CN104961740B - A kind of solid preparation containing riboflavin and preparation method thereof - Google Patents
A kind of solid preparation containing riboflavin and preparation method thereof Download PDFInfo
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- CN104961740B CN104961740B CN201510297198.9A CN201510297198A CN104961740B CN 104961740 B CN104961740 B CN 104961740B CN 201510297198 A CN201510297198 A CN 201510297198A CN 104961740 B CN104961740 B CN 104961740B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
- C07D475/14—Benz [g] pteridines, e.g. riboflavin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to a kind of solid preparation containing riboflavin, it is characterized in that comprising Riboflavin Tetrabutyrate 3.0 ~ 65.0 % by weight, thinner 18.0 ~ 65.0 % by weight, disintegrating agent 0.25 ~ 7.5 % by weight, tackiness agent 0.1 ~ 5.5 % by weight and lubricant 0.5 ~ 2.0 % by weight, the wherein spherulite of riboflavin to be particle diameter be 25-35 micron, purity is greater than 98%.Riboflavin in the present invention has that purity is high, the advantage of processing characteristics and good fluidity, and obtained solid preparation disintegration is rapid, and good stability.
Description
Technical field
The invention belongs to field of medicine preparations, particularly relate to a kind of solid preparation containing riboflavin and preparation method thereof.
Background technology
Riboflavin is also known as vitamins B
2(be called for short " VB
2"), be a kind of isoalloxazine derivative containing ribityl.VB
2based on nutrition use very extensive, in a large number for feed and foodstuffs industry, be only second to vitamin A, D, content can make feed at the product of 80%.Sometimes also use as tinting material in food, feed and pharmaceutical industry.It is a kind of water-soluble vitamins of needed by human.Riboflavin has physiological function widely, can synthesize in microorganism and higher plant body, animals and humans then can not, must absorb from food, thus one of six large indexs being classified as the growth of appraiser's bulk-growth and nutritional status by the World Health Organization (WHO), it all has important value in fields such as clinical treatment, feed manufacturing, foodstuffs industry and makeup manufactures.
Riboflavin is yellow to orange-yellow crystalline powder, has multiple different crystalline form, and shows different physical propertiess, typical VB
2crystalline form be yellow needles.Up to now, to produce and the VB that sells on market
2mostly be needle crystal, part is in very thin powder (being still needle crystal).The riboflavin processing characteristics extreme difference of this needle crystal, have the feature of not easily process and poor fluidity, bulk density is minimum, and these features make riboflavin not easily compressing tablet or hybrid process.Such as when processing riboflavin nutrient tablet, due to VB
2poor fluidity and destroy the processing characteristics of overall tablet, causes the mass distribution of riboflavin after film-making uneven.In order to overcome these difficulties, people process after often making riboflavin form particle with subsidiary again, improve its mobility and compressibility, and granulation process add riboflavin production cost and time, also reduce the purity of riboflavin.
At present, the production method of riboflavin mainly contains 4 kinds: plant materials extraction method, chemical synthesis, microbe fermentation method and half fermentable semi-chemical synthesis.Wherein, microbe fermentation method is the very cost-effective method of one grown up in recent years, and the riboflavin purity of producing can reach 98%, and compare with additive method, microbe fermentation method cost is low, pollutes few, is therefore day by day subject to the favor of world riboflavin manufacturer.BASF (BASF) company of Germany, Switzerland Roche (Roche) company and Hubei China Guanji medicine company mainly adopt Production by Microorganism Fermentation riboflavin.
