High-quality ferrous succinate composition tablet and industrialization process thereof

Abstract

The invention relates to the technical field of pharmacy, in particular to a high-quality ferrous succinate composition tablet and an industrialization process thereof. The preparation method comprises the following steps: mixing the ferrous succinate, the succinic acid part A, the calcium hydrogen phosphate dihydrate, the corn starch part A and the povidone K30 to obtain a granulation mixture; performing dry granulation on the granulation mixture to obtain a granulation mixture; mixing the granulation mixture, a succinic acid part B, a corn starch part B and magnesium stearate to obtain a total mixture; carrying out tabletting treatment on the total mixture to obtain the ferrous succinate tablets; and coating the ferrous succinate tablet to obtain the ferrous succinate tablet. According to the technical scheme, the technical problems that in the prior art, the stability of functional components of ferrous succinate composition tablets is not ideal, and the bioavailability is not ideal can be solved. According to the scheme, the product quality and stability of the ferrous succinate tablet are greatly improved, the production process is simplified, the production cost is reduced, and a new way is opened up for industrial production of the product.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a high-quality ferrous succinate composition tablet and its industrialization process. Background Art

[0002] Ferrous succinate tablets are a commonly used iron supplement, mainly used for the prevention and treatment of iron deficiency anemia. The main active ingredient of ferrous succinate tablets is ferrous succinate, which is an organic iron compound with the chemical formula FeC4H4O4. Compared with other forms of iron supplements, ferrous succinate has a relatively high bioavailability. After being absorbed in the body, ferrous succinate can be effectively converted into an available form of iron and participate in the synthesis of hemoglobin, thereby helping to correct the anemia state. The succinate radical in its structure can participate in the tricarboxylic acid cycle (TCA cycle) in the body, which helps to improve the absorption efficiency of iron.

[0003] Chinese Patent CN117599004A provides a ferrous succinate tablet, its preparation method and a preparation for iron supplementation. In this technical solution, the preparation method of the ferrous succinate tablet includes the following steps: mixing ferrous succinate with a diluent, adding a binder solution, granulating, drying to prepare ferrous succinate granules; mixing the ferrous succinate granules with a solubilizer and a lubricant, and then tabletting to prepare the ferrous succinate tablet; wherein, the solvent of the binder solution includes organic alcohol, the solubilizer includes succinic acid, and the diluent includes calcium hydrogen phosphate.

[0004] Chinese Patent CN114557974B provides a stable ferrous succinate pharmaceutical composition, a forming method and an application. The pharmaceutical composition contains the active ingredient ferrous succinate and the auxiliary material calcium hydrogen phosphate dihydrate. As a key auxiliary material, the hydrogen ions dissociated from calcium hydrogen phosphate dihydrate can inhibit the formation of iron hydroxide, and at the same time, calcium ions can chelate the succinate radical and inhibit its ability to attract water molecules, thereby preventing the dissociation and oxidation of ferrous succinate into ferric ions. After preparing a tablet drug using the above pharmaceutical composition, due to the effective reduction of the generation of ferric ions, the disintegration speed is significantly shortened.

[0005] However, the above existing technologies all have the following problems: They all use wet granulation, resulting in unsatisfactory dissolution performance of the products (such as the dissolution of active ingredients), which in turn affects the bioavailability of the products. Therefore, there is an urgent need to develop a production process that can simultaneously improve the stability of the active ingredients of the products and the bioavailability of the products. Summary of the Invention

[0006] The present invention aims to provide a method for preparing a high-quality ferrous succinate composition tablet to solve the technical problems of unsatisfactory stability of the active ingredient and unsatisfactory bioavailability in the ferrous succinate composition tablet existing in the prior art.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] A method for preparing a high-quality ferrous succinate composition tablet, comprising the following steps carried out in sequence:

[0009] S1: Mix ferrous succinate, part A of succinic acid, calcium hydrogen phosphate dihydrate, part A of corn starch, and polyvinylpyrrolidone K30 to obtain a granulation mixture;

[0010] S2: Perform dry granulation on the granulation mixture to obtain a granulation mixture;

[0011] S3: Mix the granulation mixture, part B of succinic acid, part B of corn starch, and magnesium stearate to obtain a total mixture;

[0012] S4: Perform tabletting on the total mixture to obtain a ferrous succinate core tablet;

[0013] S5: Coat the ferrous succinate core tablet to obtain a ferrous succinate tablet;

[0014] The ratio of part A of succinic acid to the total amount of succinic acid fed is 85% - 95%; the ratio of part A of corn starch to the total amount of corn starch fed is 85% - 95%, the ratio of part B of succinic acid to the total amount of succinic acid fed is 5% - 15%; the ratio of part B of corn starch to the total amount of corn starch fed is 5% - 15%.

[0015] Furthermore, the mass ratio of ferrous succinate to succinic acid is 100:80 - 110.

[0016] Furthermore, succinic acid is pulverized and passed through a 60 - 80 mesh sieve.

[0017] Furthermore, in S1, the mixing speed is 20 - 30 revolutions per minute, and the mixing time is 10 - 20 minutes.

