CN106588907A

CN106588907A - Crystallization method of thiamine mononitrate

Info

Publication number: CN106588907A
Application number: CN201610974192.5A
Authority: CN
Inventors: 王定军; 刘玉亭; 付林; 李桂莲; 魏旭力
Original assignee: HUAZHONG PHARMACEUTICAL CO Ltd
Current assignee: HUAZHONG PHARMACEUTICAL CO Ltd
Priority date: 2016-11-07
Filing date: 2016-11-07
Publication date: 2017-04-26

Abstract

The invention relates to an improvement in a crystallization method of thiamine mononitrate. A traditional method comprises the following steps: mixing a crude nitric acid B1, namely, thiamine sulfate solution with an ammonium nitrate aqueous solution in a matched amount, then adding 20%-25% ammonia dropwise until the PH of the mixture reaches 7.2 to 7.5, performing cooling, and separating the solid-liquid mixture to obtain crystals of nitric acid B1. The invention relates to the improvement in the crystallization method of thiamine mononitrate, the mixing sequence and the proportion of three solutions (the thiamine sulfate solution, the ammonium nitrate solution and ammonia) are adjusted, the three solutions are mixed simultaneously, and accordingly, the crystal form of thiamine mononitrate is changed with adoption of the crystallization method. The crystallization method of thiamine mononitrate is improved to replace a traditional crystallization process, the crystal form of a product is changed from the original needle shape into a rod or ball shape, the product particles become larger, the bulk density increases, the packaging volume decreases, and great benefit is provided for reducing the transportation cost and the operating cost and improving the market competitiveness of the product.

Description

The method for crystallising of vitamin B1 thiamine nitrate

Technical field

The present invention relates to a kind of method for crystallising of medical compoundss, the specifically crystallization of vitamin B1 thiamine nitrate Method.

Background technology

Vitamin B1 is a kind of vitaminss ancillary drug, maintains normal sugar metabolism and nerve, digestive system function.For Prevent and treat the B that is deficient in vitamin₁Caused vitamin B1 deficiency, is also used for neuritiss, dyspeptic auxiliary treatment.

Vitamin B1 can be divided into two kinds of forms of hydrochlorate and nitrate, and the two mutually can convert, and be used equally to feedstuff and add Plus agent, food additive and pharmaceutical preparation.

Vitamin B1, also known as thiamine, is white crystal or crystalline powder, and its hydrochlorate is soluble in water, is slightly soluble in first Alcohol, ethanol, insoluble in ether, in sour environment, stability is preferable；Its nitrate is slightly soluble in water, methanol, ethanol, acid and It is unstable in alkaline environment, it is very stable in neutral conditions.

Current about 7500 tons of the annual demand of whole world vitamin B1, in China, high-end market is by European DSM for 80% production Manufacturer is monopolized, and its production technology is different from my domestic manufacturer, and its quality includes outward appearance crystal formation better than domestic production producer, Therefore domestic manufacturer is based on the production technology of oneself, the property of VB1 raw materials is studied, improve product quality and competitiveness seem very heavy Will.

For these reasons, the property of product must be studied by manufacturer, including outward appearance crystal formation is to improve product competitiveness One of key factor, this reduces cost of transportation for exploiting the overseas market, and improves the market competitiveness and has particularly significant meaning Justice.

With regard to vitamin b1 nitrate or the crystallization of hydrochlorate, foreign countries were studied early in 60～seventies of last century, Delivered by University Of Tianjin in the beginning of this century country《Thiamine mononitrate crystal habit constructs the research with precipitation process》Me is shown State payes attention to crystal presentation quality, but the crystallization of the finished products of different technique productions has differences, and is conventional acicular crystal, Crystal poor fluidity, heap density are little, and the market competitiveness is little.

Conventional thiamine nitrate method for crystallising step is：

The preparation of first step ammonium nitrate solution：To prevent from crystallizing under ammonium nitrate solution low temperature, now by a collection of of the amount of desired substance Ammonium nitrate is dissolved in more than 50 DEG C of purified water, with the aqueous ammonium nitrate solution of pump handle it is standby enter refining kettle in, carry out cooling make it is molten The temperature of liquid is in 20～25 DEG C.

Second mixing by sulfuric acid thiamine element solution：By thiamine nitrate intermediate --- the sulfuric acid thiamine of vitamin B1 Element is mixed with the ammonium nitrate solution of the first step in refining kettle through fine straining lauter tub sucking filtration.

Weak ammonia is mixed regulation pH value by the 3rd step with mixed liquor：Start after stirring fully mixed with second step mixed liquor, Prepare in advance 20～25% weak ammonia is slowly added dropwise, until pH value reaches 7.2, then cooling carries out solid-liquid separation.

The content of the invention

The purpose of the present invention is namely based on the production technology of domestic vitamin B1, has invented and has been different from vitamin b1 nitrate The preparation method of tradition crystallization.

The present invention relates to the improved method of the method for crystallising of vitamin b1 nitrate finished products comprises the following steps：

The first step mixes：The intermediate of thiamine nitrate that will decolourize to finish --- a collection of solution of sulfuric acid thiamine element with dissolved The aqueous ammonium nitrate solution of the amount of a collection of desired substance carries out being sufficiently mixed uniformly, and mixing temperature is controlled at 20～25 DEG C, mixing knot The control of above-mentioned mixed liquor keeping temperature is stored in standby in transfer container by beam at 20～25 DEG C.The temperature of aqueous ammonium nitrate solution is needed Highest is controlled according to the temperature requirement of thiamine solution and must not exceed 30 DEG C, will otherwise destroy unstable thiamine nitrate Intermediate.

