Process applied to preparation of Esomeprazole and used for inhibiting drug insoluble particles

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a process applied to preparation of isiomerazole and used for inhibiting drug insoluble particles. In the production process, a metal ion complexing agent edetate disodium is added, insoluble particles of the medicine are inhibited, and adverse reactions are effectively avoided. According to the present invention, the edetate disodium can effectively enhance the stability of the drug, and the principle is that the edetate disodium can form the stable water-soluble chelate with the metal ions so as to prevent the oxidation of the edetate disodium, such that the stability of the drug during the preparation, storage and clinical preparation process can be easily improved;

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and in particular relates to a process for inhibiting drug insoluble particles used in the preparation of esomeprazole. Background Art

[0002] Esomeprazole is the S-isomer of omeprazole. It reduces gastric acid secretion through specific proton pump inhibition. The R-isomer and S-isomer of omeprazole have similar pharmacodynamic properties. Esomeprazole is a weakly alkaline drug. It is concentrated and converted into an active form in the high acid environment of the acid secretory microtubules of parietal cells, thereby inhibiting the H+ / K+-ATPase (proton pump) in this area, and inhibiting both basal gastric acid secretion and gastric acid secretion after stimulation.

[0003] Freeze-drying technology refers to a technology that directly sublimates water from solid to gas in a vacuum environment below zero degrees, extracting the moisture in the product and thus completely preserving the activity of biological components.

[0004] Esomeprazole is a lyophilized powder for injection. The production process mainly includes drug solution preparation, sterilization filtration, and freeze drying. The key steps include the pH range of the drug solution, the temperature and light stability of the drug solution, filtration, freeze drying, etc.

[0005] Visible foreign matter often exists in the research and development and production process of injections, eye drops and other liquid medicines. It is an insoluble substance that can be observed visually under specific conditions. Its particle size or length is usually greater than 50μm. The light inspection method is usually used to detect visible foreign matter.

[0006] The so-called insoluble particles in injections refer to tiny granular impurities that are contaminated by drugs through various channels during production or application. Their particle size ranges from 1 micron to 50 microns. They are invisible to the naked eye, mobile, non-metabolic harmful particles. Summary of the invention

[0007] The object of the present invention is to provide a process for inhibiting drug insoluble particles used in the preparation of esomeprazole, which is conducive to large-scale mass production and optimizes the freeze-drying process of the preparation.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] A process for inhibiting drug insoluble particles used in the preparation of esomeprazole comprises the following steps:

[0010] The metal ion complexing agent disodium edetate is added during the production of sterile freeze-dried preparations to inhibit the formation of insoluble drug particles.

[0011] The preparation of the metal ion complexing agent disodium edetate comprises the following steps:

[0012] (1) firstly adding a certain amount of deionized water into the membrane chemical reactor, and then alternately adding liquid sodium hydroxide and ethylenediaminetetraacetic acid into the membrane chemical reactor in 4 to 10 batches at a mass ratio of 1:3.5 to 3.7, that is, adding a batch of ethylenediaminetetraacetic acid and then adding a batch of sodium hydroxide, and during the process of adding the last batch of sodium hydroxide, repeatedly testing the pH value of the neutralization solution, controlling the feeding speed and feeding amount of the remaining sodium hydroxide according to the pH value, and stopping the feeding when the pH value reaches 4 to 4.5;

[0013] (2) After the addition of materials is completed, the reaction solution is kept warm at a temperature of 90 to 95° C. for 30 to 40 minutes, and the pH value of the reaction solution is controlled to be 4 to 4.5; further, the step (2) is specifically as follows: after the addition of materials is completed, the reaction solution is kept warm at a temperature of 90 to 95° C. for 30 to 40 minutes, the pH value of the reaction solution is detected every 5 to 15 minutes during the insulation period, and ethylenediaminetetraacetic acid or sodium hydroxide is added to the reaction solution according to the change in pH value to adjust the pH value of the reaction solution to 4 to 4.5.