[0018] Furthermore, in S2, the technical parameters of dry granulation are: roller pressure 240 - 260 bar, roller gap 0.3 - 1.0 mm, feeding speed 20 - 25 rpm, screw feeding speed 90 - 100 rpm, roller speed 24 - 28 rpm, pulverizing speed 60 - 80 rpm, and sizing speed 80 - 90 rpm;

[0019] During the granulation process of dry granulation, a 20 - mesh sieve is set; then, it is sieved using a 20 - mesh sieve on the upper part and a 60 - mesh sieve on the lower part, and the particles retained between the upper and lower sieves are taken to obtain a granulation mixture.

[0020] Further, in S3, the mixing speed is 20 - 30 revolutions per minute and the mixing time is 10 - 20 minutes.

[0021] Further, in S4, the hardness of the ferrous succinate tablets is 70 - 90 N.

[0022] Further, in S5, under the condition of a tablet bed temperature of 40°C - 50°C, the coating solution is sprayed onto the ferrous succinate tablets at a speed of 140 - 180 ml / minute.

[0023] Further, the weight gain of the ferrous succinate tablets after coating is 2 - 4%; the coating solution is a gastric-soluble film coating premix solution with a mass fraction of 10% - 14% prepared with anhydrous ethanol as the solvent.

[0024] This technical solution also provides a ferrous succinate coated tablet prepared by a method for preparing a high-quality ferrous succinate composition tablet.

[0025] Further, for a ferrous succinate coated tablet prepared by a method for preparing a high-quality ferrous succinate composition tablet, calculated by weight, its raw materials include: 100 parts of ferrous succinate, 80 - 110 parts of succinic acid, 70 - 90 parts of dicalcium hydrogen phosphate dihydrate, 40 - 60 parts of corn starch, 10 - 15 parts of polyvinylpyrrolidone K30, 5 - 10 parts of magnesium stearate, and 10 - 20 parts of coating powder.

[0026] The technical principle of this solution lies in:

[0027] The present invention provides a high-quality ferrous succinate composition tablet and its industrialization process, aiming to solve the problems of poor stability and low bioavailability of ferrous succinate composition tablets in the prior art. This method uses dry granulation instead of traditional wet granulation to avoid the oxidative degradation effect of moisture on ferrous succinate. In addition, by optimizing the formulation ratio (such as the mass ratio of part A to part B of succinic acid, and part A to part B of corn starch), and using specific excipients (such as dicalcium hydrogen phosphate dihydrate, polyvinylpyrrolidone K30, etc.) to stabilize the active ingredient and prevent it from converting into an ineffective or harmful form (such as ferric ions) during the preparation and storage process. The entire preparation process includes mixing, dry granulation, total mixing, tabletting, and coating steps, and the product quality is ensured by controlling temperature, pressure, and other process parameters.

[0028] The key technical points of this solution are:

[0029] (1) Under the process conditions of this solution, the dosage ratio of ferrous succinate and succinic acid is controlled (10:8 - 11). Too high or too low dosage of succinic acid will have a significant negative impact on the bioavailability of tablets (disintegration time limit, dissolution rate of active ingredients), and this negative impact shows a significant increase with the increase of storage time (the stability of disintegration time limit and dissolution rate of active ingredients during the accelerated experiment is not ideal).

[0030] (2) Under the process conditions of this solution, the distribution method and process sites of succinic acid and corn starch in the preparation process are crucial for improving the bioavailability of drugs. Preferably, succinic acid is divided into part A of succinic acid and part B of succinic acid; corn starch is divided into part A of corn starch and part B of corn starch. Part A of succinic acid and part A of corn starch are added in the dry granulation step to form a granulation mixture; part B of succinic acid and part B of corn starch are added in the step of preparing the total mixture to obtain the total mixture. The tablets prepared in this way not only have an ideal content of active ingredients, but also can improve the disintegration performance of tablets and the dissolution rate of active ingredients.

[0031] (3) Using absolute ethanol as the solvent for preparing the coating solution can effectively reduce the content of ferric iron in the product and improve the drug quality.

[0032] The beneficial effects of this solution are as follows:

[0033] (1) Improve stability: By avoiding the use of water, reducing operations in high-temperature and high-humidity environments, the risk of ferrous succinate being oxidized into high-iron impurities during preparation and storage is reduced, so that the high-iron content of the product remains at a low level throughout its life cycle.

[0034] (2) Enhance bioavailability: Due to the adoption of dry granulation technology and optimized formula design, the finished tablets have a faster disintegration speed, and the dissolution amount and dissolution speed of active ingredients are significantly higher than those of traditional wet granulation products, thus improving the bioavailability of drugs.

[0035] (3) Improve safety: Reducing the impurity content not only helps to improve the safety of drugs, but also reduces the safety risks that may be brought about by the accumulation of impurities, providing a safer treatment option for patients.