Along with people's deepening continuously to riboflavin character and commercial process research, riboflavin quality standard is constantly upgraded, to improve constantly the quality product of riboflavin, riboflavin European Pharmacopoeia (EP8.0) British Pharmacopoeia (BP2010) in recent years, Chinese Pharmacopoeia (CP2010) both increases Related substances separation project, riboflavin Chinese Pharmacopoeia standard-required: riboflavin HPLC detects in solution if any impurity peaks, single impurity peak area must not be greater than three times (1.0%) of contrast solution impurity peak area, each impurity peak area and contrast solution main peak area 2.0% must not be greater than, riboflavin European Pharmacopoeia (EP8.0) British Pharmacopoeia (BP2010) standard-required, impurity A: 0.25 times (0.025%) being no more than main peak area in contrast solution (a) color atlas, impurity B, C, D: each impurity is no more than the twice (0.2%) of main peak area in contrast solution (a) color atlas, total assorted: 5 times (0.5%) being no more than main peak area in contrast solution (a) color atlas.According to standard control, riboflavin European Pharmacopoeia (EP8.0) British Pharmacopoeia (BP2010) standard requires more concrete to impurity, A impurity is 7, 8, 10-trimethylammonium-3, 10-dihydrobenzo pteridine-2, 4 diketone, B impurity is 7, 8,-dimethyl-2, 4-(1H, 3-H) diketone, C impurity is 6, 7-dimethyl-8[(2s, 3s, 4R)-2, 3, 4, 5-tetrahydroxy amyl group]-pteridine-2, 4 (3H, 8H) diketone, D impurity is 8-(methylol)-7-methyl isophthalic acid 0-[(2s, 3s, 4R)-2, 3, 4, 5-tetrahydroxy amyl group]-benzo pteridine-2, 4 (3H, 8H) diketone.Riboflavin European Pharmacopoeia (EP8.0) British Pharmacopoeia (BP2010) standard requires higher to limit of impurities simultaneously.For vitamins B
2requirement under European Pharmacopoeia EP8.0 version related substance item, we are to different manufacturers on domestic market, the vitamins B of different batches
2product detects according to European Pharmacopoeia EP8.0 standard-required, to find that there is under related substance item A, B, C, D and other impurity and total impurities and to be all above standard requirement.
In patent application CN1774438A, CN1275375A, CN1765898A, need the riboflavin of high level just can obtain granular core flavine crystal by acid-soluble and corresponding step.Such as, the preferred riboflavin initial content of method that patent application CN1774438A provides is 95-99%.The content of the riboflavin of the method choice that patent application CN1275375A provides is 97.2%.The content of the riboflavin of the method choice that patent application CN1765898A provides is 96%.The riboflavin starting raw material adopted in these patented technologies all requires higher content.
Patent application CN1774438A relates to improving one's methods of a kind of pure riboflavin of the B/C of preparation in granular form type.The preferred purity of the method is that the riboflavin of 97-99% is under 5-15 DEG C of condition, be the dissolving with hydrochloric acid of 18-28% by mass concentration, dissolution time 30-150 minute, because the method solvent temperature selects lower 5-15 DEG C, so the riboflavin of equal in quality needs more main solvent hydrochloric acid to dissolve, causing needing a large amount of water to precipitate riboflavin, adding the amount of cost and sewage disposal.
Patent application CN1275375A relates to a kind of novel method preparing the flowable riboflavin particle without powder adhesive-free, the method selects pure riboflavin content to be that 97.2% (HPLC) is as initial feed, dissolve with the hydrochloric acid of 24% under the condition of 22 DEG C, after add activated carbon treatment, hydrochloric acid riboflavin solution is obtained by membrane filtration, then by coutroi velocity, riboflavin hydrochloric acid is dropped into upper agitator, precipitation agent is dropped into lower agitator, crystallization when about 10 DEG C.This crystallisation process is wayward, and strict to equipment requirements, the grain diameter obtained is less, is not easy to filter, washing.
Patent application CN1765898A discloses a kind of solvent supersonic synergetic effect and prepares spherical crystal formation riboflavin method, the method be by purity be 96% needle crystal riboflavin be dissolved completely in main solvent, impose ul-trasonic irradiation 10-60min during precipitation.But, be that the riboflavin of 96% carries out dissolving not only adding cost again by purity in actual industrial production, and operating process becomes complicated.On the other hand, riboflavin in acid condition overlong time can increase new impurity, makes the requirement of product impurity not reach the contamination levels requirement of European Pharmacopoeia EP7.0.In addition, impose ul-trasonic irradiation in the industrial production, need to increase new equipment, make troubles to actual production, be difficult to realize.The method is not suitable for suitability for industrialized production.And what the method obtained is spheroidal particle riboflavin, and particle diameter is less, be not easy to filter, washing.
