A method for detecting the limit of methanamine acetonitrile residue

Abstract

The present invention relates to the technical field of impurity limit detection in the fields of medicine and biochemistry, and discloses a method for detecting the limit of methylaminoacetonitrile residue. The limit detection method comprises the following steps: precisely measuring the reference solution and the test solution respectively and placing them in colorimetric tubes, adding an acetonitrile solution of triethylamine and an acetonitrile solution of phenyl isothiocyanate, mixing well with water, and heating for derivatization to obtain tube A and tube B; separately and precisely measuring equal amounts of the reference solution and the test solution and placing them in the same colorimetric tube, and operating in the same manner to obtain tube C. Looking through from top to bottom, compare the depths of the colors of the solutions in the three tubes, thereby determining whether the methylaminoacetonitrile in the sample to be tested exceeds the limit. The method for detecting the limit of methylaminoacetonitrile residue according to the present invention has high generality. The required instruments, derivatization reagents, etc. are all routinely configured by most pharmaceutical enterprises and research institutions. The operation is simple and the cost is low, and it is suitable for large-scale promotion and use.

Description

Technical Field

[0001] The present invention relates to the technical field of impurity limit detection in the fields of medicine and biochemistry, and specifically to a method for detecting the limit of methylaminoacetonitrile residue. Background Art

[0002] Methylaminoacetonitrile, also known as methylaminoacetonitrile, 2-methylaminoacetonitrile, and sarcosonitrile, is mostly stored in the form of hydrochloride, i.e., methylaminoacetonitrile hydrochloride. It is a chemical intermediate and raw material with a relatively large consumption, mainly used in the preparation of synephrine hydrochloride, N-methylethylenediamine, sarcosine, etc., and has a wide range of applications in the fields of pesticides and medicine.

[0003] Synephrine is an alkaloid present in various plants (such as Fructus Aurantii Immaturus), and itself is a natural stimulant, mainly used in weight loss products and stomach-strengthening products. As a pharmaceutical and chemical intermediate and raw material with a relatively large consumption, synephrine hydrochloride is mainly synthesized starting from methylaminoacetonitrile hydrochloride.

[0004] However, the chemical, physical, and toxic properties of methylaminoacetonitrile have not been fully studied, and its residue in synephrine hydrochloride may affect the safety of drug use. According to the requirements of the "General Principles for the Analysis of Pharmaceutical Impurities 9102" in the Chinese Pharmacopoeia 2020 Edition, methylaminoacetonitrile belongs to process-related impurities. Methylaminoacetonitrile has very weak absorption in the ultraviolet region. When controlling the quality of methylaminoacetonitrile hydrochloride itself, the chloride ions of itself are usually titrated by acid-base titration to control the product quality. However, when controlling at a trace level as an impurity, there is a lack of corresponding methods, resulting in the current research on the detection method for the residue limit of methylaminoacetonitrile being imperfect and lacking a general detection method for the limit. It has been reported that high performance liquid chromatography combined with mass spectrometry (HPLC-MS) can be used to detect the content of methylaminoacetonitrile, but the equipment required for this method is expensive, and its cost is difficult to bear by most pharmaceutical enterprises and research institutions. It is difficult to promote in conventional drug research and development and actual production of enterprises. Therefore, a method for detecting the limit of methylaminoacetonitrile residue is proposed. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the present invention provides a method for detecting the limit of methylaminoacetonitrile residue, and this limit detection method includes the following steps:

[0006] Step 1. Sample treatment: Precisely measure the reference solution and the test solution and place them in colorimetric tubes respectively. Add acetonitrile solutions of triethylamine and phenyl isothiocyanate, mix well with water, and react at 30 °C for 40 min to obtain Tube A and Tube B;

[0007] Step 2: Accurately measure equal amounts of the reference solution and the test solution into the same colorimetric tube, and operate in the same manner to obtain tube C. Look through the tubes from top to bottom and compare the color intensities of the solutions in the three tubes to determine whether the methylaminoacetonitrile in the test sample exceeds the limit.

[0008] Preferably, in Step 1, the volume ratio of triethylamine to acetonitrile in the acetonitrile solution of triethylamine is (0.5 - 1.5):(0.5 - 1.5), and the preferred volume ratio is 0.5:1.5.

