Folic acid tablet with low oxidation impurity content and preparation method of folic acid tablet

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a folic acid tablet with low oxidation impurities and a preparation method thereof, and discloses the folic acid tablet with low oxidation impurities, which comprises the following components: a mixture of folic acid and an antioxidant, a porous starch; wherein the mass ratio of the mixture of the folic acid and the antioxidant to the porous starch is (1-2): (3-4); the mass ratio of the folic acid to the antioxidant is 1: (1-3); the invention discloses a folic acid tablet with low oxidation impurities and a preparation method thereof, folic acid and an antioxidant tert-butylhydroquinone are mixed and crushed together, the folic acid can be fully wrapped by the antioxidant, oxidation of the folic acid is prevented or delayed, the particle size D90 of the mixture is controlled to be less than 5 [mu] m, then the mixture is fully mixed with porous starch, and the folic acid tablet with low oxidation impurities is prepared. By utilizing the porosity of the porous starch, the folic acid and the antioxidant can be adsorbed in concave holes of the porous starch, and meanwhile, the contact of the folic acid with oxygen and light is reduced, so that the generation of oxidized impurities in the long-term placement process is reduced.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a folic acid tablet with low oxidative impurities and a preparation method thereof. Background Art

[0002] Folic acid, chemical name is N-[4-[(2-amino-4-oxo-1,4-dihydro-6-pterygium)methylamino]benzoyl]. The chemical structure is as follows: Folic acid is an essential B vitamin for the human body, also known as vitamin B9. It is closely related to important biochemical processes in the human body and plays a key role in cell proliferation, regulation of gene activity, erythropoiesis, cardiovascular system and skin and mucous membrane renewal. It is used to prevent congenital neural tube defects of the fetus. Women should take appropriate folic acid supplements in the early stages of pregnancy.

[0003] The inventors found that folic acid has poor stability and is very sensitive to temperature and humidity. The shelf life of the reference preparation is only 18 months, which brings difficulties and inconvenience to storage and transportation. Through the stability experiment of the reference preparation, it was found that the impurities detected in the accelerated experiment with a relative retention time of about 4.5 times that of folic acid increased significantly, and exceeded the identification threshold of 0.2% of the preparation. The ICH guidelines indicate that the amount of impurities above this limit has reached the limit that may cause harm to the human body. Therefore, the structure of the impurity was confirmed and the impurity was identified as an oxidized impurity of folic acid.

[0004] Oxidized impurity of folic acid, molecular weight 455.38, molecular formula C 19 H 17 N7O7, chemical structure is as follows: Oxidized impurities (Folic acid impurities 40) Therefore, there is an urgent need for a preparation process that can improve the stability of folic acid tablets and control the growth of oxidative impurities during long-term storage. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present application provides a folic acid tablet with low oxidative impurities and a preparation method thereof, aiming to effectively reduce the generation of oxidative impurities during the long-term storage of folic acid tablets and improve the stability of the drug.

[0006] In a first aspect, the present application provides a pharmaceutical composition, which adopts the following technical solution: A pharmaceutical composition comprising the following components: a blend of folic acid and antioxidants; porous starch; Wherein, the mass ratio of the mixture of folic acid and antioxidant to the porous starch is (1-2):(3-4); The mass ratio of folic acid to antioxidant is 1:(1-3).

[0007] Preferably, the particle size D90 of the mixture of folic acid and antioxidant is less than 5 μm.

[0008] Preferably, the antioxidant is tert-butylhydroquinone.

[0009] In the present application, the raw materials are improved and tert-butylhydroquinone is added as an antioxidant. The added tert-butylhydroquinone can provide hydrogen free radicals, which can combine with free radicals to block oxidation reactions, thereby protecting folic acid from oxidation.

[0010] In the present application, the raw materials are improved and porous starch is added as a filler. By utilizing the porosity of the porous starch, folic acid and the antioxidant tert-butylhydroquinone can be adsorbed in the concave pores of the porous starch, while reducing the contact of folic acid with oxygen and light, thereby reducing the generation of oxidative impurities during long-term storage.