Second mixing：The purified water that appropriate temperature is 20～25 DEG C is added in refining reaction kettle, to guarantee to refine The stirring of kettle can contact and can stir the purified water, open stirring, and rotating speed reaches 20r/min, takes vacuum, and the first step is standby With mixed liquor, Jing fine straining lauter tub suction refining kettles in the presence of vacuum, enter while opening and preparing 20～25% weak ammonia in advance Material valve, mixed liquor is quickly mixed with weak ammonia according to certain ratio, mixing temperature control at 20～25 DEG C, make mixed liquor and The weak ammonia of required adjustment pH value has simultaneously mixed, and makes the pH value of last mixed liquor be 6.7～7.0, then, lays down vacuum guarantor It is normal pressure to hold refining kettle, and it is 7.2～7.5 to make the pH value of mixed liquor with precision test paper fine setting.

3rd step decrease temperature crystalline：The chilled saline cooling of mixed liquor that acid-base value is mixed up, mixing speed are controlled in 20r/ Feed temperature is made under min, stirring up to less than 10 DEG C, you can obtain the granular crystal as fine sand, be ready for solid-liquid separation, Obtain thiamine mononitrate cellulose crystal.

Compared with the prior art, the present invention has advantages below：

1. the crystal of the vitamin B1 thiamine nitrate of present invention production whether feel or is bar-shaped or spherical soon Fine grained.

2. the heap density of the crystal finished product of the vitamin B1 thiamine nitrate of present invention production is up to 0.35～0.40g/ml, compared with The heap density of conventional crystallization finished products wants big 0.05～0.1g/ml.

3. the method for the crystal of the vitamin B1 thiamine nitrate of present invention production is that liquid mixing order is adjusted Whole change, has carried out strict control in the details such as temperature and stirring, does not increase complicated processes, production cost and input and routine Crystallization mode is than little.

Specific embodiment

For purposes of simplicity and clarity, the description of known conventional production process is hereafter rightly eliminated, in order to avoid those Unnecessary details affects the description to the technical program.

The present invention is illustrated with example below, these examples are intended to the technological means for helping understand the present invention.But It should be understood that these embodiments are exemplary, this is the invention is not limited in.

Embodiment 1

The first step mixes：Take the synthetic intermediate thiothiamine 380kg of vitamin B1（Scale）, about 3500kg is obtained by oxidation 90kg ammonium nitrates are put in the heating kettle for containing 80kg purified water in temporary storage tank by sulfuric acid thiamine element solution, and temperature is heated to 50 More than DEG C, it is completely dissolved ammonium nitrate, it is appropriate to lower the temperature, by ammonium nitrate solution addition sulfuric acid thiamine element solution in temporary storage tank Carry out being sufficiently mixed uniformly, mixing temperature is controlled at 20～25 DEG C, mixing terminates above-mentioned mixed liquor keeping temperature to be controlled 20 ～25 DEG C be stored in it is standby in transfer container.

Second mixing：The purified water that 100kg temperature is 20～25 DEG C is added in refining reaction kettle, to guarantee refining kettle Stirring can contact and can stir the purified water, open stirring, rotating speed is controlled in 20r/min, takes vacuum, and the first step is standby With mixed liquor, Jing fine straining lauter tub suction refining kettles in the presence of vacuum, enter while opening and preparing 20～25% weak ammonia in advance Material valve, according to mass ratio 45：Mixed liquor is quickly mixed by 1 ratio with weak ammonia, and mixing temperature is controlled at 20～25 DEG C, makes to mix The weak ammonia that liquid is closed with required adjustment pH value has mixed simultaneously, and the pH value of the mixed liquor is 6.7～7.0, then, lays down vacuum guarantor It is normal pressure to hold refining kettle, and it is 7.2～7.5 to make the pH value of mixed liquor with precision test paper fine setting.

3rd step decrease temperature crystalline：The chilled saline cooling of mixture that acid-base value is mixed up, controlling speed of agitator is 20r/min, feed temperature is up to less than 10 DEG C, you can obtains the granular crystal as fine sand, is ready for solid-liquid separation, obtains Thiamine mononitrate cellulose crystal.

Claims

1. a kind of method for crystallising of vitamin B1 thiamine nitrate, by adjusting three kinds of solution（Sulfuric acid thiamine element solution, ammonium nitrate Aqueous solution and ammonia）Order by merging and ratio reaches three kinds of solution while the crystalline substance for having mixed to change vitamin b1 nitrate The method for crystallising of type.

2. the method for crystallising of vitamin B1 thiamine nitrate according to claim 1, the order by merging of three kinds of solution are referred to It is first that sulfuric acid thiamine element solution is uniform with the aqueous solution of ammonium nitrate, then at the uniform velocity it is mixed into the desired amount of ammonia simultaneously Refining kettle is crystallized.

3. the method for crystallising of vitamin B1 thiamine nitrate according to claim 2, when three kinds of solution be mixed in proportion into After entering refining kettle, the pH value of mixed liquor reaches 6.7～7.0 requirement, and being then finely adjusted with ammonia makes the solution after crystallization PH value reaches 7.2～7.5 alkalescence.

4. the method for crystallising of vitamin B1 thiamine nitrate according to claim 1, sulfuric acid thiamine element solution and ammonium nitrate The mixing temperature of aqueous solution be 20～25 DEG C, the mixing of mixed liquor and the ammonia of sulfuric acid thiamine element solution and aqueous ammonium nitrate solution Temperature is 20～25 DEG C, and the temperature of decrease temperature crystalline is less than 10 DEG C.

5. the method for crystallising of vitamin B1 thiamine nitrate according to claim 1, sulfuric acid thiamine element solution and ammonium nitrate The mixing speed during mixing of the mixed liquor and ammonia of aqueous solution is 20r/min, and the mixing speed of decrease temperature crystalline is 20r/min.