A preparation method of medicinal formaldehyde casein

Abstract

The invention discloses a preparation method of medicinal formaldehyde casein, comprising the steps of (1) adding casein and 0.5M carbonate aqueous solution into a reaction vessel, stirring and dissolving; adding paraformaldehyde; reacting to obtain a reaction solution containing formaldehyde casein; (2) adding ammonia water into the reaction solution containing formaldehyde casein, reacting; filtering, washing the filter cake with water, and obtaining a crude formaldehyde casein product; (3) dissolving the crude formaldehyde casein product in an organic solvent, stirring and beating to obtain a beating mixed solution; (4) filtering the beating mixed solution, washing with an organic solvent, obtaining a filter cake; drying under reduced pressure to obtain a dry material; (5) transferring the dry material into a rotary vibrating screen, sieving with a 35-mesh screen; collecting the material passing through the screen, namely, the medicinal formaldehyde casein. The invention is simple to operate, has readily available raw materials, low free formaldehyde content, high casein content, excellent product quality, high operational safety, environmental friendliness, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the pharmaceutical field, and particularly relates to a method for preparing medicinal formaldehyde casein. Background Art

[0002] Formaldehyde casein is a cross-linked casein connected by methylene bridges, a tasteless and odorless amorphous white solid. Casein is the main protein component in milk and exists stably in milk in a micellar structure. Compared with casein, formaldehyde casein has significantly lower water solubility, improved shrinkage and mechanical properties, is biodegradable, non-allergenic, antistatic and almost non-flammable. As a new type of polymer material, formaldehyde casein not only has the biodegradability of casein, but also the hardness and durability of plastic.

[0003] As a new type of pharmaceutical excipient, medical formaldehyde casein has been used in marketed pharmaceutical preparations, but it is not currently included in Chinese and foreign pharmacopoeias, and no literature on related production technology is available. Due to its hard nature, formaldehyde casein is used as an additive to increase the hardness of tablets in the pharmaceutical field. It can improve the mechanical strength of tablets, prevent breakage during storage and transportation, and ensure the accuracy and stability of drug dosage. Formaldehyde casein can also improve the taste of tablets, making them smoother and easier to swallow.

[0004] At present, formaldehyde is generally used as a cross-linking agent to undergo cross-linking polymerization with casein amino groups to obtain formaldehyde casein. However, the free formaldehyde content of commercially available products is relatively high, and there are a large number of hydroxyl groups, thiol groups, and amino groups in human cells and enzyme systems. After contacting a certain concentration of formaldehyde, they will immediately react, produce cytotoxicity, and denature the protein. The demand for formaldehyde casein in the pharmaceutical industry is increasing. Preparation customers have extremely strict requirements on the casein content, free formaldehyde content, moisture, free ammonia, residual solvents, etc. of this excipient. Poor quality control will affect the efficacy of the preparation and even have adverse effects on the human body. Therefore, it is necessary to finely control the synthesis and refining process to reduce the residual impurities, improve product quality, and meet pharmaceutical needs.

[0005] Based on the above situation, there is an urgent need for a preparation method for medicinal formaldehyde casein with simple process operation, low free formaldehyde content, high casein content, excellent product quality, low cost and high yield, environmental friendliness, and suitability for industrial production. Summary of the invention

[0006] The purpose of the present invention is to overcome the deficiencies of the prior art and to provide a method for preparing medicinal formaldehyde casein which has the advantages of simple process, high conversion rate, low free formaldehyde content, high casein content, mild reaction conditions, low cost and product quality standards meeting enterprise standards.

[0007] The technical solution of the present invention is summarized as follows:

[0008] A method for preparing medicinal formaldehyde casein comprises the following steps:

[0009] (1) adding casein and 0.5M carbonate aqueous solution into a reaction container and stirring to dissolve; adding paraformaldehyde; reacting at 10-40° C. for 5-8 hours to obtain a reaction solution containing formaldehyde casein;

[0010] The mass ratio of casein, 0.5M carbonate aqueous solution and paraformaldehyde is 1:5.5-12.5:0.012-0.05;

[0011] (2) adding aqueous ammonia to the reaction solution containing formaldehyde casein, stirring and reacting at 10-40° C. for 1-3 hours; filtering, washing the filter cake with water until the pH value of the filtrate is 6.7-7.2, and obtaining a crude formaldehyde casein product, wherein the mass ratio of the polyformaldehyde to the aqueous ammonia is 1:1.9-3.5;

[0012] (3) dissolving the crude formaldehyde casein obtained in step (2) in an organic solvent, heating to 30 to 60° C., stirring and beating for 0.5 to 1.5 hours to obtain a beating mixture, wherein the mass ratio of casein to organic solvent is 1:1.8 to 3.2;

[0013] (4) filtering the pulped mixed solution obtained in step (3), washing with an organic solvent to obtain a filter cake; and drying under reduced pressure at 40 to 90° C. for 2 to 4 hours to obtain a dry material, wherein the mass of the organic solvent in this step is 10% to 15% of the mass of the organic solvent in step (3);

[0014] (5) The dried material obtained in step (4) is transferred to a rotary vibrating screen, and sieved using a 35-mesh screen. The material passing through the screen is collected to obtain the medicinal formaldehyde casein.

