Ferrous succinate tetrahydrate crystal form, preparation method and pharmaceutical composition

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a ferrous succinate tetrahydrate crystal form, and in an X-ray diffraction pattern, the ferrous succinate tetrahydrate crystal form has characteristic peaks at 2 theta angles of 7.34 degrees, 12.0 degrees, 15.05 degrees, 16.53 degrees, 19.27 degrees, 21.25 degrees, 23.82 degrees, 30.58 degrees, 36.07 degrees, 37.05 degrees and 38.15 degrees. The ferrous succinate tetrahydrate crystal form is high in ferrous content, low in high iron content and good in stability. The invention also discloses a preparation method of the ferrous succinate tetrahydrate crystal form. The preparation method has the advantages of low cost, simplicity in operation, high yield, strong repeatability and the like. The invention also discloses a pharmaceutical composition, which comprises a therapeutically effective amount of ferrous succinate tetrahydrate and pharmaceutic adjuvants.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and relates to a new crystal form of ferrous succinate tetrahydrate, a preparation method and a pharmaceutical composition. Technical Background

[0002] Ferrous succinate is a second-generation small molecule organic iron with the characteristics of good absorption and few side effects. The British Pharmacopoeia shows that ferrous succinate is an anhydrous basic salt in the form of an amorphous powder. Iron is mainly absorbed in the small intestine, and the absorption of ferrous iron is significantly better than that of ferric iron. However, ferrous iron is easily oxidized to ferric iron during storage or molding, which affects the absorption of iron. However, the solubility of ferrous succinate basic salt is low and its gastrointestinal absorption is poor. Therefore, there is an urgent need to develop a new crystal form of ferrous succinate in both sample storage and clinical practice.

[0003] CN115141096A discloses a crystalline form of ferrous succinate tetrahydrate, which has better solubility at high pH values ​​than basic salts, which aroused great interest of the inventors. However, the inventors repeated experiments using the method provided in CN115141096A, and the resulting ferrous succinate tetrahydrate had a low yield and a brown appearance. Summary of the invention

[0004] The present invention provides a new crystal form of ferrous succinate tetrahydrate. In addition, the present invention also provides a method for preparing the above crystal form, which has simple process, high yield, easy industrialization, and simple operation, and is superior to the existing preparation process of ferrous succinate tetrahydrate. The present invention also provides a solid preparation prepared from the above crystal form raw materials.

[0005] The objective of the present invention is achieved through the following technical solutions:

[0006] A crystal form of ferrous succinate tetrahydrate has characteristic peaks at 2θ angles of about 7.34, 12.0, 15.05, 16.53, 19.27, 21.25, 23.82, 30.58, 36.07, 37.05 and 38.15 degrees in its X-ray diffraction diagram.

[0007] Preferably, in the crystal X-ray diffraction pattern of ferrous succinate tetrahydrate, there are characteristic peaks at 2θ angles of approximately 7.34, 12.0, 15.05, 16.27, 16.53, 19.27, 21.25, 23.82, 25.64, 29.2, 30.58, 36.07, 37.05, and 38.15°.

[0008] The ferrous succinate tetrahydrate crystal form has the following characteristics: Figure 1 The X-ray diffraction pattern shown in Figure 2The X-ray diffraction pattern shown in Figure 4 X-ray diffraction pattern shown.

[0009] Another object of the present invention is to provide a method for preparing the ferrous succinate tetrahydrate crystal form, comprising the following steps:

[0010] Step (1), neutralization reaction: adding sodium hydroxide and succinic acid in a molar ratio of 1.5:1.0 to 2.0:1.0, reacting succinic acid and sodium hydroxide in a reaction solvent at a temperature of 40 to 80° C. for 10 min to 5 h to obtain a neutralization solution for standby use;

[0011] Step (2), dissolving iron: dissolving ferrous sulfate heptahydrate in purified water at a temperature of 70 to 100° C. under nitrogen protection to obtain a ferrous solution;

[0012] Step (3), synthesis reaction: under nitrogen protection, at a temperature of 30 to 65° C., according to the feeding molar ratio of succinic acid to ferrous sulfate of 1.0:0.9 to 1.0:1.2, the ferrous solution is added dropwise to the neutralization solution, after the addition is completed, the pH value is adjusted to 4.9 to 5.5 with a sodium hydroxide solution, and the mixture is stirred at 30 to 65° C. for 1 to 30 minutes, and the reaction solution is cooled to a temperature of 20 to 60° C. for crystallization, filtered, and washed with anhydrous ethanol or 95% ethanol or acetone. By washing with anhydrous ethanol or 95% ethanol or acetone, water is removed and the generation of high iron is reduced, and drying is facilitated and the drying time is shortened, and vacuum drying is performed to obtain a ferrous succinate tetrahydrate crystal form.