[0014] (3) After the reaction in the membrane chemical reactor is completed, the process is sequentially followed by filter pressing, crystallization, dehydration, and drying to obtain disodium edetate powder.

[0015] Compared with the prior art, the present invention has the following beneficial effects:

[0016] Adding the metal ion chelating agent disodium edetate during the production process can inhibit the insoluble particles of the drug and effectively avoid adverse reactions. It can effectively enhance the stability of the drug. The principle is that disodium edetate can form a stable water-soluble chelate with metal ions, which can prevent its own oxidation and help improve the stability of the drug during preparation, storage and clinical preparation. DETAILED DESCRIPTION

[0017] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0018] Example

[0019] A process for inhibiting drug insoluble particles used in the preparation of esomeprazole comprises the following steps:

[0020] The metal ion complexing agent disodium edetate is added during the production of sterile freeze-dried preparations to inhibit the formation of insoluble drug particles.

[0021] The preparation of the metal ion complexing agent disodium edetate comprises the following steps:

[0022] (1) firstly adding a certain amount of deionized water into the membrane chemical reactor, and then alternately adding liquid sodium hydroxide and ethylenediaminetetraacetic acid into the membrane chemical reactor in 4 to 10 batches at a mass ratio of 1:3.5 to 3.7, that is, adding a batch of ethylenediaminetetraacetic acid and then adding a batch of sodium hydroxide, and during the process of adding the last batch of sodium hydroxide, repeatedly testing the pH value of the neutralization solution, controlling the feeding speed and feeding amount of the remaining sodium hydroxide according to the pH value, and stopping the feeding when the pH value reaches 4 to 4.5;

[0023] (2) After the addition of materials is completed, the reaction solution is kept warm at a temperature of 90 to 95° C. for 30 to 40 minutes, and the pH value of the reaction solution is controlled to be 4 to 4.5; further, the step (2) is specifically as follows: after the addition of materials is completed, the reaction solution is kept warm at a temperature of 90 to 95° C. for 30 to 40 minutes, the pH value of the reaction solution is detected every 5 to 15 minutes during the insulation period, and ethylenediaminetetraacetic acid or sodium hydroxide is added to the reaction solution according to the change in pH value to adjust the pH value of the reaction solution to 4 to 4.5.

[0024] (3) After the reaction in the membrane chemical reactor is completed, the process is sequentially followed by filter pressing, crystallization, dehydration, and drying to obtain disodium edetate powder.

[0025] This product is a sterile lyophilized preparation for intravenous injection. According to the provisions of Appendix IX of Part II of the Pharmacopoeia of the People's Republic of China (2010 edition), this test item is included in the quality standard. Take this product and check it according to the following method. The results are: the insoluble particulate matter test of the stability sample meets the requirements.

[0026] The color of the drug solution and its difference from the specified color can reflect the purity of the drug to a certain extent. This method compares the color of the drug solution with the specified standard colorimetric solution, or measures its absorbance at a specified wavelength to check its color.

[0027] The term “colorless or almost colorless” specified under the item “colorless” means that the color of the test solution is the same as the solvent used, and “almost colorless” means that the color is lighter than the corresponding hue of the No. 1 standard colorimetric solution after dilution by 1 time with water.

[0028] 2.1 The First Law

[0029] Unless otherwise specified, take the specified amount of test sample under each item, dissolve it in water, place it in a 25ml Nessler colorimetric tube, and dilute it to 10ml with water. Take another 10ml of the standard colorimetric solution of the specified hue and color number, place it in another 25ml Nessler colorimetric tube, place the two tubes on a white background, and look through them from top to bottom, or place them in front of a white background and observe them horizontally; the color presented by the test sample tube shall not be darker than that of the control tube. If the color presented by the test sample tube is very close to the color depth of the control tube or the hue is not consistent, so that the depth of the two cannot be distinguished by visual observation, the third method (colorimeter method) should be used instead, and its measurement result shall be used as the basis for judgment.