[0036] In summary, the present invention provides an improved method for preparing ferrous succinate tablets, which solves the main problems in the prior art, including the unsatisfactory stability of active ingredients and bioavailability of ferrous succinate composition tablets. It not only greatly improves the product quality and stability of ferrous succinate tablets, but also greatly simplifies the production process, reduces the production cost, and opens up a new way for the industrial production of this product. Detailed implementation manners

[0037] The following embodiments are only used to more clearly illustrate the technical solutions of the present invention. Therefore, they are only examples and cannot be used to limit the protection scope of the present invention. The specific embodiments listed in the present invention are only examples of the present invention, and the present invention is not limited to the specific embodiments described below. For those skilled in the art, any equivalent modifications and substitutions made to the embodiments described below are also within the scope of the present invention. Therefore, equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention. In order to better illustrate the present invention, numerous specific details are given in the following specific implementation manners. Those skilled in the art should understand that the present invention can also be implemented without certain specific details. In other embodiments, methods, means, equipment, and steps well-known to those skilled in the art are not described in detail in order to highlight the gist of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. Unless otherwise specified, the units used in this specification are all international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0038] Unless otherwise specified, the experimental methods used in the following embodiments are all conventional methods; the materials, reagents, or instruments used without indicating the manufacturer are all reagents and materials that can be obtained from commercial channels. For those not indicating specific conditions in the embodiments, they are all carried out according to conventional conditions or the conditions recommended by the manufacturer. At the same time, the present invention does not limit the source of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are all ordinary commercially available products in the technical field. Unless otherwise specified, the "ratio" mentioned in the following embodiments is the ratio of mass parts.

[0039] The overall situation of ferrous succinate preparations and the preparation process is as follows:

[0040] A high-quality ferrous succinate composition tablet, the prescription composition of which is as follows:

[0041] By weight, 100 parts of ferrous succinate, 80 - 110 parts of succinic acid, 70 - 90 parts of calcium hydrogen phosphate dihydrate, 40 - 60 parts of corn starch, 10 - 15 parts of polyvinylpyrrolidone K30, and 5 - 10 parts of magnesium stearate. The above raw materials are used to prepare the core tablets. If it is necessary to prepare coated tablets, the raw materials to be added are: 10 - 20 parts of coating powder. The coating powder is a gastric-soluble film coating premix (gastric-soluble film coating premix), which is a conventional raw material in the pharmaceutical industry and can be directly purchased.

[0042] According to the following preparation process, the preparation of ferrous succinate composition tablets is carried out:

[0043] (1) Crush the succinic acid raw material, sieve it through a 60-80 mesh sieve, and set aside.

[0044] (2) Preparation of the granulation mixture: Add ferrous succinate, 85%-95% of the prescription amount of succinic acid (Part A of succinic acid), calcium hydrogen phosphate dihydrate, 85%-95% of the prescription amount of starch (Part A of corn starch), and polyvinylpyrrolidone K30 into a three-dimensional motion mixer for mixing (the rotation speed of the mixer is 20-30 revolutions per minute, and the mixing time is 10-20 minutes) to obtain the granulation mixture.

[0045] (3) Dry granulation: Take the granulation mixture, add it to a dry granulator for granulation, sieving and sizing, and obtain the product.

[0046] More specifically, the operation process is as follows: Turn on the vacuum conveyor, suck the mixed powder into the dry granulator, turn on the dry granulator, and adjust the technical parameters of the dry granulator in the following way: the pressure of the pressing wheel is 240-260 bar, the gap of the pressing wheel is 0.3-1.0 mm, the feeding speed is 20-25 rpm, the screw feeding speed is 90-100 rpm, the pressing roller speed is 24-28 rpm, the crushing speed is 60-80 rpm, and the sizing speed is 80-90 rpm. After the technical parameters meet the requirements of the granulation process parameters, granulate with a 20-mesh sieve, and collect the granules with a clean container.

[0047] Turn on the vacuum conveyor, suck the granules collected in the clean container into the high-efficiency sieving machine, and sieve them with a stainless steel sieve with 20 meshes on the upper layer and 60 meshes on the lower layer to obtain qualified granules (hereinafter referred to as the granulation mixture). Collect the unqualified coarse and fine powders and suck them into the dry granulator, granulate again according to the aforementioned method, and mix the qualified granules obtained each time (hereinafter referred to as the granulation mixture) for the next step to improve the utilization rate of the materials.

[0048] (4) Preparation of the total mixture; Take the granulation mixture, 5%-15% of the prescription amount of succinic acid (Part B of succinic acid, the remaining succinic acid in the prescription), calcium hydrogen phosphate dihydrate, 5%-15% of the prescription amount of corn starch (Part B of corn starch, the remaining corn starch in the prescription), and magnesium stearate, add them into a three-dimensional motion mixer and mix evenly to obtain the total mixture. Among them, the parameters of the three-dimensional motion mixer are set as follows: the rotation speed is 20-30 revolutions per minute, and the mixing time is 10-20 minutes.

[0049] (5) Tableting: Use a φ9 mm round shallow concave scored mold for tableting, which is a conventional form of the prior art. Adjust the specified tablet weight and the rotation speed of the high-speed rotary tablet press (30-40 revolutions per minute), and tablet to obtain the product. Control the hardness of the obtained plain tablets at 70-90 N to obtain ferrous succinate plain tablets.