[0013] In step (1), preferably, the reaction temperature is 50-60° C. and the reaction time is 0.5 h-1.5 h.

[0014] The usage ratio of the succinic acid to the reaction solvent is 1:0.2-1:0.3 mol / L.

[0015] The reaction solvent is one or more of water, methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, and dimethyl sulfoxide; preferably one or more of water, acetone, tetrahydrofuran, ethanol, and 1,4-dioxane; more preferably a mixed solvent of one selected from acetone, tetrahydrofuran or 1,4-dioxane and water, and the volume ratio of one selected from acetone, tetrahydrofuran or 1,4-dioxane and water is 1.0:1 to 3.0:1.

[0016] In step (2), the concentration of ferrous sulfate in the ferrous solution is 5 to 5.5 mol / L.

[0017] Preferably, under nitrogen protection, ferrous sulfate heptahydrate is dissolved in purified water at a temperature of 85-95° C. to obtain a ferrous solution.

[0018] In step (3), preferably, the ferrous solution is added dropwise to the neutralizing solution according to the molar ratio of succinic acid to ferrous sulfate of 1.0:1.0 to 1.0:1.1. The present invention adds the ferrous solution dropwise to the neutralizing solution, which can avoid the situation that when the neutralizing solution is added dropwise to the ferrous solution, crystallization is too fast, ferrous sulfate is easily wrapped, and the conversion rate is reduced.

[0019] Preferably, under nitrogen protection, at a temperature of 45 to 65° C., the ferrous solution is added dropwise to the neutralized solution; after the addition is completed, the pH is adjusted to 4.9 to 5.3 with a sodium hydroxide solution, and the mixture is stirred at 45 to 65° C. for 5 to 30 minutes; the reaction solution is cooled to a temperature of 40 to 50° C. for crystallization.

[0020] Considering that some basic salts will be produced when the pH is greater than 5.5, and the yield is slightly lower when the pH is less than 5.0, it is more preferred to adjust the pH to 5.0-5.2 with sodium hydroxide solution. Within the pH range of the present invention, the crystal form is not affected.

[0021] The mass fraction of the sodium hydroxide solution is 10% to 50%, preferably 20% to 30%.

[0022] Another object of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of the ferrous succinate tetrahydrate crystal form and pharmaceutical excipients.

[0023] The dosage form of the pharmaceutical composition is tablets, pills, granules, powders, aerosols, powder mists, sprays, suspensions, dry suspensions, solutions, emulsions, syrups, suppositories, injections, gels, implants, films, creams, ointments, pastes, patches, etc.

[0024] Specifically, the pharmaceutical composition is in the form of tablets.

[0025] A ferrous succinate tablet mainly comprises an active ingredient, ferrous succinate tetrahydrate crystal form, an absorption enhancer, a filler, a disintegrant, a binder, a lubricant and a coating material; the ferrous succinate tetrahydrate crystal form, the absorption enhancer, the filler and the binder are uniformly mixed to form dry granules, the dry granules are uniformly mixed with a disintegrant and a lubricant, and the tablets are compressed to obtain plain tablets, or the plain tablets are further coated to obtain coated tablets.

[0026] The weight ratio of the ferrous succinate tetrahydrate crystal form to the absorption enhancer is 1.5:1.

[0027] The weight ratio of the ferrous succinate tetrahydrate crystal form to the filler is 1:0.9 to 1:0.95.

[0028] The weight ratio of the ferrous succinate tetrahydrate crystal form to the disintegrant is 1:0.05 to 1:0.1.

[0029] The weight ratio of the ferrous succinate tetrahydrate crystal form to the binder is 1:0.1 to 1:0.15.

[0030] The weight ratio of the ferrous succinate tetrahydrate crystal form to the lubricant is 1:0.025 to 1:0.03.

[0031] The weight ratio of the ferrous succinate tetrahydrate crystal form to the coating material is 1:0.08 to 1:0.1.