[0009] Preferably, in Step 1, the volume ratio of phenyl isothiocyanate to acetonitrile in the acetonitrile solution of phenyl isothiocyanate is (0.5 - 1.5):(4.5 - 13.5), and the preferred volume ratio is 1:5.

[0010] Preferably, in Step 1, the volume ratio of the reference solution or the test solution: triethylamine solution: phenyl isothiocyanate solution is (0.5 - 1.5):(0.5 - 1.5):(0.5 - 1.5), and the preferred volume ratio is 1:0.5:0.5.

[0011] Preferably, in Step 1, the reaction time is 20 - 40 min, and the preferred reaction time is 40 min.

[0012] Preferably, in Step 1, the reaction temperature is 30 - 50 °C, and the preferred reaction temperature is 30 °C.

[0013] Compared with the prior art, the present invention has the following beneficial effects: The method for detecting the limit of methylaminoacetonitrile residue in the present invention has high versatility. The required instruments, derivatization reagents, etc. are all conventional configurations of most pharmaceutical enterprises and research institutions. The operation is simple and the cost is low, which is suitable for large-scale promotion and use. Specific Embodiments

[0014] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0015] A method for detecting the limit of methylaminoacetonitrile residue, the limit detection method comprising the following steps:

[0016] Step 1: Sample treatment: Accurately measure the reference solution and the test solution into colorimetric tubes respectively, add the acetonitrile solution of triethylamine and the acetonitrile solution of phenyl isothiocyanate, mix well with water, and react at 30 °C for 40 min to obtain tube A and tube B;

[0017] Step 2: Accurately measure equal amounts of the reference solution and the test solution and place them in the same colorimetric tube. Operate in the same manner to obtain Tube C. Look through from top to bottom and compare the color intensities of the solutions in the three tubes to determine whether the methylaminoacetonitrile in the test sample exceeds the limit.

[0018] Among them, in the acetonitrile solution of triethylamine in Step 1, the volume ratio of triethylamine to acetonitrile is (0.5 - 1.5):(0.5 - 1.5), and the preferred volume ratio is 0.5:1.5.

[0019] Among them, in the acetonitrile solution of phenyl isothiocyanate in Step 1, the volume ratio of phenyl isothiocyanate to acetonitrile is (0.5 - 1.5):(4.5 - 13.5), and the preferred volume ratio is 1:5.

[0020] Among them, in Step 1, the volume ratio of the reference solution or the test solution: triethylamine solution: phenyl isothiocyanate solution is (0.5 - 1.5):(0.5 - 1.5):(0.5 - 1.5), and the preferred volume ratio is 1:0.5:0.5.

[0021] Among them, in Step 1, the reaction time is 20 - 40 min, and the preferred reaction time is 40 min.

[0022] Among them, in Step 1, the reaction temperature is 30 - 50 °C, and the preferred reaction temperature is 30 °C.

[0023] It should be noted that: for the limit detection method of methylaminoacetonitrile residue in the present invention, the method provided by the present invention has high generality, and the required instruments, derivatization reagents, etc. are all conventional configurations of most pharmaceutical enterprises and research institutions. Its operation is simple and the cost is low, which is suitable for large-scale promotion and use;

[0024] The content not described in detail in this specification belongs to the prior art well-known to those skilled in the art. Example

[0025] Limit detection of methylaminoacetonitrile residue in synephrine hydrochloride

[0026] Preparation of the reference solution: Take an appropriate amount of methylaminoacetonitrile hydrochloride (about 50 mg of methylaminoacetonitrile), accurately weigh it, place it in a 10 ml volumetric flask, dissolve it with water and dilute to the mark, shake well, then accurately measure 1 ml and place it in a 100 ml volumetric flask, dissolve it with water and dilute to the mark, shake well.

[0027] Preparation of the test solution: Take an appropriate amount of synephrine hydrochloride, accurately weigh it, dissolve it with water and quantitatively dilute it to make a solution containing about 50 mg per 1 ml.

