A preparation process of calcium polycarbophil

Abstract

The present invention discloses a preparation process for polycarbophil calcium in the field of pharmaceutical manufacturing process technology. The preparation process comprises the following steps: (1) preparing a magnesium sulfate aqueous solution; (2) preparing an acrylic acid monomer mixture: fully mixing acrylic acid, butadiene glycol, an initiator, and a regulator; the initiator is one or both of di-tert-butyl azodicarboxylate and diisopropyl azodicarboxylate; (3) concentrating the magnesium sulfate aqueous solution, adding the acrylic acid monomer mixture, controlling the temperature at 45-60°C to carry out a polymerization reaction, and filtering to obtain polycarbophil after the reaction is completed; (4) washing and soaking the polycarbophil; (5) performing a calcification reaction: fully mixing the polycarbophil treated in step (4) with an aqueous solution of a weakly acidic calcium salt, and performing a calcification reaction at 40-50°C; (6) after the calcification reaction is completed, centrifuging, drying, and pulverizing to obtain the finished product polycarbophil calcium. The present invention has the advantage of improving the yield.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical manufacturing processes, and in particular to a preparation process of calcium polycarbophil. Background Art

[0002] Calcium polycarbophil was first developed by Abbott Laboratories in the United States and has been widely used in Europe, the United States, and Japan. As a unique polymer, it has dual therapeutic effects in treating both constipation and diarrhea. Because it is a prodrug, its active ingredient is polycarbophil. In the presence of gastric acid, polycarbophil undergoes an ion exchange reaction, decalcifying the stomach, producing calcium as a byproduct. Therefore, polycarbophil offers the unique advantage of providing both therapeutic and calcium supplementation.

[0003] Polycarbophil calcium was initially produced using high-pressure acrylic acid polymerization, and later azobisisobutyronitrile was used as an initiator to improve the polymerization temperature and pressure. Since azobisisobutyronitrile decomposes at 70°C to initiate polymerization, for example, a synthesis method of polycarbophil calcium is disclosed in the prior art, with application publication number CN102516442A and application publication date 20210627. However, since acrylic acid is more likely to polymerize itself at 70°C, problems such as low product yield and unstable quality arise. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation process of calcium polycarbophil with improved yield.

[0005] In order to achieve the above-mentioned object of the invention, the preparation process of polycarbophil calcium of the present invention adopts the following technical scheme:

[0006] A preparation process of calcium polycarbophil comprises the following steps:

[0007] (1) preparing magnesium sulfate aqueous solution;

[0008] (2) Preparation of acrylic monomer mixture: fully mix acrylic acid, butadiene glycol, initiator and regulator; the initiator is one or both of di-tert-butyl azodicarboxylate and diisopropyl azodicarboxylate;

[0009] (3) After the magnesium sulfate aqueous solution is concentrated, the acrylic acid monomer mixture is added, and the temperature is controlled at 45-60° C. to carry out a polymerization reaction. After the reaction is completed, the polycarbophil is filtered to obtain the polycarbophil;

[0010] (4) washing and soaking the polycarbophil;

[0011] (5) Calcification reaction: the polycarbophil treated in step (4) is thoroughly mixed with an aqueous solution of a weakly acidic calcium salt, and a calcification reaction is carried out at 40 to 50° C.;

[0012] (6) After the calcification reaction is completed, the product calcium polycarbophil is obtained by centrifugation, drying and crushing.

[0013] Preferably, after the magnesium sulfate aqueous solution is prepared in step (1), the magnesium sulfate aqueous solution is subjected to vacuum dehydration and deoxygenation treatment.

[0014] Preferably, the vacuum dehydration treatment is to control the temperature at 55-60°C for vacuum concentration and dehydration.

[0015] Preferably, the deoxygenation treatment is to replace the solution with nitrogen after vacuum concentration and dehydration to form an anaerobic condition. The magnesium sulfate aqueous solution of the present invention is firstly subjected to vacuum concentration and dehydration to drive out oxygen in the system during the concentration process, and then replaced with nitrogen again to form an anaerobic condition.

[0016] Preferably, the acrylic acid monomer mixture in step (2) is prepared under nitrogen protection.

[0017] Preferably, the regulator in step (2) is one or more of isobutyraldehyde, furfural, and paraformaldehyde.

[0018] Preferably, the aqueous solution of the weakly acidic calcium salt in step (5) is a turbid solution of calcium carbonate suspended in water, and the turbid solution of calcium carbonate suspended in water is added to the reaction system. The present invention uses a turbid solution of calcium carbonate suspended in water to reduce the uneven addition of solid calcium carbonate, which may cause local calcification of the product and uneven calcium content, resulting in unqualified products; and at the same time, it is convenient to control and measure the pH value.