[0032] The absorption enhancer is succinic acid or citric acid, preferably succinic acid.

[0033] The filler is one or more combinations of dihydrated calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, starch, sucrose, dextrin, lactose, and mannitol, preferably a combination of microcrystalline cellulose and mannitol in a weight ratio of 1:1.

[0034] The disintegrant is one or more combinations of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and starch.

[0035] The adhesive is one or more combinations of polyvinyl pyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0036] The lubricant is one or more combinations of colloidal silicon dioxide, talcum powder, magnesium stearate, and sodium stearyl fumarate.

[0037] The coating material is a gastric soluble film coating, which can be specifically selected from Opadry 85F18422.

[0038] A method for preparing the ferrous succinate tablets comprises the following steps:

[0039] Step (1), sieving: sieving the ferrous succinate tetrahydrate crystal, absorption enhancer, filler, disintegrant, binder, and lubricant through a 100-mesh sieve respectively;

[0040] Step (2), mixing: placing the ferrous succinate tetrahydrate crystal, the absorption promoter, the filler, and the binder in a three-dimensional mixer and mixing them evenly;

[0041] Step (3), granulation: granulating in a dry granulator to obtain dry granules;

[0042] Step (4), total mixing: placing the dry granules, disintegrant and lubricant in a three-stage mixer and mixing them uniformly;

[0043] Step (5), tabletting: tabletting in a tablet press to obtain a plain tablet with a diameter of 10.5 mm;

[0044] Step (6), coating: placing the plain tablets in a high-efficiency coating pan, and coating with a coating solution having a solid content of 10-20%, to obtain ferrous succinate tablets.

[0045] In step (6), the coating solution is prepared by dispersing the coating material in purified water.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] The ferrous succinate tetrahydrate crystal form of the present invention has high ferrous content and low ferric content, and has good stability, and the ferric content changes little under high temperature and high humidity conditions.

[0048] Compared with the existing preparation method of ferrous succinate tetrahydrate, the preparation method of ferrous succinate tetrahydrate of the present invention has the advantages of low cost, simple operation, higher yield and the like; in the neutralization step of preparing ferrous succinate tetrahydrate, the present invention adopts succinic acid and sodium hydroxide with lower material cost, and abandons the direct use of sodium succinate (sodium succinate) with higher cost and higher pH value in the solution as raw material, and further avoids the high initial pH value caused by excessive alkali by controlling the feeding molar ratio of sodium hydroxide and succinic acid to be less than 2.0, thereby avoiding the probability of ferrous succinate basic salt being generated in the initial reaction, so that the reaction is more conducive to the generation of ferrous succinate tetrahydrate.

[0049] In addition, the present invention drips the ferrous sulfate solution into the sodium succinate solution, so that the ferrous sulfate can fully react, so that the molar amount of sodium succinate is kept greater than the molar amount of ferrous sulfate during the reaction, thereby avoiding the probability of generating ferrous succinate basic salt due to local excess of ferrous sulfate, and at the same time, by controlling the reaction system at a lower pH and shortening the reaction time, it is beneficial to transform ferrous succinate tetrahydrate into ferrous succinate basic salt; the present invention makes the ferrous succinate tetrahydrate higher in purity, and the obtained product is obviously crystalline, has better fluidity, and is significantly improved in compressibility, so that it is more suitable for preparation molding. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 This is the X-ray diffraction (X-PRD) pattern of the ferrous succinate tetrahydrate crystal prepared in Example 1.

[0051] Figure 2 This is a thermogravimetric analysis (TG) diagram of the ferrous succinate tetrahydrate crystal prepared in Example 2.

[0052] Figure 3 This is the X-ray diffraction (X-PRD) pattern of the ferrous succinate tetrahydrate crystal prepared in Example 2.

[0053] Figure 4 This is the X-ray diffraction (X-PRD) pattern of the ferrous succinate tetrahydrate crystal prepared in Example 3. DETAILED DESCRIPTION

[0054] The technical solution of the present invention is further described below through specific implementation methods.