Patent CN1056845C discloses a kind of method of riboflavin purifying, the method is the method for recovery and purifying riboflavin meat soup after fermentation, the method is that meat soup after fermentation is first carried out pasteurization, again the meat soup after sterilizing is carried out one or many centrifugal, in embodiment actual be carry out repeatedly centrifugal, obtain the riboflavin of about 90% content, again the riboflavin of 90% content is added water, acid adding is incubated 60 minutes in 120-125 DEG C under mass concentration is 0.6% hydrochloric acid condition, obtain the riboflavin of substantive purity, this riboflavin generally has the purity of at least 96%.But, the method has following shortcoming: one, in order to obtain the riboflavin that content is at least 98%, need to carry out 3 times centrifugal, the solid ejecta obtained after once centrifugal before suspending with water of productive use before at every turn centrifugal, such operation steps is many, and process is complicated, also produce a large amount of waste water, add difficulty to follow-up sewage disposal.Its two, the sour room-temperature dissolution due to the method low concentration wets riboflavin, and make riboflavin overlong time under high temperature, acidic conditions, under causing riboflavin European Pharmacopoeia (EP8.0) version item, related substance B.C.D exceeds standard.This purification process is high temperature precipitation/nuclei of crystallization flavine simultaneously, and what obtain is a kind of needle crystal riboflavin.During crystallization, acid consumption is large, and Tc is high, and the consumption of separating out deionized water when separating out completely for making riboflavin is just large, adds follow-up sewage load, makes troubles to production.
Therefore, still need to study new riboflavin preparation method, the riboflavin that purity is higher to obtain, physico-chemical property is more excellent, make granulate or compressing tablet time processing characteristics and mobility better.
Summary of the invention
In order to overcome defect of the prior art, the invention provides a kind of new riboflavin preparation method, with the riboflavin that the method prepares, there is higher purity, and there is better processing characteristics and mobility.
The spherulite of riboflavin of the present invention to be particle diameter be 25-35 micron, purity is greater than 98%.Its preparation method comprises the steps:
(1), fermented liquid solid-liquid separation: by the metabolism cultivation in the medium of riboflavin-produced microorganism, obtain fermented liquid, then by fermented liquid centrifugation, obtain the riboflavin paste containing part thalline;
(2), filtration washing: riboflavin paste is pumped into plate filter by spiral pump and carries out filtering, washing, obtain needle-like riboflavin and to wet crude product, content is 60-80%, and water capacity is 50-70%;
(3), refining: the dissolving crude product that wet by needle-like riboflavin is that in the hydrochloric acid soln of 30-36%, solvent temperature is 60-80 DEG C in mass concentration, obtains riboflavin hydrochloric acid mixed solution;
(4), filter, crystallization: by riboflavin hydrochloric acid mixed solution after filtration or the insoluble solid impurity of centrifugal segregation, obtain not containing the yellow riboflavin hydrochloric acid mixed solution of solid impurity, when not stirring, the deionized water of 1/3-1/2 times of volume is added in this solution, leave standstill 1-2 hour, separate out spherical riboflavin crystal, continue the deionized water adding 8-10 times of volume, leave standstill 4-8 hour, filter and use deionized water wash filter cake, filter cake spraying dry being obtained the riboflavin of spheroidal.
In the preparation method of above-mentioned riboflavin spherulite, riboflavin-produced microorganism is subtilis.These microorganisms all can be used to the production of riboflavin of the present invention.Described substratum, for providing the defined medium of enough nutritional needs, comprises inorganic salt, sugar, nitrogenous material etc.The present invention, by Selective agar medium composition, significantly improves the yield of riboflavin.
The riboflavin that preparation method of the present invention obtains is spheroidal, has good physics and chemistry stability, and have excellent mobility and processing characteristics under regular storage conditions.The IR collection of illustrative plates of the riboflavin of this crystal formation carries out infrared scan at 400-4000cm-1 place, wherein 1732.48,1621.64,1648.40,1579.92,1546.52, there is characteristic peak (accompanying drawing spectrum) at the place such as 4505.16.1457.73cm-1.
