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CN-121994945-A - Method for detecting di-tert-butyl phosphate potassium salt

CN121994945ACN 121994945 ACN121994945 ACN 121994945ACN-121994945-A

Abstract

The invention provides a method for detecting di-tert-butyl phosphate potassium salt, which adopts HPLC to detect impurity potassium polyphosphate in di-tert-butyl phosphate potassium salt. The method has good specificity, other impurities (such as the degradation product tertiary butyl alcohol of the di-tert-butyl potassium phosphate) do not interfere with detection, and the content of the impurity potassium polyphosphate in the di-tert-butyl potassium phosphate can be rapidly and accurately separated and detected, so that the method is beneficial to improving the product quality of the di-tert-butyl potassium phosphate, and further ensures the safety and the effectiveness of the phosphoric acid precursor drug. The method has good durability, and the separation and the determination result of the impurity potassium polyphosphate are not affected when the chromatographic condition parameters are slightly changed.

Inventors

  • CHEN HAO
  • LIU LONG
  • DENG HAIXING
  • CHEN GONGZHENG
  • CHEN GANG

Assignees

  • 四川科瑞德制药股份有限公司

Dates

Publication Date
20260508
Application Date
20241108

Claims (7)

  1. 1. A method for detecting di-tert-butyl phosphate potassium salt is characterized in that HPLC is adopted to detect impurity potassium polyphosphate in di-tert-butyl phosphate potassium salt, and chromatographic conditions are as follows: The chromatographic column with adamantyl silane bonded silica gel as filler has mobile phase comprising phase A and phase B, wherein phase A is water phase, phase B is methanol, and the chromatographic column is subjected to isocratic elution, the volume ratio of phase A to phase B is 80-90:20-10, the flow rate is 0.8-1.2 mL/min, the column temperature is 25-45 ℃, the detector is a differential refraction detector, an evaporative light scattering detector or a conductivity detector, and the differential refraction detector temperature is 25-45 ℃.
  2. 2. The method for detecting the potassium di-tert-butyl phosphate according to claim 1, wherein the packing of the chromatographic column is OSAKA SODA CAPCELL PAK ADME, the size is 4.6mm multiplied by 250mm, and the particle size of the packing is 5 μm.
  3. 3. The method for detecting the potassium di-tert-butyl phosphate according to claim 1 or 2, wherein the volume ratio of the A phase to the B phase is 83-87:17-13, the flow rate is 0.8mL/min, 1.0mL/min or 1.2mL/min, the column temperature is 30-40 ℃, and the differential refraction detector temperature is 30-40 ℃.
  4. 4. The method for detecting potassium di-tert-butyl phosphate according to claim 3, wherein the volume ratio of the phase A to the phase B is 85:15 and the column temperature is 30 ℃, 35 ℃ or 40 ℃.
  5. 5. The method for detecting di-t-butyl phosphate potassium salt according to any one of claims 1 to 4, comprising the steps of: a. preparing a test sample di-tert-butyl phosphate potassium salt solution and a potassium polyphosphate impurity reference substance solution; b. Setting the liquid chromatography detection conditions by setting the chromatography conditions according to any one of claims 1 to 4; c. precisely sucking the sample solution and the impurity reference solution respectively, injecting into a liquid chromatograph, and starting to detect and record a chromatogram; d. according to an external standard method, the content of impurity potassium polyphosphate in the potassium di-tert-butyl phosphate is calculated according to the peak area.
  6. 6. The method for detecting di-tert-butyl phosphate potassium salt according to claim 5, wherein, The preparation method of the test solution in the step a comprises the steps of weighing the test di-tert-butyl potassium phosphate, adding a diluent for dissolution and dilution to prepare a solution containing 20mg of di-tert-butyl potassium phosphate in each 1 mL; The preparation method of the impurity reference substance solution comprises precisely weighing the potassium polyphosphate reference substance, adding diluent to dissolve and dilute to obtain 40 μg solution containing potassium polyphosphate per 1 mL.
  7. 7. The method for detecting di-tert-butyl phosphate potassium salt according to claim 6, wherein the diluent is water.