[0055] Example 1

[0056] The ferrous succinate tetrahydrate crystal form is prepared by the following method, the steps are as follows:

[0057] Step (1), neutralization reaction: add 150 mL of purified water, 150 mL of acetone, 118.1 g of succinic acid, and 74.8 g of sodium hydroxide into a reaction bottle, heat to 50° C., and stir to react for 1 h to obtain a neutralization solution for standby use;

[0058] Step (2), dissolving iron: under nitrogen protection, add 200 mL of purified water and 278.0 g of ferrous sulfate heptahydrate into a reaction bottle, heat to 90° C., and stir for 1 h to dissolve the ferrous sulfate heptahydrate to obtain a ferrous solution, which is transferred to a constant pressure dropping funnel;

[0059] Step (3), synthesis reaction: under nitrogen protection, at a temperature of 55° C., add ferrous solution to the neutralized solution, after the addition is complete, adjust the pH to 5.0 with a 25% by mass sodium hydroxide solution, stir and react at 60° C. for 5 min, cool the reaction solution to 50° C. for crystallization, filter under nitrogen protection, wash with anhydrous ethanol, and dry in vacuo to obtain 218.6 g of ferrous succinate tetrahydrate crystal form, an off-white powdery solid, with a ferrous content of 22.56%, a ferrous content of 0.48%, and a yield of 89.58%.

[0060] The X-ray diffraction pattern of the product of this example is shown in Figure 1 .

[0061] Example 2

[0062] The ferrous succinate tetrahydrate crystal form is prepared by the following method, the steps are as follows:

[0063] Step (1), neutralization reaction: add 200 mL of purified water, 118.1 g of succinic acid, and 66.8 g of sodium hydroxide into a reaction bottle, heat to 55° C., and stir to react for 1.5 h to obtain a neutralization solution for standby use;

[0064] Step (2), dissolving iron: under nitrogen protection, add 200 mL of purified water and 306.0 g of ferrous sulfate heptahydrate into a reaction bottle, heat to 98° C., and stir for 30 min to dissolve the ferrous sulfate heptahydrate to obtain a ferrous solution, which is transferred to a constant pressure dropping funnel;

[0065] Step (3), synthesis reaction: under nitrogen protection, at a temperature of 65° C., add ferrous solution to the neutralized solution, after the addition is complete, adjust the pH to 5.1 with a 25% by mass sodium hydroxide solution, stir and react at 50° C. for 25 minutes, cool the reaction solution to 45° C. for crystallization; filter under nitrogen protection, wash with anhydrous ethanol, and dry in vacuo to obtain 221.5 g of ferrous succinate tetrahydrate crystal form, a white powdery solid, with a ferrous content of 22.47%, a ferric content of 0.63%, and a yield of 90.77%.

[0066] The thermogravimetric analysis (TG) results of the product of this example are shown in Figure 2 , X-ray diffraction pattern see Figure 3 .

[0067] Figure 2 It shows that the product starts to lose water at 100°C and completely loses water at 300°C. The water weight loss in this process is about 29.5%, which is consistent with the theoretical value of the water content of ferrous succinate tetrahydrate (29.53%), indicating that the present invention obtains ferrous succinate tetrahydrate.

[0068] Example 3

[0069] The ferrous succinate tetrahydrate crystal form is prepared by the following method, the steps are as follows:

[0070] Step (1), neutralization reaction: add 100 mL of purified water, 100 mL of 1,4-dioxane, 118.1 g of succinic acid, and 72.8 g of sodium hydroxide into a reaction bottle, heat to 60° C., and stir to react for 0.5 h to obtain a neutralization solution for standby use;

[0071] Step (2), dissolving iron: under nitrogen protection, add 200 mL of purified water and 292.0 g of ferrous sulfate heptahydrate into a reaction flask, stir to dissolve, heat to 95° C., stir for 1 h to dissolve the ferrous sulfate heptahydrate, obtain a ferrous solution, and transfer it to a constant pressure dropping funnel;

[0072] Step (3), synthesis reaction: under nitrogen protection, at a temperature of 60° C., add ferrous solution to the neutralized solution, after the addition is complete, adjust the pH to 5.2 with a 25% by mass sodium hydroxide solution, stir and react at 58° C. for 10 minutes, cool the reaction solution to 50° C. for crystallization; filter under nitrogen protection, wash with anhydrous ethanol, and dry in vacuo to obtain 221.9 g of ferrous succinate tetrahydrate crystal form, an off-white powdery solid, with a ferrous content of 22.41%, a ferrous content of 0.62%, and a yield of 90.93%.

