the product obtained in example 1, and it can be seen from FIG. 2 that the product is riboflavin monohydrate.

FIG. 3 is a TG graph (model number Mettler Toledo, TGA/DSC1/SF) of the product obtained in example 1, and it can be seen from FIG. 3 that the weight loss of water is present before 100 ℃.

FIG. 4 shows the DSC of the product obtained in example 1 (model Mettler-Toledo, DSC1/500, Switzerland), from FIG. 4 it can be seen that there are two exothermic peaks, one at 100 ℃ for the loss of water.

Carry out performance test to gained product, weigh the product m of certain quality, place the solid in the graduated flask, the graduated flask of vibration makes the sample compact repeatedly, and the back-off does not have the solid to drop, records product volume V, and bulk density equals m/V and knows: the bulk density of the product obtained in example 1 was 0.50 g/mL.

And (3) performing impurity measurement on the obtained product, and adopting a high performance liquid chromatography according to European pharmacopoeia to obtain the product with single impurity less than 0.2%.

Example 2

A2.4% hydrochloric acid solution was prepared, 240mL of the solution was added to the main stirred crystallizer and the temperature was maintained at 70 ℃. Weighing 10g of crude raw material of the unpurified riboflavin, dissolving the crude raw material in 50mL of hydrochloric acid solution with the mass fraction of 31% at 50 ℃, suspending for 30min, adding 45mL of supernatant into a crystallizer, stirring with a main stirrer to carry out series connection and heat preservation, dropping the saturated solution into an anti-solvent in a positive direction, allowing the solution to be used, directly pouring the dropped solution into the crystallizer at 15 ℃, growing the crystals for 2h after the crystals are generated, and after the completion, washing, drying and detecting the performance.

The same test method as in example 1 was used to test the performance of the product, and it was found that: the bulk density is 0.56g/mL, and the single impurity of the obtained product is less than 0.2 percent.

Example 3

A2.4% hydrochloric acid solution was prepared, 240mL of the solution was added to the main stirred crystallizer and the temperature was maintained at 70 ℃. Weighing 5g of crude raw material purified by riboflavin 2.4% hydrochloric acid, dissolving the raw material in 50mL of hydrochloric acid solution with the mass fraction of 31% at 50 ℃, suspending for 30min, adding 45mL of supernatant into a crystallizer, stirring with a main stirrer for series connection and heat preservation, dropping saturated solution into an antisolvent in a positive direction, allowing the solution to be used, directly pouring the dropped solution into the crystallizer at 30 ℃, growing crystals for 2h after the crystals are formed, and after the completion, washing, drying and waiting for performance detection.

The same test method as in example 1 was used to test the performance of the product, and it was found that: the bulk density is 0.61g/mL, and the single impurity of the obtained product is less than 0.2 percent.

Example 4

A2.4% hydrochloric acid solution was prepared, 240mL of the solution was added to the main stirred crystallizer and the temperature was maintained at 70 ℃. Weighing 5g of crude raw material purified by riboflavin 2.4% hydrochloric acid, dissolving the raw material in 50mL of hydrochloric acid solution with the mass fraction of 31% at 50 ℃, suspending for 30min, adding 45mL of supernatant into a crystallizer, stirring with a main stirrer for series connection and heat preservation, dropping saturated solution into an antisolvent in a positive direction, allowing the solution to be used, directly pouring the dropped solution into the crystallizer at 40 ℃, growing crystals for 2h after the crystals are formed, and after the completion, washing, drying and waiting for performance detection.

The same test method as in example 1 was used to test the performance of the product, and it was found that: the bulk density is 0.63g/mL, and the single impurity of the obtained product is less than 0.2 percent.

Example 5

A2.4% hydrochloric acid solution was prepared, 240mL of the solution was added to the main stirred crystallizer and the temperature was maintained at 70 ℃. Weighing 5g of crude raw material after riboflavin purification, dissolving the crude raw material in 50mL of hydrochloric acid solution with the mass fraction of 31% at 50 ℃, suspending for 30min, adding 45mL of supernatant into a crystallizer, stirring with a main stirrer to carry out series connection and heat preservation, dropping saturated solution into an anti-solvent in a positive direction, allowing the solution to be used, directly pouring the dropped solution into the crystallizer at 15 ℃, growing crystals for 2h after crystal growth, and after finishing, washing, drying and waiting for performance detection.

The same test method as in example 1 was used to test the performance of the product, and it was found that: the bulk density is 0.88g/mL, and the single impurity of the obtained product is less than 0.2 percent.

Comparative example 1

The only difference from example 1 is that the temperature decrease rate was controlled at 4 deg.C/min.