[0030] 2.1.1 Potassium dichromate solution for colorimetry

[0031] Accurately weigh 0.4000g of standard potassium dichromate dried to constant weight at 120℃, place in a 500ml volumetric flask, add appropriate amount of water to dissolve and dilute to scale, shake well, and you have it. Each 1ml of solution contains 0.800mg of K2Cr2O7.

[0032] 2.1.2 Copper sulfate solution for colorimetry

[0033] Take about 32.5g of copper sulfate, add an appropriate amount of hydrochloric acid solution (1→40) to dissolve into 500ml, accurately measure 10ml, place in an iodine volumetric flask, add 50ml of water, 4ml of acetic acid and 2g of potassium iodide, titrate with sodium thiosulfate titrant (0.1mol / L), add 2ml of starch indicator solution when it is close to the end point, and continue to titrate until the blue color disappears. Each 1ml of sodium thiosulfate titrant (0.1mol / L) is equivalent to 24.97mg of CuSO4·5H2O. According to the above determination results, add an appropriate amount of hydrochloric acid solution (1→40) to the remaining original solution so that each 1ml of solution contains 62.4mg of CuSO4·5H2O.

[0034] 2.1.3 Cobalt chloride solution for colorimetry

[0035] Take about 32.5g of cobalt chloride, add an appropriate amount of hydrochloric acid solution (1→40) to dissolve it into 500ml, accurately measure 2ml, put it in a conical flask, add 200ml of water, shake well, add ammonia test solution until the solution changes from light red to green, add 10ml of acetic acid-sodium acetate buffer (pH6.0), heat to 60℃, add 5 drops of xylenol orange indicator solution, and titrate with disodium ethylenediaminetetraacetic acid titration solution (0.05mol / L) until the solution turns yellow. Each 1ml of disodium ethylenediaminetetraacetic acid titration solution (0.05mol / L) is equivalent to 11.90mg of CoCl2·6H2O. According to the above measurement results, add an appropriate amount of hydrochloric acid solution (1→40) to the remaining original solution so that each 1ml of the solution contains 59.5mg of CoCl2·6H2O.

[0036] 2.1.4 Preparation of standard stock solutions of various hues

[0037] According to the standard, precisely measure the cobalt chloride solution, potassium dichromate solution, copper sulfate solution and water for colorimetry, shake well and you have it.

Claims

1. A process for inhibiting drug insoluble particles used in the preparation of esomeprazole, characterized in that The steps include: The metal ion complexing agent disodium edetate is added during the production of sterile freeze-dried preparations to inhibit the formation of insoluble drug particles.

2. The process for inhibiting drug insoluble particles used in the preparation of esomeprazole according to claim 1, characterized in that The preparation of the metal ion complexing agent disodium edetate comprises the following steps: (1) firstly adding a certain amount of deionized water into the membrane chemical reactor, and then alternately adding liquid sodium hydroxide and ethylenediaminetetraacetic acid into the membrane chemical reactor in 4 to 10 batches at a mass ratio of 1:3.5 to 3.7, that is, adding a batch of ethylenediaminetetraacetic acid and then adding a batch of sodium hydroxide, and during the process of adding the last batch of sodium hydroxide, repeatedly testing the pH value of the neutralization solution, controlling the feeding speed and feeding amount of the remaining sodium hydroxide according to the pH value, and stopping the feeding when the pH value reaches 4 to 4.5; (2) After the addition of materials is completed, the reaction solution is kept warm at a temperature of 90 to 95° C. for 30 to 40 minutes, and the pH value of the reaction solution is controlled to be 4 to 4.5; further, the step (2) is specifically as follows: after the addition of materials is completed, the reaction solution is kept warm at a temperature of 90 to 95° C. for 30 to 40 minutes, the pH value of the reaction solution is detected every 5 to 15 minutes during the insulation period, and ethylenediaminetetraacetic acid or sodium hydroxide is added to the reaction solution according to the change in pH value to adjust the pH value of the reaction solution to 4 to 4.

5. (3) After the reaction in the membrane chemical reactor is completed, the process is sequentially followed by filter pressing, crystallization, dehydration, and drying to obtain disodium edetate powder.