[0073] The X-ray diffraction pattern of the product of this example is shown in Figure 4 .

[0074] Example 4

[0075] The ferrous succinate tetrahydrate crystal form is prepared by the following method, the steps are as follows:

[0076] Step (1), neutralization reaction: add 150 mL of purified water, 150 mL of 1,4-dioxane, 118.1 g of succinic acid, and 76.8 g of sodium hydroxide into a reaction bottle, heat to 55° C., stir and react for 1 h to obtain a neutralization solution for standby use;

[0077] Step (2), dissolving iron: under nitrogen protection, add 200 mL of purified water and 278.0 g of ferrous sulfate heptahydrate into a reaction bottle, heat to 96° C., and stir for 1 h to dissolve the ferrous sulfate heptahydrate to obtain a ferrous solution, which is transferred to a constant pressure dropping funnel;

[0078] Step (3), synthesis reaction: under nitrogen protection, at 60° C., add ferrous solution to the neutralized solution, after the addition is complete, adjust the pH to 5.0 with 25% by mass sodium hydroxide solution, stir and react at 50° C. for 25 minutes, cool the reaction solution to 45° C. for crystallization; filter under nitrogen protection, wash with anhydrous ethanol, and dry in vacuo to obtain 217.5 g of ferrous succinate tetrahydrate crystal form, an off-white powdery solid, with a ferrous content of 22.61%, a ferrous content of 0.52%, and a yield of 89.13%.

[0079] Example 5

[0080] Crystalline Characterization of Ferrous Succinate Tetrahydrate

[0081] The products of Examples 1 to 3 were respectively subjected to X-ray powder diffraction tests, using Philips X'pert MPD Pro X-ray diffractometer. Testing conditions: Cu Kα ray (=0.15418 nm), 2θ range: 5-50°, tube voltage 40 kV, tube current 40 mA, room temperature.

[0082] The crystalline powder diffraction patterns obtained in Example 1, Example 2 and Example 3 are shown in Figure 1 , Figure 3 , Figure 4 , showing that the obtained product has similar characteristic peaks at 2θ angles of 77.34, 12.0, 15.05, 16.27, 16.53, 19.27, 21.25, 23.82, 25.64, 29.2, 30.58, 36.07, 37.05, 38.15° and nearby positions, indicating that the same crystalline form of ferrous succinate tetrahydrate was prepared in the four embodiments of the present invention.

[0083] The X-ray diffraction data of the product of Example 1 are shown in Table 1.

[0084] Table 1. X-ray diffraction data of the ferrous succinate tetrahydrate crystal obtained in Example 1

[0085]

[0086]

[0087] Comparative Example 1

[0088] Dissolve 125.0 g of sodium succinate hexahydrate in 250 mL of water, heat to 60°C, stir to dissolve, filter to obtain a sodium succinate solution, and keep it at 60°C for later use;

[0089] Heat 250 mL of water to 60°C, add 0.7 mL of sulfuric acid (mass fraction 98%); then add 125.0 g of ferrous sulfate heptahydrate, stir and dissolve, introduce nitrogen to replace the air in the reaction container, and keep the temperature at 60°C;

[0090] The sodium succinate solution was slowly added dropwise to the ferrous sulfate solution, the dropping speed was controlled, the dropping was completed within 15 minutes, and nitrogen was passed to protect the entire reaction process. The pH of the reaction solution was adjusted to 4.5 with 5wt% dilute sulfuric acid and 10wt% sodium hydroxide solution. The reaction temperature was 70°C. Under slow stirring conditions, the reaction was kept warm for 40 minutes. When the reaction solution began to change from light green to brown and slightly whitish turbid, the reaction was completed. At this time, the reaction solution was slowly cooled to 55°C, and then the temperature of the reaction solution was gradually cooled to 25°C at a cooling rate of 18°C / h. Stirring was continued for 30 minutes to obtain a crystallized liquid.

[0091] After filtration, the filter cake was washed twice with deionized water and ethanol at the same temperature (20 mL each time), and then dried in vacuum at 60°C to obtain 47.1 g of ferrous succinate tetrahydrate as a light brown powdery solid with a ferrous content of 20.50%, a ferrous content of 2.57%, and a yield of 41.71%.

