Segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid

Abstract

The present invention discloses a segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid, comprising: dry-mixing ferric pyrophosphate with microcrystalline cellulose, hydroxypropyl methylcellulose and silicon dioxide to prepare preadsorbed granules; preparing a folic acid premix from folic acid, microcrystalline cellulose and silicon dioxide by an equal incremental method; preparing a water-soluble vitamin premix from water-soluble vitamins, directly compressible mannitol, microcrystalline cellulose and silicon dioxide; separately premixing fat-soluble vitamin microcapsule powders; then performing short-time total blending in a low-humidity environment, directly compressing powder into single-layer tablet cores and carrying out film coating. The method of the present invention can improve the mixing uniformity of trace folic acid and low-content components such as vitamin B12 in a composite vitamin and mineral single-layer tablet containing an iron source, and reduce the risks of content decrease and appearance spots during tablet storage.

Description

[0001] DESCRIPTION

[0002] Segmented Premixing Preparation Method for a Composite Vitamin and Mineral Single-Layer Tablet Containing Trace Folic Acid Technical Field

[0003] The present invention belongs to the technical field of nutritional supplement tablet preparation, and particularly relates to a segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid.

[0004] Background Art

[0005] Composite vitamin and mineral tablets usually contain water-soluble vitamins, fat-soluble vitamins, minerals and excipients, and are an important dosage form for daily supplementation of multiple vitamins and minerals. In such tablets, components such as folic acid and vitamin B12 are added in relatively low amounts (folic acid is generally only 0.3 -0.5 mg / tablet, and vitamin B12 is only 2-3 pg / tablet), and therefore are trace components; meanwhile, water-soluble vitamins such as vitamin C and vitamin Bl are also relatively prone to degradation under the influence of moisture, temperature, metal ions and the state of mixed contact. In iron- source-containing composite systems, fluctuations in the distribution of trace active components, decreases in content of some active components and surface color spots are more likely to occur during storage, which has become a long-standing technical problem in the field of preparing composite vitamin and mineral tablets.

[0006] Existing composite vitamin and mineral tablets are mostly prepared by direct blending of all powders, wet granulation, fluidized-bed granulation, dry granulation or multilayer tableting. The direct blending of all powders is simple to operate; however, because low-dose components such as folic acid and vitamin B12 are difficult to disperse uniformly in a large amount of excipients, insufficient mixing uniformity tends to occur, resulting in large differences in content among tablets. Although wet granulation helps improve powder flowability, it introduces moisture and a drying heat process, which is unfavorable to the stability of heat-sensitive and moisture- sensitive vitamins such as folic acid and vitamin C. Although multilayer tableting can reduce direct contact between some components, the process is relatively complex and is not conducive to direct implementation on an ordinary single-layer tablet production line. In addition, there have been attempts in the prior art to prepare folic acid and iron-containing compounds by wet granulation; however, the moisture introduced by wet granulation and the heating and drying process still adversely affect the stability of active components.

[0007] Therefore, it is necessary to provide a preparation method suitable forDESCRIPTION

[0008] single-layer tablets, which, without using wet granulation or multilayer tableting, enables low-content components such as trace folic acid and vitamin B12 to have good mixing uniformity through segmented premixing, short-time total blending and low-moisture control, while reducing the risk of content decrease and appearance color spots in an iron-source-containing composite vitamin and mineral system during storage.

[0009] Summary of the Invention

[0010] In order to overcome the above defects of the prior art, the present invention provides a segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid, which solves the problems in the prior art that, in a coexistence system containing an iron source, trace folic acid and multiple vitamins, the mixing uniformity of trace active components is insufficient, and the contents of some active components decrease and appearance color spots occur during storage.

[0011] To achieve the above purpose, the present invention provides the following technical solution:

[0012] A segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid comprises the following steps:

[0013] (1) Dry-mixing ferric pyrophosphate, microcrystalline cellulose, hydroxypropyl methylcellulose and silicon dioxide at a weight ratio of 100:40-55:5-8:3-5 to prepare ferric pyrophosphate preadsorbed granules as a first premix;

[0014] (2) Mixing folic acid, microcrystalline cellulose and silicon dioxide at a weight ratio of 1:120-160:5-8 by an equal incremental method to prepare a folic acid premix as a second premix;

[0015] (3) Mixing vitamin C, vitamin Bl, vitamin B2, vitamin B6, vitamin B12, nicotinamide, D-calcium pantothenate and biotin with directly compressible mannitol, microcrystalline cellulose and silicon dioxide at a weight ratio of total water-soluble vitamins: directly compressible mannitol: microcrystalline cellulose: silicon dioxide of 100:60-100:30-60:3-5 to prepare a water-soluble vitamin premix as a third premix;