[0028] Preparation of the acetonitrile solution of triethylamine: Take 5 ml of triethylamine and add acetonitrile to make 15 ml, and you will get it.

[0029] Preparation of phenyl isothiocyanate acetonitrile solution: Take 1 ml of phenyl isothiocyanate, add 6 ml of acetonitrile, and mix well to obtain the solution.

[0030] Derivatization process: Take 2 ml of the test solution, add 1 ml of triethylamine acetonitrile solution, add 1 ml of phenyl isothiocyanate acetonitrile solution, and add water to 10 ml, mix well to obtain tube B; Take 2 ml of the reference solution and operate in the same manner to obtain tube A. Additionally, take 2 ml of the test solution and 2 ml of the reference solution and place them in the same colorimetric tube, add 2 ml of triethylamine acetonitrile solution, add 2 ml of phenyl isothiocyanate acetonitrile solution, and add water to 10 ml, mix well to obtain tube C; Place tubes A, B, and C at 30 °C for 40 minutes.

[0031] Test results: Observe tubes A, B, and C obtained in the previous step from top to bottom. The color shown in tube B is lighter than that in tube A (<0.1%), and the color shown in tube C is darker than that in tube A.

[0032] In summary, the analytical method for methylaminoacetonitrile residue provided by the present invention has high accuracy and good operability, and can be widely applied to the analysis and detection of methylaminoacetonitrile residue.

[0033] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variation thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0034] Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for detecting the limit of methylaminoacetonitrile residue, characterized in that, The limit detection method includes the following steps: Step 1. Sample treatment: Accurately measure the reference solution and the test solution and place them in two colorimetric tubes respectively. Add acetonitrile solutions of triethylamine and phenyl isothiocyanate to each colorimetric tube. After adding water and mixing evenly, react at 30 - 50 °C for 20 - 40 min to obtain Tube A and Tube B; Step 2. Another accurately measure equal amounts of the reference solution and the test solution and place them in the same colorimetric tube. Operate according to the same method as in Step 1 to obtain Tube C. Look through from top to bottom and compare the color depths of the solutions in the three tubes to determine whether the methylaminoacetonitrile in the test sample exceeds the limit; In Step 1, the volume ratio of triethylamine to acetonitrile in the acetonitrile solution of triethylamine is: (0.5 - 1.5):(0.5 - 1.5); In Step 1, the volume ratio of phenyl isothiocyanate to acetonitrile in the acetonitrile solution of phenyl isothiocyanate is: (0.5 - 1.5):(4.5 - 13.5); In Step 1, the volume ratio of the reference solution or the test solution: triethylamine solution: phenyl isothiocyanate solution is (0.5 - 1.5):(0.5 - 1.5):(0.5 - 1.5); Preparation of the reference solution: Take an appropriate amount of methylaminoacetonitrile hydrochloride, accurately weigh it, place it in a 10 ml volumetric flask, dissolve it with water and dilute to the mark, shake well. Then accurately measure 1 ml and place it in a 100 ml volumetric flask, dissolve it with water and dilute to the mark, shake well; Preparation of the test solution: Take an appropriate amount of synephrine hydrochloride, accurately weigh it, dissolve it with water and quantitatively dilute it to a solution containing about 50 mg per 1 ml.

2. The limit detection method for methylaminoacetonitrile residue according to claim 1, wherein: In Step 1, the volume ratio of triethylamine to acetonitrile in the acetonitrile solution of triethylamine is 0.5:1.

5.

3. The limit detection method for methylaminoacetonitrile residue according to claim 1, wherein: In Step 1, the volume ratio of phenyl isothiocyanate to acetonitrile in the acetonitrile solution of phenyl isothiocyanate is 1:

5.

4. The limit detection method for methylaminoacetonitrile residue according to claim 1, characterized in that: In Step 1, the volume ratio of the reference solution or the test solution: triethylamine solution: phenyl isothiocyanate solution is 1:0.5:0.

5.

5. The limit detection method for methylaminoacetonitrile residue according to claim 1, characterized in that: In Step 1, the reaction time is 40 min.

6. The limit detection method for the residue of methylaminoacetonitrile according to claim 1, wherein: In Step 1, the reaction temperature is 30 °C.