[0092] Example 6

[0093] Crystal quality test of ferrous succinate tetrahydrate

[0094] The ferrous succinate tetrahydrate crystal form of Example 1 was taken to observe its properties, and the ferrous and ferrous contents and powder properties were determined respectively, wherein the ferrous and ferrous contents were determined as follows:

[0095] High-speed iron (Fe 3+ ) Determination: Take about 3g of this product, weigh it accurately, put it in a 250mL iodine bottle, add 100mL of freshly boiled cold water and 10mL of hydrochloric acid to dissolve, add 3g of potassium iodide, immediately seal it, shake it gently, place it in a dark place for 5 minutes, titrate it with sodium thiosulfate titration solution (0.1mol / L), add 2mL of starch indicator solution when it is close to the end point, continue titrating until the blue color disappears, and correct the titration result with a blank test. Each 1mL of sodium thiosulfate titration solution (0.1mol / L) is equivalent to 5.585mg Fe 3+ .

[0096] Ferrous iron determination: Take about 0.5g of this product, weigh accurately, dissolve it in a mixture of 20mL of dilute sulfuric acid and 30mL of water, add 2 drops of o-phenanthroline indicator solution, immediately titrate with cerium sulfate titration solution (0.1mol / L), and correct the titration result with a blank test. Each 1mL of cerium sulfate titration solution (0.1mol / L) is equivalent to 5.585mg Fe 2+ .

[0097] Powder properties: The angle of repose, bulk density (ρa) and tap density (ρp) of ferrous succinate tetrahydrate were measured using a BT-1000 powder comprehensive properties tester, and the Carr coefficient ((ρp-ρa) / ρp*100%) was calculated.

[0098] The test results are shown in Table 2. It shows that the ferrous succinate tetrahydrate crystal form of the present invention has a high ferrous content and a low ferric content; and the ferrous succinate tetrahydrate crystal form of the present invention has better fluidity and significantly improved compressibility, and is more suitable for formulation molding.

[0099] Table 2. Results of quality test of ferrous succinate tetrahydrate crystal form

[0100] Detection items Example 1 Comparative Example 1 Characteristics Off-white crystalline solid Light brown crystalline solid High iron content (%) 0.48 2.57 Ferrous content (%) 22.56 20.50 Angle of repose(°) 38.6 40.3 Carl coefficient 19.3 21.6

[0101] Example 9

[0102] The prescription of ferrous succinate tablets is as follows:

[0103]

[0104] The preparation process is as follows:

[0105] Step (1), sieving: respectively sieving the ferrous succinate tetrahydrate crystal form (Example 1), succinic acid, microcrystalline cellulose, mannitol, hypromellose, and colloidal silicon dioxide through a 100-mesh sieve;

[0106] Step (2), mixing: placing the ferrous succinate tetrahydrate crystal, succinic acid, microcrystalline cellulose, mannitol, and hypromellose in a dry granulation three-dimensional mixer and mixing them evenly;

[0107] Step (3), granulation: the mixed material is granulated by a dry granulator to obtain dry granules;

[0108] Step (4), total mixing: placing the dry particles in a mixer and mixing with low-substituted hydroxypropyl cellulose and colloidal silicon dioxide;

[0109] Step (5), tableting: placing the granules in a tablet press, and tableting to obtain plain tablets, each tablet containing 150 mg of ferrous succinate tetrahydrate crystal form, with a diameter of 10.5 mm, a hardness of 6-8 kg, and a friability of <1%.

[0110] Step (6), coating: prepare a film coating premix (gastric soluble type) coating solution with a solid content of 15% with purified water, place the plain tablets in a high-efficiency coating pan for coating, and obtain ferrous succinate tablets.

Claims

1. A ferrous succinate tetrahydrate crystal form, characterized in that: In the X-ray powder diffraction pattern of the ferrous succinate tetrahydrate crystal form, there are characteristic peaks at 2θ angles of 7.34, 12.0, 15.05, 16.53, 19.27, 21.25, 23.82, 30.58, 36.07, 37.05, and 38.15°.

2. The ferrous succinate tetrahydrate crystal form according to claim 1, characterized in that: In the X-ray powder diffraction pattern of the ferrous succinate tetrahydrate crystal form, there are characteristic peaks at 2θ angles of 7.34, 12.0, 15.05, 16.27, 16.53, 19.27, 21.25, 23.82, 25.64, 29.2, 30.58, 36.07, 37.05, and 38.15°.