[0016] (4) Mixing vitamin A acetate microcapsule powder, vitamin D3 microcapsule powder and vitamin E acetate powder with microcrystalline cellulose and silicon dioxide to prepare a fat- soluble vitamin premix as a fourth premix;

[0017] (5) In an environment with a relative humidity not higher than 35%, pre-total-blending the four premixes obtained in steps (1) to (4) with zinc citrate,DESCRIPTION

[0018] selenium yeast, the remaining microcrystalline cellulose, the remaining directly compressible mannitol, the remaining silicon dioxide and croscarmellose sodium at 12-18 rpm for 6-9 minutes, and then adding magnesium stearate and mixing for 1-3 minutes to obtain a total blend having a moisture content not higher than 3.0%;

[0019] (6) Directly compressing the total blend powder into single-layer tablet cores having a moisture content not higher than 3.0%;

[0020] (7) Film-coating the single-layer tablet cores to obtain the composite vitamin and mineral single-layer tablet.

[0021] Preferably, the ferric pyrophosphate preadsorbed granules obtained in step (1) have a moisture content not higher than 2.8% and a D50 particle size of 120-200 pm.

[0022] Preferably, the dry mixing in step (1) lasts 8-15 minutes.

[0023] Preferably, the folic acid premix obtained in step (2) has a moisture content not higher than 2.5%, and the premixing time is 10-15 minutes.

[0024] Preferably, the water-soluble vitamin premix obtained in step (3) has a moisture content not higher than 2.8%, and the premixing time is 8-12 minutes.

[0025] Preferably, in step (4), the weight ratio of total fat-soluble vitamins to microcrystalline cellulose to silicon dioxide is 100:50-70:3-5.

[0026] Preferably, the total blend obtained in step (5) has a moisture content of 2.3-3.0%.

[0027] Preferably, the single-layer tablet core has a weight of 760-860 mg, a hardness of 75-110 N, a friability not higher than 1.0%, and a disintegration time limit not exceeding 30 minutes.

[0028] Preferably, in step (7), the weight gain of film coating is 2.0-3.0%, the coating inlet air temperature is 38-45°C, and the tablet bed temperature is 32-38°C.

[0029] Preferably, each single-layer tablet core contains per tablet: vitamin C 50-60 mg, vitamin E acetate powder 15-25 mg, vitamin A acetate microcapsule powder 3-5 mg, vitamin D3 microcapsule powder 5-7 mg, vitamin Bl 0.9-1.3 mg, vitamin B2 0.9-1.3 mg, vitamin B6 1.0-1.6 mg, vitamin B12 2-3 pg, nicotinamide 10-14 mg, D-calcium pantothenate 4-6 mg, biotin 20-40 pg, folic acid 0.30-0.50 mg, ferric pyrophosphate 20-30 mg, zinc citrate 18-22 mg and selenium yeast 18-22 mg.

[0030] Technical effects and advantages of the segmented premixing preparation method for the composite vitamin and mineral single-layer tablet containing trace folic acid according to the present invention are as follows:

[0031] 1. In the present invention, folic acid is separately premixed by an equal incremental method, which is conducive to improving content uniformity ofDESCRIPTION

[0032] low-content folic acid in the total blend and tablets. Experimental data show that the RSD of folic acid content in the total blend of the examples of the present invention can be as low as 3.9%, and the RSD of folic acid content in the tablets can be as low as 4.8%, which is significantly better than comparative examples involving direct mixing or not using equal incremental premixing.

[0033] 2. In the present invention, ferric pyrophosphate is prepared into preadsorbed granules, which can reduce direct contact between the iron source and folic acid and some water-soluble vitamins during the premixing stage, reduce the catalytic degradation effect of iron ions on sensitive components, and help improve content stability of the product during storage.

[0034] 3. In the present invention, a low-humidity environment (relative humidity not higher than 35%), short-time total blending (6-9 minutes) and powder direct compression are adopted, thereby avoiding the introduction of moisture and a drying heat process by wet granulation and effectively protecting heat- sensitive and moisture-sensitive active components such as folic acid and vitamin C. Experimental data show that, under accelerated conditions, the folic acid retention rate in the examples of the present invention can reach more than 84%, and the vitamin C retention rate can reach more than 82%, which is significantly better than those of the comparative examples.

