Doxofylline injection

A technology for doxofylline and injection, applied in the field of determination of related substances in injection, can solve the problems of unsolved, no impurity reference substance, difficulty in structure and traceability, etc.

Active Publication Date: 2015-10-07
HEILONGJIANG FUHE HUAXING PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the existing quality standards for doxofylline injection, only the quality standard of 10ml:0.2g stipulates the detection of related substances, and there is no limit requirement for a single impurity. It only stipulates that the total impurity should not exceed 0.8%, and there is no impurity Participation of controls
In this field, factors such as the general situation of the related substances of the raw materials used in the research of the related substances of the injection, the formulation process of the preparation, the research results of the degradation pathway, etc. will all have an impact on the related substances, so it is difficult to clarify the structure and traceability of each related substance , the methods in the prior art cannot characterize and quantify the related substances in doxofylline injection. Although doxofylline injection has been on the market for many years, the above problems have not been solved
[0004] In addition, there are many synthetic routes of doxofylline, so the related substances brought by different production routes, storage conditions and preparation processes are not completely the same

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0154] The preparation of embodiment 1 impurity B (Impurity B) theophylline acetaldehyde:

[0155]

[0156] Preparation process: Add 10.20g (37.50mmol) of doxofylline, 35.0mL of water and 6.0mL of 2.0M hydrochloric acid to a 250mL three-necked bottle in sequence, and gradually heat to reflux, and the reaction solution gradually becomes homogeneous. Continue to reflux for 8h, HPLC monitors that there is no remaining raw material. Concentrate under reduced pressure until about 10 mL of solvent remains, and add 20.0 mL of tetrahydrofuran to disperse to obtain a white solid. Suction filtration, rinse with a small amount of tetrahydrofuran, and dry to obtain 7.81 g of Impurity B, with a yield of 93.8%.

[0157] Structural Confirmation:

[0158] Name: Theophylline acetaldehyde

[0159] Molecular formula: C 9 h 10 N 4 o 3 ;

[0160]Molecular weight: 222.20;

[0161] CAS No: 5614-53-9

[0162] Structural formula:

[0163] Theophylline acetaldehyde purity: HPLC method 9...

Embodiment 2

[0183] The preparation of embodiment two impurity F (Impurity F), theophylline ethanol:

[0184] preparation Process: 4.20g (18.0mmol) of Impurity B and 30.0mL of methanol were sequentially added into a 100mL three-necked flask, and 1.11g (29.0mmol) of sodium borohydride was slowly added in an ice-water bath. After the addition was completed, the reaction was gradually raised to room temperature for 2 hours, and no raw materials were detected by HPLC. Adjust the pH to 3-4 with 2.0M hydrochloric acid in an ice-water bath, then adjust the pH to 8-9 with saturated sodium carbonate solution, and distill methanol off under reduced pressure. Extract with water-ethyl acetate, combine the organic layers and dry. Filter and concentrate to obtain a milky white solid. Recrystallize from ethanol, filter, and dry to obtain 2.21 g of Impurity F, with a yield of 55.5%.

[0185] Structural Confirmation:

[0186] Name: Theophylline ethanol

[0187] Molecular formula: C 9 h 12 N 4 o ...

Embodiment 3

[0211] The preparation of embodiment three impurity A (Impurity A):

[0212]

[0213] Preparation process: Add 7.52g (28.15mmol) of doxofylline and 15.0mL of 20% sodium hydroxide aqueous solution to a 250mL three-necked bottle in sequence, heat slowly to 80°C, keep warm for 3 hours, and monitor the end of the reaction by HPLC. Add 50.0 mL of absolute ethanol, cool in an ice-water bath, adjust the pH to 8 with hydrochloric acid, and a large amount of solids are precipitated. Filter and dry to obtain the crude product of Impurity A. After twice recrystallization from ethyl acetate, 5.41 g of Impurity A was obtained, with a yield of 79.8%.

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Abstract

The invention relates to a doxofylline injection-related substance determination method. According to the method, a high-efficiency liquid chromatography is used for determination. The invention provides a method capable of effectively controlling the doxofylline injection-related substances by using the high-efficiency liquid chromatography, which has the beneficial effects being good in durability, simple and rapid in operation, high in system suitability. According to the method, at least three reference substances containing theophylline, theophylline ethanol and theophylline acetaldehyde are used for the determination of the related substances. At the same time, the invention provides impurity reference substances such as impurity A, impurity B, impurity C, impurity D, impurity E, impurity G, impurity caffeine, methylxanthine, impurity C', impurity D', impurity E', impurity 2, theophylline acetic acid and the like for the determination of the doxofylline injection-related substances, so that the related substances caused by different synthetic routes, and preparation processes and storage processes of preparations. The invention also provides a synthesis method for separating and synthesizing the reference substances containing impurity A, impurity A'', impurity B, impurity C, impurity D, impurity E, impurity G and the like for the determination of the doxofylline injection-related substances.

Description

[0001] This application is a divisional application of the parent application with the application number 2013105339455, the application date is November 04, 2013, and the invention title is "Method for Determination of Related Substances in Doxofylline Injection". technical field [0002] The invention belongs to the field of determination of related substances of injection, and mainly relates to a method for determining related substances of doxofylline injection. Background technique [0003] Doxofylline injection (10ml: 0.2g, 10ml: 0.1mg, 20ml: 0.3mg) is a small volume injection made of doxofylline. As a dosage form directly administered to the human body intravenously, due to its high incidence of adverse reactions and other safety issues, the safety of injections is a major issue that the majority of doctors and patients and regulatory authorities attach great importance to. Among the factors that affect the safety of injections, the confirmation and control of related...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/522A61K9/08C07D473/08A61P11/06C07D405/06
CPCC07D405/06C07D473/08
Inventor 吴光彦
Owner HEILONGJIANG FUHE HUAXING PHARMA GROUP
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