[0015] Preferably, in step (1), the mass ratio of casein, 0.5M carbonate aqueous solution and paraformaldehyde is 1:6.5-9:0.025-0.042.

[0016] Preferably, the carbonate is sodium carbonate, potassium carbonate or ammonium carbonate.

[0017] Preferably, the organic solvent in step (3) is ethyl acetate, dichloromethane, chloroform or methanol.

[0018] Preferably, the organic solvent in step (4) is ethyl acetate, dichloromethane, chloroform or methanol.

[0019] Preferably, the temperature of the reduced pressure drying in step (4) is 55 to 80°C.

[0020] Advantages of the present invention:

[0021] 1. The method of the present invention uses casein and paraformaldehyde as raw materials. Paraformaldehyde releases formaldehyde when heated, and then the formaldehyde reacts with the amino group of casein to generate α-amino alcohol, and the α-amino alcohol reacts with another casein amino group to generate a methylene bridge to obtain formaldehyde casein. The method has mild reaction conditions, controllable residual formaldehyde, and high casein content;

[0022] 2. The present invention uses paraformaldehyde as a crosslinking agent. Paraformaldehyde is a crystalline powder, which is convenient to weigh and can accurately control the amount of addition. In addition, paraformaldehyde slowly releases formaldehyde during the reaction, which can effectively control the reaction process and reduce the generation of by-products.

[0023] 3. Raw material casein is not easily soluble in water, and reacts slowly with formaldehyde in a heterogeneous system. The present invention uses carbonate to adjust the aqueous solution to be weakly alkaline, increase the solubility of casein, and react in a homogeneous phase, greatly improving the reaction rate;

[0024] 4. The present invention uses ethyl acetate, dichloromethane, chloroform or methanol as a purification solvent, and can effectively remove impurities such as unreacted raw materials and by-products in the reaction solution through a pulping method, and the casein content of the obtained formaldehyde casein is more than 92%;

[0025] 5. Compared with commercially available formaldehyde casein, the medicinal formaldehyde casein prepared by the method of the present invention has higher casein content, lower free formaldehyde content, lower moisture content, lower ignition residue and free ammonia, and the product quality standard fully meets the enterprise standard and meets the medicinal needs;

[0026] 6. The production process used in the present invention is simple to operate, the raw materials are readily available, the operation is highly safe, the environment is friendly and pollution-free, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the infrared spectrum of medicinal formaldehyde casein. DETAILED DESCRIPTION

[0028] The present invention is further described in detail below through specific examples, which should not be construed as limiting the claims of the present invention.

[0029] Casein (content ≥ 95%) was purchased from Linxia Huaan Biological Products Co., Ltd.

[0030] Paraformaldehyde (97% to 99% formaldehyde) was purchased from Shandong Xuchen Chemical Technology Co., Ltd.

[0031] The description of casein and paraformaldehyde is to enable those skilled in the art to better understand the present invention, and does not limit the present invention. The above products produced by other companies can also be used in the present invention.

[0032] Ammonia water is an aqueous solution containing 25% to 28% ammonia.

[0033] Example 1

[0034] A method for preparing medicinal formaldehyde casein comprises the following steps:

[0035] (1) adding 1000 g of casein (content 96.25%) and 5500 g of 0.5 M sodium carbonate aqueous solution into a reaction container and stirring to dissolve; adding 50 g of paraformaldehyde (content 98.3% as formaldehyde); reacting at 10° C. for 8 hours to obtain a reaction solution containing formaldehyde casein;

[0036] (2) adding 95 g of aqueous ammonia to the reaction solution containing formaldehyde casein, stirring at 10° C. for 3 hours; filtering, and washing the filter cake with water until the pH of the filtrate is 7.2 to obtain a crude formaldehyde casein product;

[0037] (3) dissolving the crude formaldehyde casein obtained in step (2) in 3200 g of dichloromethane, heating to 60° C., stirring and beating for 0.5 hours to obtain a beating mixture;

[0038] (4) filtering the pulped mixed solution obtained in step (3), washing with 320 g of dichloromethane to obtain a filter cake; and drying under reduced pressure at 40° C. for 4 hours to obtain a dry material;

[0039] (5) The dried material obtained in step (4) is transferred to a rotary vibrating screen and sieved using a 35-mesh screen. The material passing through the screen is collected to obtain medicinal formaldehyde casein.