[0035] 4. In the present invention, fat-soluble vitamin microcapsule powders are premixed and a single-layer film coating is applied, which is conducive to tablet appearance stability and finished product storage, and effectively reduces the risk of color spots during tablet storage.

[0036] Brief Description of the Drawings

[0037] FIG. 1 is a flowchart of the segmented premixing preparation method for the composite vitamin and mineral single-layer tablet containing trace folic acid proposed by the present invention.

[0038] Specific Embodiments

[0039] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some, rather than all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by a person of ordinary skill in the art without creative labor shall fall within the protection scope of the present invention.

[0040] It should be noted that, in this document, relational terms such as first and second are used only to distinguish one entity or operation from another entity orDESCRIPTION

[0041] operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms comprise, include or any other variants thereof are intended to cover non-exclusive inclusion, such that a process, method, article or device comprising a series of elements includes not only those elements, but also other elements not explicitly listed, or also elements inherent to such process, method, article or device. Without further limitation, an element defined by a statement comprising the element does not exclude the existence of other identical elements in the process, method, article or device that comprises the element.

[0042] The present invention is further described below with reference to examples. The raw materials and excipients used in the examples may all be corresponding-grade raw materials acceptable for food or nutritional supplement production. Unless otherwise specified, the parts or contents are by weight.

[0043] Moisture was determined by Karl Fischer titration. The contents of folic acid, vitamin C, vitamin Bl, vitamin D3 and vitamin B12 were determined by a methodologically validated high-performance liquid chromatography method or another corresponding applicable detection method. In the mixing uniformity test, after completion of total blending, 10 samples were taken from different positions of the mixing equipment, the contents of target components were determined, and the relative standard deviation (RSD) was calculated. In the tablet content uniformity test, 20 tablets were randomly sampled, the contents of target components were determined, and the relative standard deviation was calculated.

[0044] In the present invention, the specific operation steps of mixing by the equal incremental method are as follows: weighing the formula amounts of folic acid and microcrystalline cellulose, placing folic acid and an equal amount of microcrystalline cellulose in a mixer and mixing uniformly, then adding microcrystalline cellulose in an amount equal to the current mixture and continuing to mix uniformly, repeating the above operation until all microcrystalline cellulose is added, and finally adding the formula amount of silicon dioxide and mixing uniformly to obtain the folic acid premix. The mixing time in each of the above steps is subject to visually observed uniformity.

[0045] The accelerated stability test conditions were 40°C±2°C and relative humidity 75%±5%, with storage for 3 months. The retention rate was calculated as the ratio of the content after the test to the initial content. Appearance color spots were observed and recorded on tablets from the same batch against a white background.

[0046] Example 1

[0047] A composite vitamin and mineral single-layer tablet with a tablet core weightDESCRIPTION

[0048] of 800 mg was prepared according to the formula shown in Table 1.

[0049] TABLE 1 Formula of the tablet core in Example 1

[0050] AMOUNT COMPONENT

[0051] (MG / TABLET) Vitamin C 55.000 Vitamin E acetate powder 20.000 Vitamin A acetate microcapsule powder 4.000 Vitamin D3 microcapsule powder 6.000 Vitamin Bl 1.100 Vitamin B2 1.100 Vitamin B6 1.300 Vitamin B12 0.002 Nicotinamide 12.000

[0052] D-Calcium pantothenate 5.000 Biotin 0.030

[0053] Folic acid 0.400 Ferric pyrophosphate 24.000 Zinc citrate 20.000 Selenium yeast 20.000 Microcrystalline cellulose 205.013 Directly compressible mannitol 376.734 Hydroxypropyl methylcellulose 1.440 Silicon dioxide 12.881 Croscarmellose sodium 30.000 Magnesium stearate 4.000 Total 800.000

[0054]

[0055] The preparation steps were as follows:DESCRIPTION

[0056] Ferric pyrophosphate 24.000 mg / tablet, microcrystalline cellulose 10.800 mg / tablet, hydroxypropyl methylcellulose 1.440 mg / tablet and silicon dioxide 0.960 mg / tablet were weighed and dry-mixed for 12 minutes, and then passed through a 60-mesh sieve to prepare ferric pyrophosphate preadsorbed granules; the preadsorbed granules had a moisture content of 2.4% and a D50 particle size of 158 pm.

[0057] Folic acid 0.400 mg / tablet, microcrystalline cellulose 56.000 mg / tablet and silicon dioxide 2.400 mg / tablet were weighed and mixed by the equal incremental method for 12 minutes to prepare a folic acid premix; the folic acid premix had a moisture content of 2.2%.