[0050] (6) Coating: Take ferrous succinate tablets and perform coating operation with 10% (optional range: 10 - 14%) anhydrous ethanol gastric-soluble coating solution. The anhydrous ethanol gastric-soluble coating solution specifically refers to a solution obtained by using anhydrous ethanol as a solvent to dissolve the conventional gastric-soluble film coating premix in the prior art. The gastric-soluble film coating premix (coating powder) is a conventional preparation in the pharmaceutical field and can be obtained through commercial means. It is not the original raw material of this solution and will not be elaborated here. In the prior art, water is generally used as a solvent to dissolve the gastric-soluble film coating premix, while this technical solution uses anhydrous ethanol as a solvent to dissolve the gastric-soluble film coating premix. The coating operation process adopted in this technical solution is also a conventional means in the prior art. The specific parameter settings are: coating solution spraying speed 140 - 180 ml / minute, tablet bed temperature 40°C - 50°C, and the weight gain of the coated tablets is 2% - 4%.

[0051] (7) Packaging: Take the coated ferrous succinate tablets and perform vacuum double-aluminum packaging to obtain the product.

[0052] Example 1

[0053] A high-quality ferrous succinate composition tablet has the following prescription composition: calculated by weight, 100 parts of ferrous succinate, 100 parts of succinic acid, 80 parts of calcium hydrogen phosphate dihydrate, 50 parts of corn starch, 12 parts of polyvinylpyrrolidone K30, 8 parts of magnesium stearate, and 15 parts of coating powder.

[0054] Prepare the ferrous succinate composition tablets according to the following preparation process:

[0055] (1) Take the succinic acid raw material, crush it, and pass through a 60-mesh sieve for standby.

[0056] (2) Preparation of the granulation mixture: Add ferrous succinate, 80% succinic acid, calcium hydrogen phosphate dihydrate, 80% corn starch, and polyvinylpyrrolidone K30 into a three-dimensional motion mixer for mixing (mixer rotation speed 20 revolutions per minute, mixing time 10 minutes) to obtain the granulation mixture.

[0057] (3) Dry granulation: Take the granulation mixture, add it to a dry granulator for granulation, sieving, and sizing to obtain the product.

[0058] More specifically, the operation process is as follows: Turn on the vacuum conveyor, suck the mixed powder into the dry granulator, turn on the dry granulator, and adjust the technical parameters of the dry granulator in the following way: pressure of the pressing wheel about 250 bar, gap of the pressing wheel about 0.7 mm, feeding speed about 23 rpm, screw feeding speed about 95 rpm, pressing roller speed about 26 rpm, crushing speed about 70 rpm, and sizing speed about 85 rpm. After the technical parameters meet the requirements of the granulation process parameters, granulate with a 20-mesh sieve and collect the granules with a clean container.

[0059] Turn on the vacuum conveyor, suck the particles collected in the clean container into the high-efficiency sieving machine, and sieve them through a stainless steel sieve mesh with 20 meshes on the upper layer and 60 meshes on the lower layer to obtain qualified particles (hereinafter referred to as the granulation mixture). Collect the unqualified coarse and fine powders and suck them into the dry granulator to granulate again according to the aforementioned method. Mix the qualified particles obtained each time (hereinafter referred to as the granulation mixture) for the next step to improve the material utilization rate.

[0060] (4) Preparation of the total mixture: Take the granulation mixture, the remaining succinic acid, the remaining corn starch and magnesium stearate, and add them to a three-dimensional motion mixer to mix evenly to obtain the total mixture. Among them, the parameters of the three-dimensional motion mixer are set as follows: rotation speed 20 revolutions per minute, mixing time 10 minutes.

[0061] (5) Tabletting: Use a die with a φ9mm round shallow concave indentation for tabletting, which is a conventional form of the prior art. Adjust the specified tablet weight and the rotation speed of the high-speed rotary tablet press (30 revolutions per minute), and the tablets can be obtained by tabletting. Control the hardness of the obtained plain tablets at 70 - 90N to obtain ferrous succinate plain tablets.

[0062] (6) Coating: Take the ferrous succinate plain tablets and perform coating operation with a 10% anhydrous ethanol gastric-soluble coating solution. The specific parameter settings are as follows: coating solution spraying speed 140 ml / minute, tablet bed temperature 40 °C, and the weight gain of the plain tablets after coating is 2% - 4%.

[0063] (7) Packaging: Take the coated ferrous succinate tablets and perform vacuum double-aluminum packaging to obtain the product.

[0064] Example 2

[0065] This example is basically the same as Example 1, the difference is that: the dosage of succinic acid is 90 parts, the dosage of corn starch is 60 parts (the dosages of other materials in the formula are the same as those in Example 1), and the mass ratio of ferrous succinate to succinic acid is 10:9.

[0066] Example 3

[0067] This example is basically the same as Example 1, the difference is that: the dosage of succinic acid is 80 parts, the dosage of corn starch is 60 parts (the dosages of other materials in the formula are the same as those in Example 1), and the mass ratio of ferrous succinate to succinic acid is 10:8.

[0068] Example 4

[0069] This example is basically the same as Example 1, the difference is that: the dosage of succinic acid is 110 parts, the dosage of corn starch is 40 parts (the dosages of other materials in the formula are the same as those in Example 1), and the mass ratio of ferrous succinate to succinic acid is 10:11.