[0040] After sampling and testing, the product is qualified and then packaged and stored. 942.81g of medicinal formaldehyde casein, purification yield 94.28%, infrared spectrum see Figure 1 After inspection, the quality indicators all meet the pharmaceutical enterprise standards, see Table 1.

[0041] Example 2

[0042] A method for preparing medicinal formaldehyde casein comprises the following steps:

[0043] (1) adding 1000 g of casein (content 96.25%) and 12500 g of 0.5 M ammonium carbonate aqueous solution into a reaction vessel and stirring to dissolve; adding 12 g of paraformaldehyde (content 98.3% as formaldehyde); reacting at 40° C. for 5 hours to obtain a reaction solution containing formaldehyde casein;

[0044] (2) adding 42 g of aqueous ammonia to the reaction solution containing formaldehyde casein, stirring at 40° C. for 1 hour; filtering, and washing the filter cake with water until the pH of the filtrate is 6.7 to obtain a crude formaldehyde casein product;

[0045] (3) dissolving the crude formaldehyde casein obtained in step (2) in 1800 g of ethyl acetate, heating to 30° C., stirring and beating for 1.5 hours to obtain a beating mixture;

[0046] (4) filtering the pulped mixed solution obtained in step (3), washing with 270 g of ethyl acetate to obtain a filter cake; and drying under reduced pressure at 90° C. for 2 hours to obtain a dry material;

[0047] (5) The dried material obtained in step (4) is transferred to a rotary vibrating screen and sieved using a 35-mesh screen. The material passing through the screen is collected to obtain medicinal formaldehyde casein.

[0048] After sampling and testing, the product was qualified and then packaged and stored. 937.36g of medicinal formaldehyde casein, purification yield 93.73%. After inspection, the quality indicators all met the pharmaceutical enterprise standards, see Table 1.

[0049] Example 3

[0050] A method for preparing medicinal formaldehyde casein comprises the following steps:

[0051] (1) adding 1000 g of casein (content 96.25%) and 9000 g of 0.5 M potassium carbonate aqueous solution into a reaction container and stirring to dissolve; adding 25 g of paraformaldehyde (content 98.3% as formaldehyde); reacting at 20° C. for 7 hours to obtain a reaction solution containing formaldehyde casein;

[0052] (2) adding 75 g of aqueous ammonia to the reaction solution containing formaldehyde casein, stirring and reacting at 20° C. for 2.5 hours; filtering, and washing the filter cake with water until the pH of the filtrate is 7.0 to obtain a crude formaldehyde casein product;

[0053] (3) dissolving the crude formaldehyde casein obtained in step (2) in 2600 g of methanol, heating to 50° C., stirring and beating for 0.5 hours to obtain a beating mixture;

[0054] (4) filtering the pulped mixed solution obtained in step (3), washing with 338 g of methanol to obtain a filter cake; and drying under reduced pressure at 80° C. for 2.5 hours to obtain a dry material;

[0055] (5) The dried material obtained in step (4) is transferred to a rotary vibrating screen and sieved using a 35-mesh screen. The material passing through the screen is collected to obtain medicinal formaldehyde casein.

[0056] After sampling and testing, the product is qualified and then packaged and stored. 950.46g of medicinal formaldehyde casein, purification yield 95.05%. After inspection, the quality indicators all meet the pharmaceutical enterprise standards, see Table 1.

[0057] Example 4

[0058] A method for preparing medicinal formaldehyde casein comprises the following steps:

[0059] (1) adding 1000 g of casein (content 96.25%) and 6500 g of 0.5 M potassium carbonate aqueous solution into a reaction vessel and stirring to dissolve; adding 42 g of paraformaldehyde (content 98.3% as formaldehyde); reacting at 30° C. for 6 hours to obtain a reaction solution containing formaldehyde casein;

[0060] (2) adding 105 g of aqueous ammonia to the reaction solution containing formaldehyde casein, stirring and reacting at 30° C. for 1.5 hours; filtering, and washing the filter cake with water until the pH of the filtrate is 6.9 to obtain a crude formaldehyde casein product;

[0061] (3) dissolving the crude formaldehyde casein obtained in step (2) in 2000 g of chloroform, heating to 30° C., stirring and beating for 1.5 hours to obtain a beating mixture;

[0062] (4) filtering the pulped mixed solution obtained in step (3), washing with 220 g of chloroform to obtain a filter cake; and drying under reduced pressure at 55° C. for 3.5 hours to obtain a dry material;

[0063] (5) The dried material obtained in step (4) is transferred to a rotary vibrating screen and sieved using a 35-mesh screen. The material passing through the screen is collected to obtain medicinal formaldehyde casein.