[0058] Vitamin C, vitamin Bl, vitamin B2, vitamin B6, vitamin B12, nicotinamide, D-calcium pantothenate and biotin were weighed and mixed with directly compressible mannitol 60.426 mg / tablet, microcrystalline cellulose 30.213 mg / tablet and silicon dioxide 3.021 mg / tablet for 10 minutes to prepare a water-soluble vitamin premix; the water-soluble vitamin premix had a moisture content of 2.5%.

[0059] Vitamin A acetate microcapsule powder, vitamin D3 microcapsule powder and vitamin E acetate powder were weighed and mixed with microcrystalline cellulose 18.000 mg / tablet and silicon dioxide 1.200 mg / tablet for 8 minutes to prepare a fat-soluble vitamin premix.

[0060] Under the condition of ambient relative humidity of 32%, the above four premixes, zinc citrate, selenium yeast, the remaining microcrystalline cellulose, the remaining directly compressible mannitol, the remaining silicon dioxide and croscarmellose sodium were added to a mixer, pre-total -blended at 15 rpm for 8 minutes, and then magnesium stearate was added and mixed for 2 minutes to obtain a total blend; the total blend had a moisture content of 2.6%.

[0061] The total blend powder was directly compressed into single-layer tablet cores, wherein the tablet core weight was 800 mg, the tablet core moisture content was 2.6%, the hardness was 92 N, the friability was 0.31%, and the disintegration time limit was 18 minutes. A gastric-soluble film-coating premix was used for coating, the coating inlet air temperature was 42°C, the tablet bed temperature was 35°C, and the coating weight gain was 2.5%, thereby obtaining the composite vitamin and mineral single-layer tablet.

[0062] Example 2

[0063] Tablets were prepared according to the method of Example 1, except that calcium carbonate 120 mg / tablet and magnesium oxide 35 mg / tablet were additionally added to the tablet cores, and the amounts of directly compressibleDESCRIPTION

[0064] mannitol and microcrystalline cellulose were correspondingly reduced, with the tablet core weight adjusted to 900 mg. The pre-total blending time was 8 minutes, the moisture content of the total blend was 2.7%, the hardness of the tablet cores was 98 N, the disintegration time limit was 22 minutes, and the coating weight gain was 2.4%.

[0065] Example 3

[0066] Tablets were prepared according to the method of Example 1 , except that the weight ratio of ferric pyrophosphate, microcrystalline cellulose, hydroxypropyl methylcellulose and silicon dioxide in the ferric pyrophosphate preadsorbed granules was 100:55:8:5; the weight ratio of folic acid, microcrystalline cellulose and silicon dioxide in the folic acid premix was 1:160:8; and the weight ratio of total water-soluble vitamins, directly compressible mannitol, microcrystalline cellulose and silicon dioxide in the water-soluble vitamin premix was 100:100:60:5. The pre-total blending time was 9 minutes, the moisture content of the total blend was 2.8%, the hardness of the tablet cores was 101 N, and the disintegration time limit was 21 minutes.

[0067] Comparative Example 1

[0068] Tablets were prepared according to the formula of Example 1, except that segmented premixing was not performed, and ferric pyrophosphate, folic acid, water-soluble vitamins, fat-soluble vitamin microcapsule powders, minerals and excipients were added into a mixer at one time, total-blended for 15 minutes, then directly compressed from powder and coated.

[0069] Comparative Example 2

[0070] Tablets were prepared according to the formula of Example 1, except that folic acid was not premixed by the equal incremental method, but was directly added to the water-soluble vitamin premixing step together with the remaining water-soluble vitamins.

[0071] Comparative Example 3

[0072] Tablets were prepared according to the formula of Example 1 , except that the pre-total blending time was extended to 20 minutes, with the total blending speed being 15 rpm.

[0073] Comparative Example 4

[0074] Tablets were prepared according to the formula of Example 1, except that ferric pyrophosphate was replaced with an equivalent iron amount of ferrous fumarate, and all active components were directly mixed and then directly compressed from powder.

[0075] Comparative Example 5DESCRIPTION

[0076] Tablets were prepared according to the formula and segmented premixing method of Example 1 , except that the relative humidity of the pre-total blending and tableting environment was controlled at 60%, and the other process parameters remained unchanged.

[0077] Test results:

[0078] The mixing uniformity, tablet content uniformity and accelerated stability of the materials or tablets obtained in Examples 1-3 and Comparative Examples 1-5 were tested. The results are shown in Table 2 and Table 3.

