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CN-121994942-A - Determination method for residual impurity DMAP and EDU in synthesis of antitumor drug

CN121994942ACN 121994942 ACN121994942 ACN 121994942ACN-121994942-A

Abstract

The invention discloses a method for measuring residual impurity DMAP and EDU in the synthesis of an antitumor drug, and belongs to the technical field of drug analysis. The method adopts a high performance liquid chromatography to detect, takes dimethyl sulfoxide as a solvent to dissolve a sample for detection, and adopts a detection condition of the high performance liquid chromatography, wherein a chromatographic column is an octadecyl bonded silica gel column, a mobile phase A is sodium perchlorate buffer solution or potassium hexafluorophosphate buffer solution, a mobile phase B is acetonitrile, a detector is an ultraviolet detector, the detection wavelength of DMAP is 278-282 nm, the detection wavelength of EDU is 198-202 nm, and a gradient elution mode is adopted. The method is used for detecting DMAP and EDU residues in the bulk drug, has high sensitivity and accuracy, does not need special columns, can meet the control limit of ICH (information technology) guidelines on genotoxic impurities and general impurities of the bulk drug, provides reliable guarantee for impurity control of the bulk drug, and further ensures the safety of clinical medication.

Inventors

  • ZHOU BUGAO
  • JIA JIA
  • LI SHUANGHUA
  • ZHENG JIAYI

Assignees

  • 南京一心和医药科技有限公司
  • 南京方生和医药科技有限公司
  • 江苏利泰尔药业有限公司

Dates

Publication Date
20260508
Application Date
20241107

Claims (10)

  1. 1. A method for measuring the residual amount of DMAP and EDU which are residual impurities in the synthesis of an antitumor drug is characterized by adopting a high performance liquid chromatography for detection, and taking dimethyl sulfoxide as a solvent to dissolve a sample for detection; The detection conditions of the high performance liquid chromatography comprise: The chromatographic column is octadecyl bonded silica gel column; the mobile phase A is sodium perchlorate buffer solution or potassium hexafluorophosphate buffer solution; Mobile phase B is acetonitrile; The detector is an ultraviolet detector; detecting DMAP with detection wavelength of 278-282 nm and EDU with detection wavelength of 198-202 nm; the gradient elution mode is adopted, and the elution program is set as follows:
  2. 2. The method according to claim 1, wherein the conditions for detecting the high performance liquid chromatography further comprise a column temperature of 25-35 ℃, a sample injection amount of 5-10 μl, and a flow rate of 0.8-1.2ml/min.
  3. 3. The assay of claim 1 wherein the chromatographic column is a ZORBAX SB-C18 column.
  4. 4. The method according to claim 3, wherein the column size is 3.5 μm. Times.4.6 mm. Times.150 mm.
  5. 5. The method according to claim 1, wherein the ultraviolet detector is a DAD detector or a multi-wavelength ultraviolet detector.
  6. 6. The method according to claim 2, wherein the column temperature is 30 ℃, the flow rate is 1.0ml/min, and the sample injection amount is 5 μl.
  7. 7. The method according to claim 1, wherein the DMAP detection wavelength is 280nm and the EDU detection wavelength is 200nm.
  8. 8. The method according to claim 1, wherein the concentration of the sodium perchlorate buffer or the potassium hexafluorophosphate buffer is 15 to 25mmol/L.
  9. 9. The method according to claim 8, wherein the pH of the sodium perchlorate buffer solution is 4 to 5.
  10. 10. The method according to claim 8, wherein the pH of the potassium hexafluorophosphate buffer is 2 to 3.