Description

Method for detecting di-tert-butyl phosphate potassium salt Technical Field The invention relates to a detection method of di-tert-butyl phosphate potassium salt, and belongs to the technical field of medicine analysis. Background In recent years, the research range of phosphorus-containing organic medicaments is gradually expanded from the directions of anti-tumor, disinsection and the like to a plurality of fields of central nervous system, antibiosis, antivirus, heart strengthening, depressurization, enzyme inhibition and the like, and the appearance of phosphoric acid precursor medicaments such as sodium phosphophenytoin, betamethasone sodium phosphate, dexamethasone sodium phosphate, clindamycin phosphate and the like shows that the phosphorylation has become an important means for developing the prodrugs in the pharmaceutical industry and plays an important role in improving the biological and chemical characteristics of the pharmaceutical compounds. The di-tert-butyl phosphate potassium salt is a key material for synthesizing a phosphoric acid precursor medicament, has the CAS number of 33494-80-3, and is widely applied to the preparation process of medicaments such as sodium phosphophenytoin, betamethasone sodium phosphate, dexamethasone sodium phosphate, clindamycin phosphate and the like by virtue of the characteristics of easy removal of protecting groups, good storage stability and the like in the reaction process. The potassium di-tert-butyl phosphate has the following structure: Polyphosphate is an inorganic compound with polyphosphate groups, wherein the molecular formula of the polyphosphate is (KPO 3) n, the polyphosphate is crystalline at normal temperature, and the solubility of the polyphosphate in water is high. The inventor researches and discovers that potassium polyphosphate is a main process impurity formed in the preparation process of di-tert-butyl phosphate potassium salt. If such impurities remain in high amounts, delivery into the finished pharmaceutical product may increase the risk of administration (especially to those suffering from underlying diseases). For example, the alkalinity of such impurities may cause moderate irritation to the mucosa of the digestive tract of a patient, and for example, such impurities may be hydrolyzed into orthophosphate with smaller molecular weight before being absorbed by the intestinal tract, thereby inducing metabolic acidosis and increasing the possibility of cardiovascular and cerebrovascular diseases of the patient, and it is reported that the intake of such impurities in large doses may cause kidney stones to be generated or induce the activation of lung cancer cells and accelerate the growth thereof. Potassium polyphosphate may also participate in subsequent preparation processes of finished pharmaceutical products, producing undesirable side-reaction impurities, thereby affecting the safety and effectiveness of the pharmaceutical. Therefore, the potassium polyphosphate in the di-tert-butyl phosphate potassium salt is required to be strictly controlled, the quality of the di-tert-butyl phosphate potassium salt is ensured, and the safety and the effectiveness of the medicament are further ensured. Disclosure of Invention The invention aims to provide a method for measuring the content of impurity potassium polyphosphate in a medicine intermediate di-tert-butyl potassium phosphate by using a high performance liquid chromatography, which can be used for rapidly, effectively, accurately and reliably separating and detecting the content of impurity potassium polyphosphate in the di-tert-butyl potassium phosphate, and is beneficial to ensuring the product quality of the di-tert-butyl potassium phosphate. The invention provides a method for detecting di-tert-butyl phosphate potassium salt, which adopts HPLC to detect impurity potassium polyphosphate in di-tert-butyl phosphate potassium salt, and the chromatographic conditions are as follows: The chromatographic column with adamantyl silane bonded silica gel as filler has mobile phase comprising phase A and phase B, wherein phase A is water phase, phase B is methanol, and the chromatographic column is subjected to isocratic elution, the volume ratio of phase A to phase B is 80-90:20-10, the flow rate is 0.8-1.2 mL/min, the column temperature is 25-45 ℃, the detector is a differential refraction detector, an evaporative light scattering detector or a conductivity detector, and the differential refraction detector temperature is 25-45 ℃. Wherein the packing of the chromatographic column is OSAKA SODA CAPCELL PAK ADME mm, the size is 4.6mm×250mm, and the particle size of the packing is 5 μm. The volume ratio of the phase A to the phase B is 83-87:17-13, the flow rate is 0.8mL/min, 1.0mL/min or 1.2mL/min, the column temperature is 30-40 ℃, and the differential refraction detector temperature is 30-40 ℃. It is further preferred that the volume ratio of phase A to phase B is 85:15 and that the colum