[0079] TABLE 2 Results of mixing uniformity and inter-tablet content uniformity TOTAL BLEND TOTAL BLEND TABLET TABLET SAMPLE FOLIC ACID VIT. B12 FOLIC ACID VIT. Bl 2

[0080] RSD (%) RSD (%) RSD (%) RSD (%) Example 1 3.9 4.6 4.8 5.3

[0081] Example 2 4.1 4.8 5.0 5.5

[0082] Example 3 4.4 5.0 5.3 5.8 Comparative

[0083] 9.1 10.8 11.3 12.0

[0084] Example 1

[0085] Comparative

[0086] 8.4 9.7 10.6 11.4

[0087] Example 2

[0088] Comparative

[0089] 5.4 6.2 6.8 7.2

[0090] Example 3

[0091] Comparative

[0092] 8.2 9.4 10.1 10.8

[0093] Example 4

[0094] Comparative

[0095] 4.2 4.9 5.1 5.6

[0096] Example 5

[0097]

[0098] TABLE 3 Results of accelerated stability test

[0099] FOLIC ACID VIT. C VIT. Bl VIT. D3

[0100] SAMPLE APPEAR.

[0101] RET. (%) RET. (%) RET. (%) RET. (%)

[0102] No obvious brown Example 1 85.1 83.7 85.4 87.2

[0103] spots

[0104]

[0105] DESCRIPTION

[0106] FOLIC ACID VIT. C VIT. Bl VIT. D3

[0107] SAMPLE APPEAR.

[0108] RET. (%) RET. (%) RET. (%) RET. (%)

[0109] No obvious brown Example 2 84.3 82.9 84.8 86.4

[0110] spots

[0111] No obvious brown Example 3 84.0 82.6 84.2 86.0

[0112] spots Comparative

[0113] 76.5 74.8 78.1 82.0 Slight brown spots Example 1

[0114] Comparative

[0115] 75.1 73.9 77.5 81.6 Slight brown spots Example 2

[0116] Comparative

[0117] 80.2 78.6 81.3 84.2 Slight color spots Example 3

[0118] Comparative Obvious brown 72.8 72.4 76.8 80.5

[0119] Example 4 spots Comparative

[0120] 78.9 76.2 80.0 82.1 Slight brown spots Example 5

[0121]

[0122] As can be seen from Table 2, the content RSDs of folic acid and vitamin B12 in Examples 1-3 were significantly lower than those in Comparative Example 1 (direct mixing), Comparative Example 2 (folic acid was not separately premixed by the equal incremental method) and Comparative Example 4 (iron source replacement and direct mixing), indicating that the separate equal incremental premixing of folic acid and the segmented premixing process are conducive to improving the distribution uniformity of low-content components in the total blend and tablets. Although the content uniformity of Comparative Example 3 was improved compared with direct mixing, it was still inferior to that of Example 1 , indicating that the combination of an appropriate total blending time and segmented premixing has a better effect. In Comparative Example 5, which was prepared under relatively high ambient humidity, the mixing uniformity changed little, indicating that the segmented premixing process itself has a certain tolerance to humidity.

[0123] As can be seen from Table 3, under accelerated conditions, the retention rates of folic acid, vitamin C, vitamin Bl and vitamin D3 in Examples 1-3 were significantly higher than those in Comparative Examples 1, 2 and 4, and the tablets had no obvious brown spots. This indicates that, by preadsorbing ferricDESCRIPTION

[0124] pyrophosphate, the present invention effectively reduces contact between the iron source and sensitive vitamin components and the catalytic degradation effect. In Comparative Example 3, because the pre-total blending time was relatively long (20 minutes), the opportunity for degradation of active components during mixing was increased, color spots on the tablet appearance increased, and the retention rates of main active components were lower than those in Example 1. In Comparative Example 5, which was prepared under relatively high ambient humidity (60%), although the mixing uniformity changed little, the retention rates of folic acid and vitamin C after accelerated storage were significantly reduced and slight brown spots appeared, indicating that low-humidity environmental control has an important influence on finished product appearance and content retention.

[0125] The above results show that, by combining ferric pyrophosphate preadsorption, equal incremental premixing of trace folic acid, water-soluble vitamin premixing, fat-soluble vitamin microcapsule powder premixing, low-humidity short-time total blending and powder direct compression, the present invention can significantly improve the mixing uniformity of trace components in single-layer tablets and effectively reduce the risk of content decrease and appearance color spots during storage of iron- source-containing composite vitamin and mineral tablets.