[0070] Comparative Example 1

[0071] This comparative example is basically the same as Example 1, except that: the dosage of succinic acid is 120 parts, and the dosage of corn starch is 40 parts. The dosage of succinic acid in this comparative example is relatively high, and the mass ratio of ferrous succinate to succinic acid is 10:12.

[0072] Comparative Example 2

[0073] This comparative example is basically the same as Example 1, except that the dosage of succinic acid is 70 parts and the dosage of corn starch is 60 parts. The dosage of succinic acid in this comparative example is relatively low, and the mass ratio of ferrous succinate to succinic acid is 10:7.

[0074] Comparative Example 3

[0075] The formulation of this comparative example is the same as that of Example 1, except that: the conventional wet granulation process is adopted, and the specific process is as follows:

[0076] 95% ethanol is used as the solvent, and the prepared concentration of povidone K30 using all the prescription amounts is 25% povidone K30 solution. Then, all the prescription amounts of ferrous succinate, succinic acid, calcium hydrogen phosphate dihydrate, and corn starch are added. The mixture is added to a wet granulator for conventional wet granulation. Specifically, a 20-mesh rocking granulator is used for granulation. Then, fluidized bed drying is carried out (inlet air temperature 70 °C, controlling the moisture content at 1% - 4%). After drying, a 18-mesh rocking granulator is used for sizing. After sizing is completed, the granules and the prescription amount of magnesium stearate are added to a three-dimensional motion mixer to prepare the total mixture. The technical parameters of the total mixing process are the same as those of Example 1. After obtaining the total mixture, tableting and coating are carried out in the same manner as in Example 1 to obtain the coated ferrous succinate tablets.

[0077] Comparative Example 4

[0078] The formulation and process of this comparative example are basically the same as those of Example 1, and the specific differences are as follows:

[0079] In (2), the preparation process of the granulation mixture (dry granulation) is as follows: ferrous succinate, succinic acid, calcium hydrogen phosphate dihydrate, corn starch, and povidone K30 are added to a three-dimensional motion mixer for mixing (the mixer rotation speed is 20 revolutions per minute, and the mixing time is 10 minutes) to obtain the granulation mixture.

[0080] Correspondingly, in (4), the total mixture is prepared in the following manner: the granulation mixture and magnesium stearate are taken and added to a three-dimensional motion mixer for mixing to obtain the total mixture. Among them, the parameters of the three-dimensional motion mixer are set as: rotation speed 20 revolutions per minute, mixing time 10 minutes.

[0081] The remaining steps are the same as those in Example 1, and the coated ferrous succinate tablets are obtained accordingly.

[0082] Comparative Example 5

[0083] The formulation and technological process of this comparative example are basically the same as those of Example 1, and the differences are as follows:

[0084] In (2), the preparation process of the granulation mixture (dry granulation) is as follows: Ferrous succinate, 80% succinic acid, calcium hydrogen phosphate dihydrate, 80% corn starch, and polyvinylpyrrolidone K30 are added to a three-dimensional motion mixer for mixing (the mixer speed is 20 revolutions per minute, and the mixing time is 10 minutes) to obtain the granulation mixture.

[0085] Correspondingly, in (4), the total mixture is prepared in the following manner: The granulation mixture, the remaining succinic acid, magnesium stearate, and the remaining corn starch are taken and added to a three-dimensional motion mixer for mixing evenly to obtain the total mixture. Among them, the parameters of the three-dimensional motion mixer are set as: the speed is 20 revolutions per minute, and the mixing time is 10 minutes.

[0086] The remaining steps are the same as those of Example 1, and the coated ferrous succinate tablets are obtained accordingly.

[0087] Comparative Example 6

[0088] The formulation and technological process of this comparative example are basically the same as those of Example 1, and the difference in the coating solution is: A 10% gastric-soluble film coating premix coating solution is prepared using pure water as the solvent.

[0089] Comparative Example 7

[0090] The formulation and technological process of this comparative example are basically the same as those of Example 1, and the difference in the coating solution is: A 10% gastric-soluble film coating premix coating solution is prepared using 50% ethanol as the solvent.

[0091] Comparative Example 8

[0092] The formulation and technological process of this comparative example are basically the same as those of Example 1, and the difference in the coating solution is: A 10% gastric-soluble film coating premix coating solution is prepared using 80% ethanol as the solvent.

[0093] Experimental Example

[0094] The coated ferrous succinate tablets obtained in the examples and comparative examples and the uncoated plain tablets are tested for ferrous content and ferric content (expressed as a percentage of the labeled amount %) using the national drug standard for ferrous succinate tablets (WS1-(X-006)-2001Z). In addition, the dissolution rate of the ferrous succinate tablets is tested, the disintegration time limit is tested, and the accelerated stability test of the ferrous succinate tablets is carried out to clarify the stability of the content of the active ingredients, the dissolution rate, and the disintegration time limit of the product under high-temperature storage conditions.

[0095] (1) Dissolution rate detection method:

[0096] The dissolution conditions are as follows: Using 1000 ml of 1 mol / L hydrochloric acid solution as the dissolution medium, with a rotation speed of 75 revolutions per minute. Operate according to the law. After 1 hour and 2 hours, respectively take 5 ml of the dissolution solution, and immediately supplement 5 ml of 1 mol / L hydrochloric acid solution in the dissolution cup.