[0011] In the present application, the particle size of the mixture of folic acid and antioxidants is limited, and the particle size D90 of the mixture is controlled to be less than 5 μm, so that the raw materials can be better embedded in the concave pores of the porous starch.

[0012] In a second aspect, the present application provides a folic acid tablet with low oxidative impurities, which adopts the following technical solution: A folic acid tablet with low oxidative impurities comprises the above-mentioned pharmaceutical composition and pharmaceutically acceptable excipients.

[0013] Preferably, the pharmaceutically acceptable excipients include microcrystalline cellulose and magnesium stearate.

[0014] Preferably, the mass ratio of microcrystalline cellulose to folic acid is (8-12):1.

[0015] Preferably, the mass ratio of magnesium stearate to folic acid is (0.1-0.3):1.

[0016] By adopting the above technical solution, microcrystalline cellulose is selected as a filler and magnesium stearate is selected as a lubricant in the present application, and the added auxiliary materials are further mixed with the raw materials, thereby effectively improving the comprehensive performance of the folic acid tablets.

[0017] In a third aspect, the present application provides a method for preparing a folic acid tablet with low oxidative impurities, using the following technical solution: A method for preparing a folic acid tablet with low oxidative impurities, the preparation steps are as follows: (1) Weigh the raw materials of folic acid tablets according to the prescribed amount; (2) folic acid and tert-butylhydroquinone are mixed and then subjected to air flow milling to obtain a mixture of folic acid and tert-butylhydroquinone; (3) mixing the folic acid and tert-butylhydroquinone mixture with porous starch; (4) adding microcrystalline cellulose to the mixture prepared in step (3) and mixing, and then adding magnesium stearate and mixing to obtain a total mixed granule; (5) Compressing the total mixed granules into tablets to obtain folic acid tablets.

[0018] Preferably, in the step (2), after air flow pulverization, the particle size D90 of the obtained mixture of folic acid and tert-butylhydroquinone is less than 5 μm; Preferably, in step (2), the crushing pressure is 10-15 bar.

[0019] Preferably, in step (3), the mass ratio of the mixture of folic acid and tert-butylhydroquinone to the porous starch is (1-2):(3-4).

[0020] By adopting the above technical scheme, in the present application, folic acid and antioxidant tert-butylhydroquinone are mixed and then air flow-pulverized together to ensure that the antioxidant fully encapsulates the folic acid, prevents or delays the oxidation of the folic acid, and controls the particle size of the mixture to be D90 < 5 μm. The mixture is then fully mixed with porous starch, so that the folic acid and antioxidant tert-butylhydroquinone can be adsorbed in the concave pores of the porous starch, reducing the contact of folic acid with oxygen and light, thereby reducing the generation of oxidative impurities during long-term storage.

[0021] In summary, the present application includes at least one of the following beneficial technical effects: 1. The present application discloses a folic acid tablet with low oxidative impurities and a preparation method thereof. Folic acid and an antioxidant tertiary butylhydroquinone are mixed and then crushed together to ensure that the antioxidant fully encapsulates the folic acid, prevent or delay the oxidation of the folic acid, and control the particle size of the mixture to be D90 < 5 μm. The mixture is then fully mixed with porous starch. The porosity of the porous starch is utilized to allow the folic acid and the antioxidant to be adsorbed in the concave pores of the porous starch, while reducing the contact of the folic acid with oxygen and light, thereby reducing the generation of oxidative impurities during long-term storage. 2. The present application discloses a folic acid tablet with low oxidative impurities and a preparation method thereof, which effectively reduces the generation of oxidative impurities during the long-term storage of the folic acid tablet and improves the stability of the drug. DETAILED DESCRIPTION

[0022] The raw materials involved in this application are all commercially available products, among which: Folic acid: purchased from Hebei Jiheng (Group) Pharmaceutical Co., Ltd.; Tert-butylhydroquinone: purchased from Hubei Jiutian Biopharmaceutical Technology Co., Ltd.; Porous starch: purchased from Shaanxi Bolin Biotechnology Co., Ltd.; Microcrystalline cellulose: Manufacturer: Dupont Nutrition USA, Inc., Model: PH112; Magnesium stearate: purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd. Manufacturer: FAMAR LYON.; Butylated hydroxyanisole: purchased from Hubei Jiutian Biopharmaceutical Technology Co., Ltd.; Butylated hydroxytoluene: purchased from Anhui Yinghe Biotechnology Co., Ltd.; Propyl gallate: purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.; The present application is further described in detail below in conjunction with embodiments and comparative examples.