3. The ferrous succinate tetrahydrate crystal form according to claim 1, characterized in that: The ferrous succinate tetrahydrate crystal form has an X-ray diffraction pattern as shown in FIG1 , or the ferrous succinate tetrahydrate crystal form has an X-ray diffraction pattern as shown in FIG2 , or the ferrous succinate tetrahydrate crystal form has an X-ray diffraction pattern as shown in FIG4 .

4. A method for preparing the ferrous succinate tetrahydrate crystal form according to claim 1, characterized in that: The following steps are involved: Step (1), neutralization reaction: adding sodium hydroxide and succinic acid in a molar ratio of 1.5:1.0 to 2.0:1.0, reacting succinic acid and sodium hydroxide in a reaction solvent at a temperature of 40 to 80° C. for 10 min to 5 h to obtain a neutralized solution; Step (2), dissolving iron: dissolving ferrous sulfate heptahydrate in purified water at a temperature of 70-100° C. under nitrogen protection to obtain a ferrous solution; Step (3), synthesis reaction: under nitrogen protection, at a temperature of 30 to 65° C., according to the feeding molar ratio of succinic acid to ferrous sulfate of 1.0:0.9 to 1.0:1.2, the ferrous solution is added dropwise to the neutralization solution, after the addition is completed, the pH is adjusted to 4.9 to 5.5 with a sodium hydroxide solution, and the mixture is stirred at 30 to 65° C. for 1 to 30 minutes. The reaction solution is cooled to 20 to 60° C. for crystallization, filtered, washed with anhydrous ethanol or 95% ethanol or acetone, and vacuum dried to obtain a ferrous succinate tetrahydrate crystal.

5. The method for preparing the ferrous succinate tetrahydrate crystal form according to claim 4, characterized in that: In step (1), the reaction temperature is 50-60° C. and the reaction time is 0.5 h-1.5 h; In step (2), ferrous sulfate heptahydrate is dissolved in purified water at a temperature of 85 to 95° C. to obtain a ferrous solution; In step (3), under nitrogen protection, at a temperature of 45 to 65° C., the ferrous solution is added dropwise to the neutralized solution; after the addition is completed, the pH is adjusted to 4.9 to 5.3 with a sodium hydroxide solution, and the mixture is stirred at 45 to 65° C. for 5 to 30 minutes; the reaction solution is cooled to a temperature of 40 to 50° C. for crystallization.

6. The method for preparing the ferrous succinate tetrahydrate crystal form according to claim 4, characterized in that: In step (1), the amount ratio of succinic acid to reaction solvent is 1:0.2 to 1:0.3 mol / L; the reaction solvent is one or more of water, methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, and dimethyl sulfoxide; preferably one or more of water, acetone, tetrahydrofuran, ethanol, and 1,4-dioxane; more preferably a mixed solvent of one selected from acetone, tetrahydrofuran or 1,4-dioxane and water, and the volume ratio of one selected from acetone, tetrahydrofuran or 1,4-dioxane and water is 1.0:1 to 3.0:1; In step (2), the concentration of ferrous sulfate in the ferrous solution is 5 to 5.5 mol / L; In step (3), the molar ratio of succinic acid to ferrous sulfate is 1.0:1.0 to 1.0:1.

2.

7. The method for preparing the ferrous succinate tetrahydrate crystal form according to claim 3 or 5, characterized in that: In step (3), the pH is adjusted to 5.0-5.2 with sodium hydroxide solution.

8. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises a therapeutically effective amount of the ferrous succinate tetrahydrate crystal form according to claim 1 and pharmaceutical excipients.

9. The pharmaceutical composition according to claim 8, characterized in that: The dosage form of the pharmaceutical composition is tablets, pills, granules, powders, aerosols, powder sprays, sprays, suspensions, dry suspensions, solutions, emulsions, syrups, suppositories, injections, gels, implants, films, creams, ointments, pastes, and patches.

10. A ferrous succinate tablet, characterized in that: The invention mainly comprises ferrous succinate tetrahydrate crystal form, absorption promoter, filler, disintegrant, binder, lubricant and coating material; the ferrous succinate tetrahydrate crystal form, absorption promoter, filler and binder are uniformly mixed to form dry granules, the dry granules are uniformly mixed with disintegrant and lubricant, and the plain tablets are obtained by tableting, or the plain tablets are further coated to obtain coated tablets.

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