[0126] The composite vitamin and mineral single-layer tablet of the present invention can be used for production of nutritional supplement tablets. The above examples are used to illustrate the technical solutions of the present invention, and the batches of relevant raw materials and excipients, equipment models and production scale may be adjusted correspondingly without departing from the technical solution defined by the claims.

[0127] The above are only specific embodiments of the present application, and the protection scope of the present application is not limited thereto. Any change or replacement that can be readily conceived by a person skilled in the art within the technical scope disclosed in the present application shall be included in the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the protection scope of the claims.

[0128] Finally, the above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

CLAIMS1. A segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid, characterized by comprising the following steps:(1) Dry-mixing ferric pyrophosphate, microcrystalline cellulose, hydroxypropyl methylcellulose and silicon dioxide at a weight ratio of 100:40-55:5-8:3-5 to prepare ferric pyrophosphate preadsorbed granules as a first premix;(2) Mixing folic acid, microcrystalline cellulose and silicon dioxide at a weight ratio of 1:120-160:5-8 by an equal incremental method to prepare a folic acid premix as a second premix;(3) Mixing vitamin C, vitamin Bl, vitamin B2, vitamin B6, vitamin B12, nicotinamide, D-calcium pantothenate and biotin with directly compressible mannitol, microcrystalline cellulose and silicon dioxide at a weight ratio of total water-soluble vitamins: directly compressible mannitol: microcrystalline cellulose: silicon dioxide of 100:60-100:30-60:3-5 to prepare a water-soluble vitamin premix as a third premix;(4) Mixing vitamin A acetate microcapsule powder, vitamin D3 microcapsule powder and vitamin E acetate powder with microcrystalline cellulose and silicon dioxide to prepare a fat- soluble vitamin premix as a fourth premix;(5) In an environment with a relative humidity not higher than 35%, pre-total-blending the four premixes obtained in steps (1) to (4) with zinc citrate, selenium yeast, the remaining microcrystalline cellulose, the remaining directly compressible mannitol, the remaining silicon dioxide and croscarmellose sodium at 12-18 rpm for 6-9 minutes, and then adding magnesium stearate and mixing for 1-3 minutes to obtain a total blend having a moisture content not higher than 3.0%;(6) Directly compressing the total blend powder into single-layer tablet cores having a moisture content not higher than 3.0%;(7) Film-coating the single-layer tablet cores to obtain the composite vitamin and mineral single-layer tablet.

2. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1 , characterized in that the ferric pyrophosphate preadsorbed granules obtained in step (1) have a moisture content not higher than 2.8% and a D50 particle size of 120-200 pm.

3. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1, characterized in that the dry mixing in step (1) lasts 8-15 minutes.CLAIMS4. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1, characterized in that the folic acid premix obtained in step (2) has a moisture content not higher than 2.5%, and the premixing time is 10-15 minutes.

5. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1 , characterized in that the water-soluble vitamin premix obtained in step (3) has a moisture content not higher than 2.8%, and the premixing time is 8-12 minutes.

6. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1, characterized in that, in step (4), the weight ratio of total fat-soluble vitamins to microcrystalline cellulose to silicon dioxide is 100:50-70:3-5.

7. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1, characterized in that the total blend obtained in step (5) has a moisture content of 2.3-3.0%.

8. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1, characterized in that the single-layer tablet core has a weight of 760-860 mg, a hardness of 75-110 N, a friability not higher than 1.0%, and a disintegration time limit not exceeding 30 minutes.

9. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1, characterized in that, in step (7), the weight gain of film coating is 2.0-3.0%, the coating inlet air temperature is 38-45°C, and the tablet bed temperature is 32-38°C.

10. The segmented premixing preparation method for a composite vitamin and mineral single-layer tablet containing trace folic acid according to claim 1, characterized in that each single-layer tablet core contains per tablet: vitamin C 50-60 mg, vitamin E acetate powder 15-25 mg, vitamin A acetate microcapsule powder 3-5 mg, vitamin D3 microcapsule powder 5-7 mg, vitamin Bl 0.9-1.3 mg, vitamin B2 0.9-1.3 mg, vitamin B6 1.0-1.6 mg, vitamin B12 2-3 pg, nicotinamide 10-14 mg, D-calcium pantothenate 4-6 mg, biotin 20-40 pg, folic acid 0.30-0.50 mg, ferric pyrophosphate 20-30 mg, zinc citrate 18-22 mg and selenium yeast 18-22 mg.

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