Compared with prior art, the preparation method that the present invention is above-mentioned has following advantage:
1. the present invention directly centrifugal by a fermented liquid sedimentation, be separated, obtain wet riboflavin crude product after Plate Filtration.Simple to operate, owing to being mechanical separation completely when flash liberation, the degraded of riboflavin can not be caused, for quality product provides guarantee.
2. extract flow process short, greatly reduce the loss Sum decomposition of riboflavin in leaching process, make the extract yield of whole technique and quality product apparently higher than common level.Wet riboflavin content in crude product, at 60%-80%, wets crude product through the acid-soluble refining finished product riboflavin particle that just can be met requirement of a step by the riboflavin of method 60-80% content provided by the invention.
3. decrease sewage discharge, owing to eliminating alkali dissolution method, not only reduce extraction cost, and reduce intractability and the sewage quantity of sewage, for enterprise and society bring good economic benefit and social benefit.
4. the present invention adopts the spherical crystal lactochrome utilizing obtained by the method for crystallization control temperature and concentration to have excellent machinability, easily process and good fluidity, facilitates it apply, lifting riboflavin value of the product.
5. this process is compared with conventional junction crystal method, eliminates introducing crystal seed, and the steps such as grinding are simple to operate, reduce cost, shortens the cycle, improves the quality of products.
Further, present inventor finds, the riboflavin prepared with aforesaid method, due to profile rule, uniform particle diameter, has excellent mobility and processing characteristics, and dissolves very fast, after specific auxiliary material is selected, the solid dosage discharged immediately can be formulated as, such as granule, Tablet and Capsula agent etc., the physics and chemistry good stability of described solid preparation, and dissolve rapidly, riboflavin can be discharged fast.
Therefore, another aspect provides a kind of solid preparation containing riboflavin, it comprises Riboflavin Tetrabutyrate 3.0 ~ 65.0 % by weight, thinner 18.0 ~ 65.0 % by weight, disintegrating agent 0.25 ~ 7.5 % by weight, tackiness agent 0.1 ~ 5.5 % by weight and lubricant 0.5 ~ 2.0 % by weight, the wherein spherulite of riboflavin to be particle diameter be 25-35 micron, purity is greater than 98%.
Wherein, thinner is selected from starch, Microcrystalline Cellulose and lactose, and disintegrating agent is selected from hydroxypropylcellulose and croscarmellose sodium, and tackiness agent is selected from polyvinylpyrrolidone, water and ethanol, and lubricant is selected from micropowder silica gel and Magnesium Stearate.
Preferably, the present invention comprises following composition containing the solid dosage of riboflavin: riboflavin 31.5 ~ 55 % by weight, Microcrystalline Cellulose 22.0 ~ 60.5 % by weight, croscarmellose sodium 0.8 ~ 5.0 % by weight, 40% aqueous ethanolic solution 0.3 ~ 4.0 % by weight and micropowder silica gel 0.8 ~ 1.5 % by weight.
Solid dosage of the present invention is prepared by the preparation method of this area routine.But preferably adopt following method to prepare, the method comprising the steps of:
(1), make thinner, disintegrating agent crosses 80 ~ 100 mesh sieves, by riboflavin with sieve after thinner, disintegrating agent mix;
(2), in the powder mixed add tackiness agent, pinch softwood, cross 20 ~ 40 mesh sieves and granulate, dry, cross the whole grain of 40 mesh sieve;
(3), add lubricant, be filled in capsule after mixing or tabletted.
Accompanying drawing explanation
Fig. 1 is the IR collection of illustrative plates of riboflavin of the present invention, the riboflavin that preparation method of the present invention obtains is spheroidal, the IR collection of illustrative plates of the riboflavin of this crystal formation carries out infrared scan at 400-4000cm-1 place, wherein 1732.48,1621.64,1648.40,1579.92,1546.52, there is characteristic peak at the place such as 4505.16.1457.73cm-1.