A2.4% hydrochloric acid solution was prepared, 240mL of the solution was added to the main stirred crystallizer and the temperature was maintained at 70 ℃. Weighing 5g of crude raw material after riboflavin purification, dissolving the crude raw material in 50mL of hydrochloric acid solution with the mass fraction of 31% at 50 ℃, suspending for 30min, adding 45mL of supernatant into a crystallizer, stirring with a main stirrer for series connection and heat preservation, dropping saturated solution into an anti-solvent in a positive direction, standing the solution, controlling the temperature reduction rate of the dropped solution at 4 ℃/min, growing crystals for 2h after crystal growth, and after finishing, washing, drying and waiting for performance detection.

The same test method as in example 1 was used to test the performance of the product, and it was found that: the bulk density was 0.22 g/mL.

It is understood from a comparison between example 1 and comparative example 1 that a decrease in the temperature decrease rate increases the crystal aspect ratio and decreases the bulk density.

Comparative example 2

The difference from example 1 is only that the preparation method is the same as example 1 except that the addition of 2.4 mass percent hydrochloric acid solution is not included.

Weighing 10g of crude raw material of the unpurified riboflavin, dissolving the crude raw material in 50mL of hydrochloric acid solution with the mass fraction of 31% at 50 ℃, suspending for 30min, taking 45mL of supernatant, adding the supernatant into a crystallizer, keeping the temperature at 60 ℃, standing the solution for later use, directly pouring the heat-kept solution into the crystallizer with the temperature of 5 ℃, wherein no crystal is separated out because the solubility under the concentration of 31% hydrochloric acid is too high and the saturation caused by the temperature is not enough for nucleation.

It is clear from a comparison of example 1 and comparative example 2 that the necessity of adding an anti-solvent for crystallization does not allow crystals to precipitate when a quenching experiment is carried out after dissolution with a high mass fraction of hydrochloric acid as it is.

Comparative example 3

The only difference from example 1 is that the hydrochloric acid solution having a mass fraction of 2.4% was replaced with a hydrochloric acid solution having a mass fraction of 0%, and the remaining preparation method was the same as in example 1.

240mL of a 0% solution of hydrochloric acid was added to the main stirred crystallizer and incubated at 60 ℃. Weighing 10g of crude raw material of the unpurified riboflavin, dissolving the crude raw material in 50mL of hydrochloric acid solution with the mass fraction of 31% at 50 ℃, suspending for 30min, taking 45mL of supernatant, adding the supernatant into a crystallizer, stirring with a main stirrer to carry out series connection and heat preservation, dropping the saturated solution into an anti-solvent in a positive direction, directly separating out crystals in the dissolution process, growing the crystals for 2h after the crystals are separated out, and after the crystals are separated out, washing, drying and detecting the performance.

The same test method as in example 1 was used to test the performance of the product, and it was found that: the bulk density was 0.30 g/mL.

It is understood from the comparison between example 1 and comparative example 3 that the decrease in the mass fraction of hydrochloric acid causes crystals having a relatively large major axis to be directly precipitated in the elution process, and the bulk density is reduced.

Claims (10)