[0064] After sampling and testing, the product is qualified and then packaged and stored. 954.91g of medicinal formaldehyde casein, purification yield 95.49%. After inspection, the quality indicators all meet the pharmaceutical enterprise standards, see Table 1.

[0065] Example 5

[0066] A method for preparing medicinal formaldehyde casein comprises the following steps:

[0067] (1) adding 1000 g of casein (content 96.25%) and 8000 g of 0.5 M sodium carbonate aqueous solution into a reaction container and stirring to dissolve; adding 30 g of paraformaldehyde (content 98.3% as formaldehyde); reacting at 40° C. for 5 hours to obtain a reaction solution containing formaldehyde casein;

[0068] (2) adding 60 g of aqueous ammonia to the reaction solution containing formaldehyde casein, stirring at 40° C. for 1 hour; filtering, and washing the filter cake with water until the pH of the filtrate is 6.8 to obtain a crude formaldehyde casein product;

[0069] (3) dissolving the crude formaldehyde casein obtained in step (2) in 2400 g of ethyl acetate, heating to 45° C., stirring and beating for 1 hour to obtain a beating mixture;

[0070] (4) filtering the pulped mixed solution obtained in step (3), washing with 288 g of ethyl acetate to obtain a filter cake; and drying under reduced pressure at 70° C. for 3 hours to obtain a dry material;

[0071] (5) The dried material obtained in step (4) is transferred to a rotary vibrating screen and sieved using a 35-mesh screen. The material passing through the screen is collected to obtain medicinal formaldehyde casein.

[0072] After sampling and testing, the product is qualified and then packaged and stored. 955.06g of medicinal formaldehyde casein, purification yield 95.51%. After inspection, the quality indicators all meet the pharmaceutical enterprise standards, see Table 1.

[0073] Table 1 Pharmaceutical enterprise standards and test results of formaldehyde casein

[0074]

Claims

1. A method for preparing medicinal formaldehyde casein, characterized in that The following steps are involved: (1) adding casein and 0.5 M carbonate aqueous solution into a reaction vessel and stirring to dissolve; adding paraformaldehyde; React at 10-40°C for 5-8 hours to obtain a reaction solution containing formaldehyde casein; The mass ratio of casein, 0.5M carbonate aqueous solution and paraformaldehyde is 1:5.5-12.5:0.012-0.05; (2) adding aqueous ammonia to the reaction solution containing formaldehyde casein, stirring and reacting at 10-40° C. for 1-3 hours; filtering, washing the filter cake with water until the pH value of the filtrate is 6.7-7.2, and obtaining a crude formaldehyde casein product, wherein the mass ratio of the polyformaldehyde to the aqueous ammonia is 1:1.9-3.5; (3) dissolving the crude formaldehyde casein obtained in step (2) in an organic solvent, heating to 30 to 60° C., stirring and beating for 0.5 to 1.5 hours to obtain a beating mixture, wherein the mass ratio of casein to organic solvent is 1:1.8 to 3.2; (4) filtering the pulped mixed solution obtained in step (3), washing with an organic solvent to obtain a filter cake; and drying under reduced pressure at 40 to 90° C. for 2 to 4 hours to obtain a dry material, wherein the mass of the organic solvent in this step is 10% to 15% of the mass of the organic solvent in step (3); (5) The dried material obtained in step (4) is transferred to a rotary vibrating screen, and sieved using a 35-mesh screen. The material passing through the screen is collected to obtain the medicinal formaldehyde casein.

2. The method for preparing a medicinal formaldehyde casein according to claim 1, characterized in that The mass ratio of casein, 0.5M carbonate aqueous solution and paraformaldehyde in step (1) is 1:6.5-9:0.025-0.

042.

3. The method for preparing a medicinal formaldehyde casein according to claim 1 or 2, characterized in that The carbonate is sodium carbonate, potassium carbonate or ammonium carbonate.

4. The method for preparing a medicinal formaldehyde casein according to claim 1, characterized in that The organic solvent in step (3) is ethyl acetate, dichloromethane, chloroform or methanol.

5. The method for preparing a medicinal formaldehyde casein according to claim 1, characterized in that The organic solvent in step (4) is ethyl acetate, dichloromethane, chloroform or methanol.

6. The method for preparing a medicinal formaldehyde casein according to claim 1, characterized in that The temperature of the reduced pressure drying in the step (4) is 55 to 80°C.

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