Embodiment
Below by embodiment, the present invention is described in more detail, but these embodiments can not be interpreted as limitation of the present invention.
Embodiment 1: the preparation of riboflavin crystal of the present invention
(1), preparation method
Be separated through a centrifugal solid-liquid by 3000L Lactochrome fermentation liquor, the centrifugal RCF (relative centrifugal force) of whizzer is about 3000xg, obtains the 30-40L riboflavin heavy phase concentrated.Use spiral pump this riboflavin heavy phase to be pumped in plate filter to filter, and with 2000L deionized water wash riboflavin filter cake, obtain the wet riboflavin crude product that 100kg has 65.5% water capacity and 77% riboflavin purity.The hydrochloric acid soln of 120L36% is added in 3t retort, and in this hydrochloric acid soln, add 100kg to wet riboflavin crude product be heated to 70 DEG C, dissolve completely to riboflavin, from retort, extracting sample solution confirms the dissolving of riboflavin, 5kg gac is added again in this solution, be incubated 20 minutes, obtain a kind of riboflavin hydrochloric acid soln comparatively clarified, then 5kg flocculating aids is added, be in whipped state in the above process always, this mixture is carried out two-stage filtration by pressurized air, single filter is Plate Filtration, cascade filtration is acidproof secondary filter, and filtrate is collected in storage tank, after confirming do not have flocculating aids to pollute in filtrate further, filtrate in storage tank is proceeded to and separates out in tank, cool this solution to 30 DEG C, in this riboflavin hydrochloric acid mixed solution, add deionized water when not stirring and be about 80L, leave standstill this solution 2 hours, a large amount of riboflavin crystal seeds is had to separate out, sampling, examine under a microscope, obtain size distribution even, diameter is regular globose nucleus flavine crystal between 20-25um, continue to continue to add deionized water in the hydrochloric acid mixed solution of separating out spherical nucleus flavine crystal to separate out riboflavin crystal more completely, the amount that second time adds deionized water is 2000L, in order to not destroy this spheroidal, this riboflavin crystallization solution is filtered this solution by belt filter and uses about 800L deionized water drip washing filter cake, reach between 6.0-7.0 to washing water PH, collect filter cake, filter cake is joined in pulping device the about 50L that adds water to stir, obtain riboflavin slurries, these riboflavin slurries are pumped in centrifugal spray tower, control spray tower inlet temperature 190-200 DEG C, air outlet temperature 95-100 DEG C, collect about 40kg finished product riboflavin particle.
(2), the impurity analysis result of riboflavin
The riboflavin particle that aforesaid method is obtained carries out impurity analysis, the results are shown in Table 1.
The impurity analysis result of table 1 riboflavin
As can be seen from the data of table 1, in riboflavin of the present invention, the amount of impurities meets the requirement of pharmacopoeia of each country.
Embodiment 2: the preparation of riboflavin crystal of the present invention
(1), preparation method
Be separated through a centrifugal solid-liquid by 5000L Lactochrome fermentation liquor, the centrifugal RCF (relative centrifugal force) of whizzer is about 3200xg, obtains the 50-60L riboflavin heavy phase concentrated.Use spiral pump this riboflavin heavy phase to be pumped in plate filter to filter, and with about 2000L deionized water wash riboflavin filter cake, obtain the wet riboflavin crude product that about 150kg has 63.9% water capacity and 79% riboflavin purity.About 180L35.0% hydrochloric acid is added in 3t retort, and in this hydrochloric acid soln, add 150kg to wet riboflavin crude product be heated to 65 DEG C, dissolve completely to riboflavin, from retort, extracting sample solution confirms the dissolving of riboflavin, 10kg gac is added again in this solution, be incubated 20 minutes, obtain a kind of riboflavin hydrochloric acid soln comparatively clarified, then 9kg flocculating aids is added, be in whipped state in the above process always, this mixture is carried out two-stage filtration by pressurized air, single filter is Plate Filtration, cascade filtration is acidproof secondary filter, and filtrate is collected in storage tank, after confirming do not have flocculating aids to pollute in filtrate further, filtrate in storage tank is proceeded to and separates out in tank, cool this solution to 35 DEG C, in this riboflavin hydrochloric acid mixed solution, add deionized water when not stirring and be about 110L, leave standstill this solution 2 hours, a large amount of riboflavin crystal seeds is had to separate out, sampling, examine under a microscope, obtain size distribution even, diameter is regular globose nucleus flavine crystal between 20-25um, continue to continue to add deionized water in the hydrochloric acid mixed solution of separating out spherical nucleus flavine crystal to separate out riboflavin crystal more completely, the amount that second time adds deionized water is 2500L, in order to not destroy this spheroidal, this riboflavin crystallization solution is filtered this solution by belt filter and uses about 1000L deionized water drip washing filter cake, reach between 6.0-7.0 to washing water PH, collect filter cake, filter cake is joined in pulping device the about 80L that adds water to stir, obtain riboflavin slurries, these riboflavin slurries are pumped in centrifugal spray tower, control spray tower inlet temperature 190-200 DEG C, air outlet temperature 95-100 DEG C, collect about 70kg finished product riboflavin particle.