Translated fromChinese

1.一种提高核黄素晶体堆密度和流动性的方法，其特征在于，所述方法包括如下步骤：1. a method for improving riboflavin crystal bulk density and fluidity, is characterized in that, described method comprises the steps:(1)将核黄素样品溶解至质量分数为27-31％的盐酸溶液中，进行固液分离，得到饱和溶液；(1) Dissolving the riboflavin sample into a hydrochloric acid solution with a mass fraction of 27-31%, carrying out solid-liquid separation to obtain a saturated solution;(2)将步骤(1)得到的饱和溶液中加入到质量分数为1.4％-2.4％的盐酸溶液中混合，而后冷却并养晶，得到核黄素晶体。(2) adding the saturated solution obtained in step (1) into a hydrochloric acid solution with a mass fraction of 1.4%-2.4% and mixing, then cooling and growing crystals to obtain riboflavin crystals.2.根据权利要求1所述的方法，其特征在于，步骤(1)所述核黄素样品为核黄素粗品或纯化后的核黄素粗品；2. The method according to claim 1, wherein the riboflavin sample described in step (1) is a crude riboflavin product or a purified crude riboflavin product;优选地，所述纯化后的核黄素粗品的制备方法包括：将核黄素粗品溶解至质量分数为1.4％-7.5％的盐酸溶液，或，将核黄素粗品溶于水中80-90℃悬浮4-5h。Preferably, the method for preparing the purified crude riboflavin includes: dissolving the crude riboflavin into a hydrochloric acid solution with a mass fraction of 1.4%-7.5%, or dissolving the crude riboflavin in water at 80-90° C. Suspended for 4-5h.3.根据权利要求1所述的方法，其特征在于，步骤(1)中所述核黄素样品的溶解温度为30-50℃；3. The method according to claim 1, wherein the dissolution temperature of the riboflavin sample in step (1) is 30-50°C;优选地，步骤(1)所述固液分离的方法为过滤。Preferably, the method for solid-liquid separation in step (1) is filtration.4.根据权利要求1所述的方法，其特征在于，步骤(2)所述饱和溶液的加入方式为滴加，滴加速率为0.5-1mL/min；4. method according to claim 1, is characterized in that, the adding mode of the described saturated solution of step (2) is dripping, and the rate of dripping is 0.5-1mL/min;优选地，步骤(2)所述混合温度为60-80℃。Preferably, the mixing temperature in step (2) is 60-80°C.5.根据权利要求1所述的方法，其特征在于，步骤(2)所述饱和溶液与质量分数为1.4％-2.4％的盐酸溶液的体积之比为(0.16-0.19)∶1。5 . The method according to claim 1 , wherein the volume ratio of the saturated solution in step (2) to the hydrochloric acid solution with a mass fraction of 1.4%-2.4% is (0.16-0.19):1. 6 .6.根据权利要求1所述的方法，其特征在于，步骤(2)所述冷却温度为5-40℃；6. The method according to claim 1, wherein the cooling temperature of step (2) is 5-40°C;优选地，步骤(2)所述冷却速率不低于5mL/min；Preferably, the cooling rate of step (2) is not less than 5mL/min;优选地，步骤(2)所述养晶时间为0-2h。Preferably, the crystal growing time in step (2) is 0-2h.7.根据权利要求1所述的方法，其特征在于，所述步骤(2)还包括：将冷却后得到的产品依次进行洗涤、固液分离以及干燥；7. method according to claim 1, is characterized in that, described step (2) also comprises: the product obtained after cooling is successively carried out washing, solid-liquid separation and drying;优选地，所述固液分离的方式为过滤；Preferably, the method of solid-liquid separation is filtration;优选地，所述干燥是在常压条件下进行的，所述干燥的温度为60-90℃，所述干燥的时间为12-24h。Preferably, the drying is performed under normal pressure conditions, the drying temperature is 60-90° C., and the drying time is 12-24 h.8.根据权利要求1所述的方法，其特征在于，所述方法包括如下步骤：8. The method according to claim 1, wherein the method comprises the steps of:(1)将核黄素粗品或纯化后的核黄素粗品置于质量分数为27-31％的盐酸溶液中，30-50℃溶解，过滤，得到核黄素滤液；(1) placing crude riboflavin or purified crude riboflavin in a hydrochloric acid solution with a mass fraction of 27-31%, dissolving at 30-50°C, and filtering to obtain a riboflavin filtrate;(2)步骤(1)得到的核黄素滤液加热至60-80℃，以0.5-1mL/min的滴加速率滴加至质量分数为1.4％-2.4％的盐酸溶液中，得到骤冷前液；(2) The riboflavin filtrate obtained in step (1) is heated to 60-80° C., and added dropwise to a hydrochloric acid solution with a mass fraction of 1.4%-2.4% at a drop rate of 0.5-1 mL/min to obtain a pre-quenching solution. liquid;(3)将步骤(2)得到的骤冷前液，以不低于5mL/min的骤冷速率降温至5-40℃析出晶体，并养晶0-2h，得到混合物；(3) cooling the pre-quenching liquid obtained in step (2) to 5-40° C. at a quenching rate of not less than 5 mL/min to precipitate crystals, and growing the crystals for 0-2 h to obtain a mixture;(4)将步骤(3)得到的混合物进行过滤，并在常压条件下60-90℃进行干燥12-24h，得到核黄素晶体。(4) The mixture obtained in step (3) is filtered, and dried at 60-90° C. for 12-24 hours under normal pressure to obtain riboflavin crystals.9.根据权利要求1-8任一项所述的方法制备得到核黄素晶体；9. riboflavin crystals are prepared by the method according to any one of claims 1-8;优选地，所述核黄素晶体的堆密度为0.50-0.88g/mL，产品单杂低于0.2％。Preferably, the bulk density of the riboflavin crystal is 0.50-0.88 g/mL, and the mono-impurity of the product is lower than 0.2%.10.根据权利要求9所述的核黄素晶体用于制备药物或食品添加剂。10. The riboflavin crystal according to claim 9 is used for preparing medicine or food additive.

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