[0097] Standard iron solution: Take about 70 mg of ferrous ammonium sulfate (NH4)2Fe(S04)2·6H2O reference substance, accurately weighed, place it in a 10 ml volumetric flask, dissolve it with a small amount of water, add 0.4 ml of sulfuric acid, cool it, dilute it to the mark with water, shake well. Accurately measure 2 ml and place it in a 100 ml volumetric flask, dilute it to the mark with water, shake well, and obtain a solution containing about 20 μg of Fe per 1 ml. 2+ solution.

[0098] Reference substance solution: Accurately measure 3 ml of the iron standard solution, place it in a 25 ml flask, add 2 ml of 10% hydroxylamine hydrochloride, shake well, let it stand for 4 minutes, add 2 ml of 0.12% o-phenanthroline solution, shake well, add 10 ml of 2 mol / L sodium acetate solution, dilute it to the mark with water, shake well, and let it stand for 15 minutes.

[0099] Test sample solution: Take the dissolution solutions at 1 hour and 2 hours respectively, filter, accurately measure 2 ml of the continued filtrate, place them in 25 ml flasks respectively, add 2 ml of 10% hydroxylamine hydrochloride, shake well, let it stand for 4 minutes, add 2 ml of 0.12% o-phenanthroline solution, shake well, add 10 ml of 2 mol / L sodium acetate solution, dilute it to the mark with water, shake well, and let it stand for 15 minutes.

[0100] Determination method: Take the test sample solution and the reference substance solution, and according to the ultraviolet-visible spectrophotometry (General Principles 0401, Volume IV, Chinese Pharmacopoeia 2020 Edition), measure the absorbance at a wavelength of 510 nm, and calculate the dissolution rate of each tablet.

[0101] The dissolution rate is at least: The dissolution rates at 1 hour and 2 hours are 50% and 80% of the total iron content under the high iron item respectively, and further preferably 60% and more than 90%. This test condition tests the dissolution effect of the drug's active ingredient in an acidic environment, reflecting the dissolution situation and bioavailability of the drug's active ingredient in the gastric acid environment.

[0102] (2) Disintegration test detection method:

[0103] Tablet disintegration refers to the process by which a tablet splits into smaller particles or fragments in body fluids. After tablet disintegration, the surface area of the tablet increases, thus promoting the faster dissolution of the active ingredient into the liquid environment. Tablet dissolution refers to the process by which the active pharmaceutical ingredient dissolves from the preparation into the liquid environment. After the tablet disintegrates into smaller particles or fragments, the active ingredient needs to further dissolve out from these particles or fragments before it can be absorbed into the blood circulation. The dissolution rate is crucial for the bioavailability of the drug and determines the rate and extent of the drug reaching the systemic circulation. Therefore, in the research of this project, in addition to the disintegration time limit index, the inventors also further focused on the dissolution rate of the efficacy components of the tablets. The existing preparation methods of ferrous succinate tablets usually result in a relatively slow dissolution rate of the efficacy components, leading to slow drug absorption and thus delaying the drug effect.

[0104] Suspend the hanging basket on the bracket through the stainless steel shaft at the upper end, immerse it in a 1000 ml beaker, and adjust the position of the hanging basket so that when it drops to the lowest point, the sieve is 25 mm away from the bottom of the beaker. The beaker contains water at a temperature of 37 ± 1°C. Adjust the water level so that when the hanging basket rises to the highest point, the sieve is 15 mm below the water surface, and the top of the hanging basket should not be immersed in the solution. Take 6 test samples and place them in the glass tubes of the above-mentioned hanging basket respectively, and start the disintegration tester for inspection. The disintegration time limit of one group is based on the complete disintegration of all the test tablets in this group. The disintegration time limit of one group of tablets should be <15 min, and the longest should not exceed 30 min.

[0105] (3) Accelerated stability test:

[0106] In ferrous succinate tablets, the form of iron directly affects its absorption efficiency and safety. Among them, Fe 2+ can be directly absorbed through the divalent metal transporter (DMT1) of intestinal mucosal cells without additional reduction, with high bioavailability (about 10% - 20%). It is stable in an acidic environment (such as gastric juice), but is easily oxidized to Fe 2+ under neutral and alkaline conditions. At the same time, Fe 2+ needs to be reduced to Fe 2+ in gastric acid before it can be absorbed. Insufficient gastric acid secretion (such as in the elderly or patients with stomach diseases) will lead to a significant decrease in the absorption rate (only 1% - 2%), and Fe 2+ is prone to form insoluble hydroxides (such as Fe(OH)3) in the intestine, which is not only difficult to absorb, but may also stimulate the gastrointestinal tract. The unabsorbed iron ions are easily combined with intestinal hydrogen sulfide to form iron sulfide, resulting in black stools and abdominal pain, and may damage the mucosa in the long term. Therefore, the contents of ferric and ferrous iron in ferrous succinate tablets need to be strictly controlled.

[0107] The experimental method is as follows: Place the tablets in an environment of 40°C ± 2°C and 75% RH ± 5% RH, and measure the high-iron content and ferrous iron content at the specified time. The iron content of ferrous succinate tablets needs to be strictly controlled in the form of ferrous iron at 34% - 36% to ensure efficient absorption and safety.