[0023] A folic acid tablet with low oxidative impurities, comprising the following components: folic acid, tert-butylhydroquinone, porous starch, microcrystalline cellulose, and magnesium stearate; The mass ratio of folic acid, tert-butylhydroquinone, porous starch, microcrystalline cellulose and magnesium stearate is 5:(5-15):(30-40):(40-60):(0.5-1.5).

[0024] A method for preparing folic acid tablets with low oxidative impurities, which is as follows: After folic acid and antioxidant tert-butylhydroquinone are uniformly mixed, air flow pulverization is performed using a Micron JETMILL4 pulverizer, the pulverization pressure is 10-15 bar, and the particle size D90 of the pulverized mixture is controlled to be less than 5 μm, so as to obtain a mixture of folic acid and antioxidant tert-butylhydroquinone; the mixture is uniformly mixed with porous starch, and microcrystalline cellulose having passed a 60-mesh sieve is added and mixed for 5 minutes; finally, magnesium stearate having passed a 60-mesh sieve is added and mixed for 7 minutes to obtain total mixed particles; the total mixed particles are punched into tablets using a φ6.5 mm shallow concave punch to obtain folic acid tablets.

[0025] Example 1: Preparation of folic acid tablets A folic acid tablet, the prescription composition is as follows: Table 1 Composition of folic acid tablets Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 10 Porous starch 30 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 10 bar, and the particle size D90 is detected to be 4.9 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Using a DP30A tablet press, the total mixed granules obtained in step S5 were pressed into tablets at a weight of 96 mg / tablet by using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0026] Example 2: Preparation of folic acid tablets A folic acid tablet, the prescription composition is as follows: Table 2 Composition of folic acid tablets Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 10 Porous starch 35 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 10.5 bar, and the particle size D90 is detected to be 4.6 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0027] Example 3: Preparation of folic acid tablets A folic acid tablet, the prescription composition is as follows: Table 3 Composition of folic acid tablets prescription Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 10 Porous starch 40 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 10.4 bar, and the particle size D90 is detected to be 4.7 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 106 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0028] Example 4: Preparation of folic acid tablets A folic acid tablet, the prescription composition is as follows: Table 4 Composition of folic acid tablets Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 5 Porous starch 40 Microcrystalline Cellulose 60 Magnesium Stearate 1.5 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 10.6 bar, and the particle size D90 is detected to be 4.5 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 10 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 111.5 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0029] Example 5: Preparation of folic acid tablets A folic acid tablet, the prescription composition is as follows: Table 5 Composition of folic acid tablets A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 10.5 bar, and the particle size D90 is detected to be 4.6 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 20 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Using a DP30A tablet press, the total mixed granules obtained in step S5 were pressed into tablets at a weight of 101 mg / tablet by using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0030] Embodiment 6: A folic acid tablet, the prescription composition is as follows: Table 6 Composition of folic acid tablets Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 10 Porous starch 35 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 15 bar, and the particle size D90 is detected to be 2.5 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0031] Comparative Example 1: Preparation of folic acid tablets using common starch A folic acid tablet, the prescription composition is as follows: Table 7 Composition of folic acid tablets Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 10 starch 35 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 10.5 bar, and the particle size D90 is detected to be 4.6 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weigh 15 g of the mixture obtained in step S2 and mix it thoroughly with starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0032] Comparative Example 2: Preparation of folic acid tablets using butylated hydroxyanisole as an antioxidant A folic acid tablet, the prescription composition is as follows: Table 8 Composition of folic acid tablets Raw materials Weight (g / 1000 pieces) Folic acid 5 Butylated Hydroxyanisole 10 Porous starch 35 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and butyl hydroxyanisole are uniformly mixed, they are crushed by a Micron JETMILL4 type airflow mill, the crushing pressure is 10.5 bar, and the particle size D90 is detected to be 4.6 μm, to obtain a mixture of folic acid and butyl hydroxyanisole, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0033] Comparative Example 3: Preparation of folic acid tablets using butylated hydroxytoluene as an antioxidant A folic acid tablet, the prescription composition is as follows: Table 9 Composition of folic acid tablets prescription Raw materials Weight (g / 1000 pieces) Folic acid 5 Butylated Hydroxytoluene 10 Porous starch 35 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and butylated hydroxytoluene are uniformly mixed, they are crushed by a Micron JETMILL4 type air flow mill, the crushing pressure is 10.5 bar, and the particle size D90 is detected to be 4.6 μm, to obtain a mixture of folic acid and butylated hydroxytoluene, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0034] Comparative Example 4: Preparation of folic acid tablets using propyl gallate as an antioxidant A folic acid tablet, the prescription composition is as follows: Table 10 Composition of folic acid tablets prescription A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and propyl gallate are uniformly mixed, they are crushed by a Micron JETMILL4 jet mill, the crushing pressure is 10.5 bar, and the particle size D90 is detected to be 4.6 μm, to obtain a mixture of folic acid and propyl gallate, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0035] Comparative Example 5: Preparation of folic acid tablets with a particle size D90 > 5 μm of folic acid and antioxidants A folic acid tablet, the prescription composition is as follows: Table 11 Composition of folic acid tablets Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 10 Porous starch 35 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 type airflow mill, the crushing pressure is 9 bar, and the particle size D90 is detected to be 5.5 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0036] Comparative Example 6: Preparation of folic acid tablets with a particle size D90 > 5 μm of folic acid and antioxidants A folic acid tablet, the prescription composition is as follows: Table 12 Composition of folic acid tablets Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 10 Porous starch 35 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 8 bar, and the particle size D90 is detected to be 6.4 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0037] Comparative Example 7: Preparation of folic acid tablets with a particle size D90 > 5 μm of folic acid and antioxidants A folic acid tablet, the prescription composition is as follows: Table 13 Composition of folic acid tablets prescription Raw materials Weight (g / 1000 pieces) Folic acid 5 Tertiary Butyl Hydroquinone 10 Porous starch 35 Microcrystalline Cellulose 50 Magnesium Stearate 1 A preparation process of folic acid tablets, the preparation steps are as follows: S1. Pass microcrystalline cellulose and magnesium stearate through a 60-mesh sieve respectively for later use; S2, after the folic acid and tert-butylhydroquinone are uniformly mixed, they are crushed by a Micron JETMILL4 airflow mill, the crushing pressure is 5 bar, and the particle size D90 is detected to be 10.7 μm, to obtain a mixture of folic acid and tert-butylhydroquinone, which is set aside; S3, weighing 15 g of the mixture obtained in step S2 and mixing it thoroughly with the porous starch; S4, mixing the microcrystalline cellulose sieved in step S1 with the material obtained in S3 for 5 minutes; S5, mixing the magnesium stearate sieved in step S1 with the material obtained in S4 for 7 minutes to obtain a total mixed granule; S6. Use a DP30A tablet press to press the total mixed granules obtained in step S5 into tablets at a weight of 101 mg / tablet using φ6.5 mm shallow concave punches to obtain folic acid tablets.

[0038] Test example: Accelerated testing: Take reference preparation The samples prepared in Examples 1-6 and Comparative Examples 1-7 were placed in an environment of 40°C ± 2°C and 75% RH ± 5% RH for 6 consecutive months. The oxidized impurities and total impurities content of the folic acid tablets at 0 days, 3 months, and 6 months were detected by HPLC. The experimental results are as follows: Table 14 Accelerated test results From the above results, it can be seen that Comparative Example 1 is prepared using ordinary starch, which has no porous structure. During the storage process, folic acid is likely to come into contact with oxygen, resulting in a substantial increase in oxidized impurities and total impurities.