[0019] Preferably, the filtration in step (3) is performed by centrifugal filtration.

[0020] Preferably, tap water is used for washing and soaking in step (4). The present invention does not use deionized water or purified water for washing and soaking, thereby reducing production costs.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. The present invention provides a production process for initiating acrylic acid polymerization under low temperature conditions. By using one or both of di-tert-butyl azodicarboxylate and diisopropyl azodicarboxylate as initiators, the polymerization temperature is lowered to 45-60°C. The polymerization temperature is greatly reduced, and the polymerization reaction is controlled to be completed at 45-60°C. This not only ensures safety in the pharmaceutical production process, but also avoids the problem of acrylic acid self-polymerization at 70°C in the prior art, thereby improving the product yield to 100%.

[0023] 2. The present invention provides a production process for high molecular weight and high water absorption rate. By using vacuum dehydration in step (1) to remove oxygen in the system along with water vapor, and then performing deoxygenation treatment, polymerization under anaerobic conditions is further ensured, so that the molecular weight after polymerization is increased; the molecular weight after polymerization of the present invention reaches 35,000 to 50,000 and the water absorption rate is 55 to 65%; while the molecular weight of high-temperature polymerization in the prior art is 25,000 to 35,000 and the water absorption rate is 45 to 50%. DETAILED DESCRIPTION

[0024] The present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention. After reading the present invention, modifications of various equivalent forms of the present invention made by those skilled in the art all fall within the scope defined by the claims attached to this application.

[0025] Example 1

[0026] 500 g of magnesium sulfate heptahydrate was dissolved in 250 ml of purified water, and the temperature was controlled at 55° C. and the vacuum degree was 0.095 MPa. Under reduced pressure, 150 ml of water was concentrated, and the water was replaced with nitrogen after cooling. The internal oxygen content was detected to be 0. Then, while the magnesium sulfate aqueous solution was being concentrated, 50 g of acrylic acid, 5 g of 96% butadiene glycol, 1 g of isobutyraldehyde, and 100 g of di-tert-butyl azodicarboxylate were added under nitrogen protection and stirred uniformly at room temperature to prepare an acrylic acid monomer mixture for use. After the crushed magnesium sulfate aqueous solution was concentrated, the temperature was raised to 50° C. with stirring, and the acrylic acid monomer mixture was added dropwise for 30 minutes. After the addition was completed, the temperature was further raised to 55° C. and polymerization and aging were performed for 3 hours. 200 ml of water was added, the temperature was lowered by about 30° C., and polycarbophil was obtained by centrifugation. Then, the polycarbophil was washed with tap water, soaked, and centrifuged three times, and then added to 1000 ml of water. The temperature was raised to 40° C. with stirring, and a turbid solution of 30 g of calcium carbonate suspended in 150 ml of purified water was added thereto. The temperature was maintained at 40° C. for calcification for 6 hours. After the calcification reaction was completed, the polycarbophil calcium was centrifuged to obtain the wet product, which was washed with water to obtain a granular product. The wet product was then dried in a hot air circulation oven at a controlled temperature of 85° C. for 3 hours. After the drying loss was tested and qualified, the granular polycarbophil calcium was transferred to a vitrification oven, dried at a controlled temperature of 160° C. for 3 hours, and then crushed in a conventional grinder to obtain 60 g of white powder.

[0027] Example 2

[0028] 550 g of magnesium sulfate heptahydrate was dissolved in 250 ml of purified water, and the temperature was controlled at 60° C. and the vacuum degree was 0.095 MPa. Under reduced pressure, 180 ml of water was concentrated, and the water was replaced with nitrogen after cooling. The internal oxygen content was detected to be 0. Then, while the magnesium sulfate aqueous solution was being concentrated, 60 g of acrylic acid, 10 g of 96% butadiene glycol, 1 g of furfural, and 150 g of diisopropyl azodicarboxylate were added under nitrogen protection and stirred uniformly at room temperature to prepare an acrylic acid monomer mixture for use. After the pulverized magnesium sulfate aqueous solution was concentrated, the temperature was raised to 55° C. with stirring, and the acrylic acid monomer mixture was added dropwise for 30 minutes. After the addition was completed, the temperature was further raised to 60° C. and polymerization and aging were performed for 3 hours. 200 ml of water was added, the temperature was lowered by about 30° C., and the mixture was centrifuged to obtain polycarbophil. Then, the polycarbophil was washed with tap water, soaked, and centrifuged three times, and then added to 1000 ml of water. The temperature was raised to 40° C. with stirring, and a turbid solution of 30 g of calcium carbonate suspended in 150 ml of purified water was added thereto. The temperature was maintained at 50° C. for calcification for 6 hours. After the calcification reaction was completed, the mixture was centrifuged to obtain polycarbophil calcium, which was washed with water to obtain a wet granular product. The wet product was then dried in a hot air circulation oven at 95° C. for 3 hours. After the drying loss was tested to be qualified, the granular polycarbophil calcium was transferred to a vitrification oven, dried at 170° C. for 3 hours, and then crushed in a conventional grinder to obtain 70 g of white powder.