[0108] The experimental results are shown in Tables 1, 2, and 3.

[0109] Table 1 Disintegration Time Limit Test Results

[0110]

[0111] Table 2 Dissolution Quantity Test Results

[0112]

[0113] Table 3 High-Iron and Ferrous Iron Content Detection

[0114]

[0115]

[0116] The traditional preparation process of ferrous succinate (such as tablets) usually adopts wet granulation, such as Comparative Example 3 of this scheme. However, using this preparation process will result in a relatively small dissolution quantity of the active ingredient in ferrous succinate tablets, and this index further decreases as the storage time increases, indicating that the ferrous succinate tablets prepared by this method are not ideal in terms of dissolution performance and the stability of the dissolution effect of the active ingredient (see the experimental data of Comparative Example 3 in Tables 1 and 2). However, the stability of the active ingredient in ferrous succinate tablets obtained by wet granulation is acceptable (see the experimental data of Comparative Example 3 in Table 3).

[0117] This technical scheme uses dry granulation instead of traditional wet granulation to obtain ferrous succinate tablets, see Examples 1 - 4. Using the method of this scheme, the dissolution degree of the active ingredient in the obtained ferrous succinate tablets is significantly improved. And as the accelerated stability experiment progresses, the disintegration time limit and the dissolution rate of the active ingredient of the tablets do not show a significant decrease, indicating that the ferrous succinate tablets prepared by the preparation process of this scheme are ideal in terms of dissolution performance and the stability of the dissolution effect of the active ingredient. In addition, the content of the active ingredient in the ferrous succinate tablets prepared according to the process of this scheme is also relatively ideal, and as time goes by, the amount of ferrous iron converted to high-iron is less, indicating that the stability of the active ingredient in this tablet is relatively ideal. In summary, using this process can ensure that the content and stability of the active ingredient of the product meet the requirements, and it has a positive promoting effect on the disintegration effect of the tablets and the dissolution effect of the active ingredient, improving the bioavailability of the drug.

[0118] This technical solution first introduces dry granulation into the preparation of ferrous succinate. Before determining the optimal process of this solution, a large number of attempts were made, and several key technical points that determine the process effect were discovered. First, the dosage of succinic acid in the formula has a significant impact on the product quality. In the examples of this solution, the dosage ratio of ferrous succinate to succinic acid is 10:8 - 11, and within this range, good product quality (content and stability of active ingredients, disintegration time limit and its stability, dissolution rate of active ingredients and its stability) can be ensured. Generally speaking, in ferrous succinate tablets, the main purpose of adding succinic acid is to improve the stability and solubility of the drug as a ligand and promote the effective absorption of iron. Under the new process conditions of this solution, the inventor found through a large number of studies that if the dosage of succinic acid is too high (Comparative Example 1) or too low (Comparative Example 2), it will lead to an extended disintegration time limit and a decrease in the stability of the disintegration time limit, as well as a decrease in the dissolution rate of active ingredients and the stability of the dissolution rate. However, the phenomenon that the above-mentioned addition amount of succinic acid affects the disintegration time limit and dissolution rate does not occur in the preparation process of ferrous succinate tablets based on wet granulation, and it is a unique phenomenon of the dry granulation-based process of this solution. Using the formulations of Comparative Examples 1 and 2, wet granulation and the preparation of ferrous succinate tablets were carried out with reference to Comparative Example 3 respectively, and the disintegration time limit and its variation law, dissolution rate and its variation law of the products were basically the same as those of Comparative Example 3. This shows that the phenomenon of succinic acid affecting the performance of the preparation is unique to this process. Selecting the dosage ratio of ferrous succinate to succinic acid as 10:8 - 11 has achieved unexpected technical effects in improving the bioavailability of the preparation.

[0119] Secondly, the addition process positions of succinic acid and corn starch have a very significant impact on the product quality. In Comparative Example 4, all the formulated amounts of succinic acid and corn starch were used for dry granulation to obtain a granulation mixture. Compared with Example 1, the disintegration time limit of the ferrous succinate tablets obtained by this method was prolonged and the stability of the disintegration time limit was reduced, the dissolution rate of the active ingredient was reduced and the stability of the dissolution rate was reduced. In Comparative Example 5, 80% of the formulated amounts of succinic acid and corn starch were used for dry granulation to obtain a granulation mixture (step (2)), and the remaining succinic acid and corn starch were used for the preparation of the total mixture (step (4)). Compared with Example 1, the disintegration time limit of the ferrous succinate tablets obtained by this method was prolonged and the stability of the disintegration time limit was reduced, the dissolution rate of the active ingredient was reduced and the stability of the dissolution rate was reduced. From Example 1, Comparative Example 4 and Comparative Example 5, it can be seen that: the distribution method and the process sites used of succinic acid and corn starch in the preparation process are very crucial for improving the bioavailability of the drug. Divide succinic acid into succinic acid part A and succinic acid part B, where succinic acid part A accounts for 85% - 95% of the total amount, and succinic acid part B is the remainder; divide corn starch into corn starch part A and corn starch part B, where corn starch part A accounts for 85% - 95% of the total amount, and corn starch part B is the remainder. Put succinic acid part A and corn starch part A into the dry granulation step to form a granulation mixture (granular); put succinic acid part B and corn starch part B into the step of preparing the total mixture, and these materials are wrapped outside the granules obtained by dry granulation to obtain the total mixture. The tablets prepared in this way not only have an ideal content of the active ingredient (not producing too much ferric iron, nor causing excessive consumption and loss of ferrous iron), but also can improve the disintegration performance of the tablets and the dissolution rate of the active ingredient, and the above performances remain stable during the accelerated experiment. If succinic acid and corn starch are not distinguished, as in Comparative Examples 4 and 5, it will cause a very significant negative impact on the disintegration performance of the tablets and the dissolution rate of the active ingredient, which is not conducive to improving the bioavailability of the drug.