Description

Determination method for residual impurity DMAP and EDU in synthesis of antitumor drug Technical Field The invention belongs to the technical field of medicine analysis, and particularly relates to a method for measuring DMAP (DMAP) and EDU (EDU) residual impurities in synthesis of an antitumor drug. Background The vitamin Naekla tablet is a B cell lymphoma factor-2 inhibitor and is used for treating adult acute myelogenous leukemia, and FDA approval is given on the market of 2016, 4 and 11 days, and the synthetic reaction formula is as follows: 4-Dimethylaminopyridine (DMAP) is a novel efficient catalyst in chemical synthesis, can obviously improve the reaction speed and yield of chemical reaction, is successfully applied to the synthesis process of chemical medicaments in the pharmaceutical industry at present, improves the process conditions and reduces the process cost, and the molecular formula of the catalyst is shown as formula I. The molecule of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) is in a linear structure, the molecular formula is shown as a formula II, and the molecular formula is a condensing agent and a cross-linking agent for common chemical synthesis and polypeptide condensation reaction, and the molecular formula is widely applied to the fields of synthesis of polysaccharide, polypeptide, high polymer, chemical drugs and the like. The synthesis process of the valicara adopts water-adding material-separating and multi-step water-washing procedures, EDCI is unstable when meeting water, and a byproduct 1- (3-dimethylaminopropyl) -3-Ethylurea (EDU) can be generated, and the molecular formula is shown as a formula III. According to the synthesis process of the valnemulin, the condensing agent EDCI finally exists in the valnemulin raw material medicine in an EDU form. DMAP and EDU are two process impurities of the valnemulin raw material medicine, so that development of a simple and accurate detection method has very important significance for guaranteeing the safety of the valnemulin raw material medicine. DMAP has a genotoxic warning structure, and according to ICH guidelines and daily doses and administration cycles of Venezuki, the control limit is 25ppm, EDU is a common impurity, and the control limit is 0.1%. DMAP and EDU are both strongly polar compounds that do not remain under normal reverse phase chromatographic conditions, and most of the prior literature reports use of the addition of alkyl sulfonate ions in the mobile phase to increase retention of both compounds by the reagent and hydrophilic C18 column. CN115406979B discloses a method for detecting hydrolysis product EDU of EDCI by using sodium heptanesulfonate ion pair reagent and triethylamine mobile phase and Ultimate AQ-C18 chromatographic column, CN114544841N discloses a method for detecting DMAP in pneumococcal polysaccharide-protein conjugate vaccine by using sodium heptanesulfonate ion pair reagent mobile phase and Sepax HP-C18 chromatographic column, and patent 108267518a discloses a method for determining DMAP content in abiraterone acetate by using sodium alkyl sulfonate ion pair reagent mobile phase. The use of the alkyl sulfonate ion pair reagent, the chromatographic column is relatively slow to balance, the new chromatographic column is generally required to be balanced overnight when in use, the daily detection is generally required to be balanced for more than 2 hours, and a gradient program is not suitable to be used, so that the main component of a test sample (bulk drug or intermediate) cannot be eluted. The alkyl sulfonate ion pair reagent can denature the chromatographic packing, and typically, the chromatographic column using the alkyl sulfonate ion pair reagent requires special column, thereby increasing the cost of detection. Disclosure of Invention In order to solve the problems of detecting the residual high-polarity impurities DMAP and EDU in the medicines in the prior art, the invention provides a method for measuring the residual impurities DMAP and EDU synthesized by the anti-tumor medicines. The method is used for detecting DMAP and EDU residues in the Uygur autonomous region medicine, has high sensitivity and accuracy, does not need special columns, can meet the control limit of ICH (information technology) guidelines on genotoxic impurities and general impurities of the medicine, provides reliable guarantee for impurity control of the Uygur autonomous region medicine, and further ensures the safety of clinical medication. In order to achieve the above purpose, the present invention provides the following technical solutions: A method for measuring the residual impurity DMAP and EDU of antineoplastic drug synthesis comprises detecting by high performance liquid chromatography, dissolving sample with dimethyl sulfoxide (DMSO) as solvent for detection; The detection conditions of the high performance liquid chromatography comprise: The chromatographic column is octadecyl b