[0029] Example 3

[0030] 600 g of magnesium sulfate heptahydrate was dissolved in 250 ml of purified water, and the mixture was concentrated under reduced pressure to obtain 200 ml of water at a temperature of 60° C. and a vacuum degree of 0.095 MPa. After cooling, the mixture was replaced with nitrogen and the internal oxygen content was detected to be 0. Then, while the magnesium sulfate aqueous solution was being concentrated, 45 g of acrylic acid, 7.5 g of 96% butadiene glycol, 1 g of paraformaldehyde and 200 g of diisopropyl azodicarboxylate were added under nitrogen protection and stirred at room temperature to obtain an acrylic acid monomer mixture for use. After the pulverized magnesium sulfate aqueous solution was concentrated, the mixture was heated to 55° C. with stirring and the acrylic acid monomer mixture was added dropwise for 30 minutes. After the addition was completed, the mixture was further heated to 60° C. and subjected to polymerization aging for 3 hours. , then add 200 ml of water and cool down by about 30° C., centrifuge to obtain polycarbophil; then, wash the polycarbophil with tap water, soak it, and centrifuge it for 3 times, then add it to 1000 ml of water, stir and heat it to 40° C., add a turbid solution formed by 40 g of calcium carbonate suspended in 150 ml of purified water, and continue to maintain calcification at 50° C. for 6 hours; after the calcification reaction is completed, centrifuge to obtain polycarbophil calcium, wash it with water to obtain a granular wet product, and then dry it in a hot air circulation oven at a controlled temperature of 100° C. for 3 hours. After the drying loss is tested and qualified, the granular polycarbophil calcium is transferred to a vitrification oven, controlled at a temperature of 170° C. and dried for 3 hours, and then put it into a conventional grinder to be crushed to obtain 65 grams of white powder.

[0031] The yield, molecular weight and water absorption data of calcium polycarbophil prepared in Examples 1-3 of the present invention are shown in Table 1 below.

[0032] Table 1

[0033] Example 1 Example 2 Example 3 Yield 98％ 100％ 99％ Molecular weight 30,000-35,000 35,000-40,000 40,000-42,000 Water absorption 55％ 60％ 65％

Claims

1. A process for preparing calcium polycarbophil, characterized in that: The steps include: (1) preparing a magnesium sulfate aqueous solution. After the magnesium sulfate aqueous solution is prepared, the magnesium sulfate aqueous solution is subjected to vacuum dehydration and deoxygenation treatment. The deoxygenation treatment is to form an oxygen-free condition by nitrogen replacement after vacuum concentration and dehydration; (2) Preparation of acrylic monomer mixture: fully mix acrylic acid, butadiene glycol, initiator and regulator; the initiator is one or two of di-tert-butyl azodicarboxylate and diisopropyl azodicarboxylate; the regulator is one or more of isobutyraldehyde, furfural and paraformaldehyde; (3) After the magnesium sulfate aqueous solution is concentrated, the acrylic acid monomer mixture is added, and the temperature is controlled at 45-60°C to carry out polymerization reaction. After the reaction is completed, polycarbophil is obtained by filtration; (4) washing and soaking the polycarbophil; (5) Calcification reaction: The polycarbophil treated in step (4) is thoroughly mixed with an aqueous solution of a weakly acidic calcium salt and subjected to a calcification reaction at 40-50°C; (6) After the calcification reaction is completed, the product polycarbophil calcium is obtained by centrifugation, drying and crushing.

2. The process for preparing calcium polycarbophil according to claim 1, wherein: The vacuum dehydration treatment is to control the temperature at 55-60°C to perform vacuum concentration and dehydration.

3. The process for preparing calcium polycarbophil according to claim 1, wherein: The preparation of the acrylic acid monomer mixture in step (2) is carried out under nitrogen protection.

4. The process for preparing calcium polycarbophil according to claim 1, wherein: The aqueous solution of the weakly acidic salt of calcium in step (5) is a turbid solution of calcium carbonate suspended in water, and the turbid solution of calcium carbonate suspended in water is added to the reaction system.

5. The process for preparing calcium polycarbophil according to claim 1, wherein: The filtration in step (3) is performed by centrifugal filtration.

6. The process for preparing calcium polycarbophil according to claim 1, wherein: In step (4), tap water is used for both washing and soaking.