(2), the impurity analysis result of riboflavin
The riboflavin particle that aforesaid method is obtained carries out impurity analysis, the results are shown in Table 2.
The impurity analysis result of table 2 riboflavin
As can be seen from the data of table 2, in riboflavin of the present invention, the amount of impurities meets the requirement of pharmacopoeia of each country.
Embodiment 3: the present invention is containing the capsule of riboflavin
Bulk drug: the riboflavin 48 % by weight of embodiment 1 gained, Microcrystalline Cellulose 44.5 % by weight, croscarmellose sodium 1.5 % by weight, 40% aqueous ethanolic solution 2.0 % by weight, micropowder silica gel 1.0 % by weight and aspartame 3.0%.
Preparation method: make Microcrystalline Cellulose, croscarmellose sodium and aspartame cross 80 mesh sieves, add riboflavin to mix, 40% aqueous ethanolic solution is added in the powder mixed, pinch softwood, cross 20 mesh sieves to granulate, drying, crosses the whole grain of 40 mesh sieve, is filled in capsule and get final product after adding micropowder silica gel.
Embodiment 4: the present invention is containing the tablet of riboflavin
Bulk drug: the riboflavin 35 % by weight of embodiment 2 gained, starch 23%, lactose 32.6 % by weight, hydroxypropylcellulose 3.2 % by weight, 3% aqueous povidone solution 2.8 % by weight, Magnesium Stearate 1.2 % by weight, aspartame 1.8% and strawberry flavour 0.4%.
Preparation method: make starch, lactose, hydroxypropylcellulose, aspartame and strawberry flavour cross 100 mesh sieves, add riboflavin to mix, 3% aqueous povidone solution is added in the powder mixed, pinch softwood, cross 30 mesh sieves to granulate, drying, crosses 40 mesh sieve whole grain, tabletted and get final product after adding Magnesium Stearate.
Embodiment 5: the stability study of riboflavin crystal of the present invention
Investigate respectively riboflavin product (purchased from Hubei Ying Xin Chemical Co., Ltd.) in the riboflavin crystal that obtains of embodiment 1 and prior art store under high temperature (60 DEG C), high humidity (RH92%), hot and humid (40 DEG C, RH75%) after slope of repose (°), total impurities content contrasting, the results are shown in Table 3.
The stability correlation data of table 3 riboflavin crystal of the present invention and prior art products
As can be seen from the data of table 3, the slope of repose of riboflavin crystal of the present invention is less, and therefore mobility is better than prior art, and the stability under high temperature and/or high humidity is better than riboflavin powder of the prior art.
Embodiment 6: the solubility property research of riboflavin crystal of the present invention
By water-soluble the comparing of riboflavin product in the riboflavin crystal obtained in the embodiment of the present application 1 and prior art (purchased from Hubei Ying Xin Chemical Co., Ltd.), the results are shown in Table 4.