[0039] Comparative Examples 2-4 all use other antioxidants, but the antioxidant effect on folic acid tablets is not obvious, and the accelerated 6-month oxidation impurities and total impurities are also over the limit.

[0040] In the preparation process of Comparative Example 5, the particle size of the mixture of folic acid and tert-butylhydroquinone is slightly larger than 5 μm, and it cannot be well embedded in the concave pores of the porous starch. Folic acid is still likely to be exposed to oxygen and light, which accelerates the 6-month oxidation impurities and total impurities to approach the limit.

[0041] In the preparation process of Comparative Example 6-7, the particle size D90 of the mixture of folic acid and tert-butylhydroquinone was greater than 5 μm, and the particle size was too large to be well embedded in the concave pores of the porous starch. The folic acid was likely to be exposed to oxygen and light, resulting in a significant increase in oxidative impurities and total impurities during the stability storage process, and the acceleration for 6 months was slightly over the limit.

[0042] In Examples 1-6 of the present application, tert-butylhydroquinone is used as an antioxidant, which is micronized together with folic acid, and the particle size D90 is controlled to be less than 5 μm, so that it can be embedded in the pores of porous starch, blocking the contact of folic acid with oxygen and light, slowing down its degradation, and improving stability. Reference preparation The oxidative impurities and total impurities after 3 months of acceleration are close to the limit, and the shelf life of the reference preparation is 18 months. However, the impurity growth of the preparations of Examples 1-6 of the present invention is significantly slower than that of the reference preparation, and is still far below the limit after 6 months of acceleration. According to the known stability test data, the reaction kinetics can be used to infer the shelf life of the product. The data after 6 months of acceleration can predict that the product will remain stable for 3 years at 25°C. Therefore, the present invention can greatly improve the stability of the product, significantly reduce the impurity level, extend the life cycle of the product, and facilitate the transportation and clinical use of the product.

[0043] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A pharmaceutical composition, It is characterized in that Includes the following components: a blend of folic acid and antioxidants; porous starch; Wherein, the mass ratio of the mixture of folic acid and antioxidant to porous starch is (1-2): (3-4); The mass ratio of folic acid to antioxidants is 1:(1-3).

2. A pharmaceutical composition according to claim 1, Features: The particle size D90 of the mixture of folic acid and antioxidant is less than 5 μm.

3. A pharmaceutical composition according to claim 2, Features: The antioxidant is tert-butylhydroquinone.

4. A folic acid tablet with low oxidative impurities, Features: The invention comprises the pharmaceutical composition according to any one of claims 1 to 3 and pharmaceutically acceptable excipients.

5. The folic acid tablet with low oxidative impurities according to claim 4, Features: The pharmaceutically acceptable excipients include microcrystalline cellulose and magnesium stearate.

6. The folic acid tablet with low oxidative impurities according to claim 5, Features: The mass ratio of the microcrystalline cellulose to folic acid is (8-12):

1.

7. The folic acid tablet with low oxidative impurities according to claim 5, Features: The mass ratio of magnesium stearate to folic acid is (0.1-0.3):

1.

8. A method for preparing folic acid tablets with low oxidative impurities, It is characterized in that The preparation steps are as follows: (1) Weigh the raw materials of folic acid tablets according to the prescription amount; (2) folic acid and tert-butylhydroquinone are mixed and then subjected to air flow milling to obtain a mixture of folic acid and tert-butylhydroquinone; (3) mixing the folic acid and tert-butylhydroquinone mixture with porous starch; (4) adding microcrystalline cellulose to the mixture prepared in step (3) and mixing, and then adding magnesium stearate and mixing to obtain a total mixed granule; (5) The total mixed granules are compressed into tablets to obtain folic acid tablets.

9. The folic acid tablet with low oxidative impurities according to claim 8, Features: In the step (2), after air flow pulverization, the particle size D90 of the obtained mixture of folic acid and tert-butylhydroquinone is less than 5 μm.

10. The folic acid tablet with low oxidative impurities according to claim 8, Features: In the step (3), the mass ratio of the mixture of folic acid and tert-butylhydroquinone to the porous starch is (1-2):(3-4).

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