[0120] Thirdly, anhydrous ethanol needs to be used as the solvent during coating. Using other types of solvents (pure water, 50% ethanol, 80% ethanol) will affect the content of the active ingredient (too high ferric iron content) in the coated tablets.

[0121] The above are only the embodiments of the present invention, and common general technical solutions and / or characteristics in the solutions are not described in detail here. It should be noted that for those skilled in the art, without departing from the technical solution of the present invention, several deformations and improvements can still be made, and these should also be regarded as the protection scope of the present invention, and these will not affect the implementation effect of the present invention and the practicality of the patent. The protection scope required by this application should be based on the content of its claims, and the specific implementation manners in the specification can be used to interpret the content of the claims.

Claims

1. A preparation method of a high-quality ferrous succinate composition tablet, characterized in that: It includes the following steps carried out in sequence: S1: Mix ferrous succinate, part A of succinic acid, calcium hydrogen phosphate dihydrate, part A of corn starch, and polyvinylpyrrolidone K30 to obtain a granulation mixture; S2: Perform dry granulation on the granulation mixture to obtain a granulation mixture; S3: Mix the granulation mixture, part B of succinic acid, part B of corn starch, and magnesium stearate to obtain a total mixture; S4: Perform tabletting on the total mixture to obtain ferrous succinate tablets; S5: Coate the ferrous succinate tablets to obtain ferrous succinate coated tablets; The ratio of part A of succinic acid to the feeding amount of succinic acid is 85% - 95%; the ratio of part A of corn starch to the feeding amount of corn starch is 85% - 95%, the ratio of part B of succinic acid to the feeding amount of succinic acid is 5% - 15%; the ratio of part B of corn starch to the feeding amount of corn starch is 5% - 15%.

2. The preparation method of a high-quality ferrous succinate composition tablet according to claim 1, characterized in that: The mass ratio of ferrous succinate to succinic acid is 100:80 - 110.

3. The preparation method of a high-quality ferrous succinate composition tablet according to claim 1, characterized in that: Succinic acid is pulverized and sieved through a 60 - 80 mesh sieve.

4. The preparation method of a high-quality ferrous succinate composition tablet according to claim 1, characterized in that: In S1, the mixing speed is 20 - 30 revolutions per minute, and the mixing time is 10 - 20 minutes.

5. The preparation method of a high-quality ferrous succinate composition tablet according to claim 1, characterized in that: In S2, the technical parameters of dry granulation are: roller pressure 240 - 260 bar, roller gap 0.3 - 1.0 mm, feeding speed 20 - 25 rpm, screw feeding speed 90 - 100 rpm, roller speed 24 - 28 rpm, pulverizing speed 60 - 80 rpm, sizing speed 80 - 90 rpm; Set the sieve for the granulation process of dry granulation to 20 mesh; then sieve with a 20 - mesh upper sieve and a 60 - mesh lower sieve, and take the granules retained between the upper and lower sieves to obtain a granulation mixture.

6. The preparation method of a high-quality ferrous succinate composition tablet according to claim 1, characterized in that: In S3, the mixing speed is 20 - 30 revolutions per minute, and the mixing time is 10 - 20 minutes; in S4, the hardness of the ferrous succinate tablets is 70 - 90 N.

7. The preparation method of a high-quality ferrous succinate composition tablet according to claim 1, characterized in that: In S5, under the condition of a tablet bed temperature of 40°C - 50°C, spray the coating solution onto the ferrous succinate tablets at a speed of 140 - 180 ml / minute.

8. The preparation method of a high-quality ferrous succinate composition tablet according to claim 7, characterized in that: After coating, the weight gain of the ferrous succinate tablets is 2% - 4%; the coating solution is a gastric - soluble film - coating premix solution with a mass fraction of 10% - 14% prepared with absolute ethanol as the solvent.

9. Ferrous succinate coated tablets prepared by the preparation method of a high - quality ferrous succinate composition tablet according to any one of claims 1 - 8.

10. The ferrous succinate coated tablets prepared by the method for preparing a high-quality ferrous succinate composition tablet according to claim 9, characterized in that: Calculated by weight parts, its raw materials include: 100 parts of ferrous succinate, 80 - 110 parts of succinic acid, 70 - 90 parts of calcium hydrogen phosphate dihydrate, 40 - 60 parts of corn starch, 10 - 15 parts of polyvinylpyrrolidone K30, and 5 - 10 parts of magnesium stearate.

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