The water-soluble comparative data (n=20) of table 4 riboflavin of the present invention crystal and prior art riboflavin
| Sequence number | Inspection target | Prior art products | Product of the present invention |
| 1 | Sample weighting amount | 1.5g | 1.5g |
| 2 | Amount of water | 25ml | 25ml |
| 3 | Dissolution mechanism | Violent jolting | Common jolting |
| 4 | Dissolution time | 2.1 ± 0.4 minutes | 19 ± 1.1 seconds |
| 5 | Dissolved state | Wall of container hangs with a small amount of white point | Solution is clarified |
As can be seen from the data of table 4, the riboflavin crystal that the present invention prepares can be dissolved in the water rapidly through common jolting mode, dissolution time is far below prior art products, and the solubility property of the riboflavin crystal that explanation the inventive method prepares is significantly improved.
Embodiment 7: the study on the stability of solid preparation of the present invention
Respectively the riboflavin tablet of embodiment 4 is stored 10 days under high temperature (40 DEG C), high humidity (RH75%) state, the 5th day and sampling in the 10th day, detect by stability high spot reviews project, with 0 day results contrast.The results are shown in Table 5.
The high temperature of table 5 solid preparation of the present invention, high humidity stability data (n=3)
Result shows, riboflavin tablet of the present invention under high temperature 40 DEG C, high humidity RH75% condition, preparation in 10 days without noticeable change.
Claims (3)
1. the solid preparation containing riboflavin, it is characterized in that raw material packet contains riboflavin 31.5 ~ 55 % by weight, Microcrystalline Cellulose 22.0 ~ 60.5 % by weight, croscarmellose sodium 0.8 ~ 5.0 % by weight, 40% aqueous ethanolic solution 0.3 ~ 4.0 % by weight and micropowder silica gel 0.8 ~ 1.5 % by weight, the wherein spherulite of riboflavin to be particle diameter be 25-35 micron, purity is greater than 98%; The preparation method of riboflavin comprises following steps:
(1), fermented liquid solid-liquid separation: by the metabolism cultivation in the medium of riboflavin-produced microorganism, obtain fermented liquid, then by fermented liquid centrifugation, obtain the riboflavin paste containing part thalline, described riboflavin-produced microorganism is subtilis;
(2), filtration washing: riboflavin paste is pumped into plate filter by spiral pump and carries out filtering, washing, obtain needle-like riboflavin and to wet crude product, content is 60-80%, and water capacity is 50-70%;
(3), refining: the dissolving crude product that wet by needle-like riboflavin is that in the hydrochloric acid soln of 30-36%, solvent temperature is 60-80 DEG C in mass concentration, obtains riboflavin hydrochloric acid mixed solution;
(4), filter, crystallization: by riboflavin hydrochloric acid mixed solution after filtration or the insoluble solid impurity of centrifugal segregation, obtain not containing the yellow riboflavin hydrochloric acid mixed solution of solid impurity, when not stirring, the deionized water of 1/3-1/2 times of volume is added in this solution, leave standstill 1-2 hour, separate out spherical riboflavin crystal, continue the deionized water adding 8-10 times of volume, leave standstill 4-8 hour, filter and use deionized water wash filter cake, filter cake spraying dry being obtained the riboflavin of spheroidal.
2. solid preparation according to claim 1, is characterized in that for granule, tablet or capsule.
3. the preparation method of solid preparation according to claim 1, is characterized in that comprising following steps:
(1), make thinner, disintegrating agent crosses 80 ~ 100 mesh sieves, by riboflavin with sieve after thinner, disintegrating agent mix;
(2), in the powder mixed add tackiness agent, pinch softwood, cross 20 ~ 40 mesh sieves and granulate, dry, cross the whole grain of 40 mesh sieve;
(3), add lubricant, be filled in capsule after mixing or tabletted.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510297198.9A CN104961740B (en) | 2015-06-02 | 2015-06-02 | A kind of solid preparation containing riboflavin and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510297198.9A CN104961740B (en) | 2015-06-02 | 2015-06-02 | A kind of solid preparation containing riboflavin and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
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