Method for detecting element impurities in dabigatran etexilate bulk drug

Abstract

The invention discloses a method for detecting element impurities in a dabigatran etexilate bulk drug, which comprises the following steps of: carrying out dynamic gradient microwave digestion: precisely weighing a proper amount of a dabigatran etexilate mesylate bulk drug, and sequentially carrying out HNO3 / H2O2 pre-reaction, HF / HClO4 complex breaking and H2O2 incremental oxidation; adding a gold stabilizer to inhibit palladium volatilization; and a corresponding detection result is obtained through DRC-ICP-MS detection. The method has the beneficial effects that firstly, the problem of palladium catalyst residue detection is solved, and the volatilization inhibition and recovery rate of gradient digestion and an Au stabilizer are improved; according to the invention, through DRC multi-gas mode (He / NH3) switching, the high-throughput detection is improved, the anti-interference capability is improved, the detection sensitivity is improved, the HF corrosion resistant life of the Pt cone is prolonged, and the detection cost of a single sample is saved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of raw material detection, in particular to a detection method for element impurities in dabigatran etexilate raw material. BACKGROUND

[0002] Dabigatran etexilate mesylate, as a direct thrombin inhibitor, has become the first new class of oral anticoagulant drugs in the past fifty years since it was approved for marketing in Europe in 2008. The drug effectively prevents thrombosis by specifically inhibiting thrombin activity, and is widely used in the clinical fields of postoperative venous thromboembolism prevention, stroke prevention in patients with non-valvular atrial fibrillation, and deep vein thrombosis treatment, becoming a heavy-hitter drug in the field of cardiovascular therapy. Its chemical structure contains multiple sensitive functional groups, including two amide bonds and two ester bonds, which makes the compound prone to degradation during synthesis, storage and preparation, producing various organic impurities such as hydrolysis impurities, process by-products and potential genotoxic impurities.

[0003] At present, the quality control research of dabigatran etexilate mainly focuses on the analysis and control of organic impurities. Although the organic impurity control system of dabigatran etexilate has been relatively perfect, the existing detection technology has obvious directional limitations. The existing HPLC / GC method is only suitable for organic impurities and residual solvents, and cannot detect heavy metals, catalyst residues and other inorganic element impurities. Although GC-MS method can detect ppb level of methanesulfonate impurities, the sensitivity is limited to specific organic matter, and the trace detection capability of element impurities has not been established.

[0004] Metal-containing catalysts are extremely likely to be used in the synthesis route of dabigatran etexilate. The most common one is palladium catalyst, which is used for key coupling reactions (such as Suzuki coupling, Heck coupling, etc.) or reduction reactions; Some reagents or solvents used may contain metal impurities; production equipment (reaction kettle, pipeline, drying equipment, etc.) is usually made of stainless steel (containing chromium, nickel, iron, etc.) or other alloys, which may corrode or wear under certain process conditions (such as strong acid, strong base, high temperature, high shear force), leading to dissolution or shedding of metal elements and possible carry-over of metal impurities in starting materials or intermediates.

[0005] The conventional element impurities in dabigatran etexilate bulk drug under general conditions include: starting material As, Pb, Cd (mineral source); catalytic hydrogenation Pd, Pt, Ru (catalyst); Lewis acid treatment Al, Zn, Fe (reagent impurities); methanesulfonic acid salt As, Pb (acid impurities); purified water / solvent system Cu, Cr, Ni (equipment dissolution). The pharmacopoeia conventional heavy metal test method (such as sulfide precipitation colorimetry) can only semi-quantitatively determine the total heavy metal (usually calculated by lead), and cannot distinguish the specific element types, and cannot meet the independent control requirements of ICH Q3D for high-risk elements such as cadmium (Cd), arsenic (As), mercury (Hg) and lead (Pb). SUMMARY

[0006] In view of the above problems, the present application solves the problems by the following technical scheme: A detection method for element impurities in dabigatran etexilate bulk drug, comprising the following steps: S1. High-precision sample pretreatment Dynamic gradient microwave digestion: accurately weigh an appropriate amount of dabigatran etexilate methanesulfonate bulk drug, and sequentially use HNO3 / H2O2 pre-reaction, HF / HClO4 complex breaking, and H2O2 incremental oxidation; add gold stabilizer to inhibit the volatilization of palladium; and then constant volume by ultrapure water; S2. DRC-ICP-MS detection The DRC uses He collision mode (KED) with a He flow rate of 4-6 mL / min or NH3 reaction mode with a NH3 flow rate of 0.3-0.5 mL / min; The internal standard system of the DRC-ICP-MS detection device is configured to be added online 115 In / 193 Ir / 187 Re corrects signal drift and matrix suppression; The RPq value of the DRC-ICP-MS device is set to be light element As / P, RPq=0.3-0.5; heavy metal Pd / Cd, RPq=0.6-0.7; The sample reagent obtained in S1 is detected by the DRC-ICP-MS device set as above.

[0007] Further, the gold stabilizer used in the S1 step is a 1wt% gold chloride AuCl3 solution.

[0008] Further, in the HNO3 / H2O2 pre-reaction, HF / HClO4 complex breaking, and H2O2 incremental oxidation, the volume ratio of nitric acid to hydrogen peroxide in the HNO3 / H2O2 pre-reaction is 5:1, the volume ratio of HF / HClO4 complex breaking is 4:1, and the volume ratio of H2O2 increment to nitric acid and HF in the H2O2 incremental oxidation is 5:3:2.

[0009] Further, the atomizer of the DRC-ICP-MS detection device is a PFA hydrogen fluoride acid-resistant atomizer, which is compatible with the HF digestion solution. Further, the light elements As / P include As, Si, P, Ge, Ni, Cr, etc., and Pd, Cd, Hg, Pt, etc.

[0010] Further, the DRC-ICP-MS detection device is configured to enable mass offset for oxide / ammonide generating elements.

[0011] Further, the dynamic gradient microwave digestion is performed in a closed microwave digestion system.

[0012] Further, the hydrogen peroxide is a 30wt% concentration aqueous solution.

[0013] Further, the hydrogen fluoride acid is a 49wt% aqueous solution.

[0014] Further, the perchloric acid is a 70wt% aqueous solution.

[0015] The beneficial effects of the present application are: 1. First, solve the problem of residual palladium catalyst detection, improve gradient digestion + Au stabilizer to inhibit volatilization, increase and decrease drug recovery rate; 2. The present application improves high-throughput detection by DRC multi-gas mode (He / NH3) switching, improves anti-interference ability, improves detection sensitivity, and prolongs the service life of Pt cone against HF corrosion, saving single sample detection cost. DETAILED DESCRIPTION

[0016] The technical solutions in the embodiments of the present application will be described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of the present application.

[0017] Mass spectrometer ICPMS NexION 1100G Reagent preparation: Hydrofluoric acid is a 49wt% aqueous solution; perchloric acid is a 70wt% aqueous solution; hydrogen peroxide is a 30wt% concentration aqueous solution; 1% gold chloride (AuCl3) solution; ultrapure water (resistance > 18.2MΩ); Example 1 Dynamic gradient microwave digestion Step 1: precisely take 0.5 g of dabigatran etexilate mesylate raw material drug sample, add 5 mL of HNO3 and 1 mL of H2O2, set the microwave power to 1000 W, heat to 80±5℃ at a rate of 5℃ / min, and pre-react for 5 min; Step 2: add 2 mL of HF and 0.5 mL of HCIO4, heat to 120±5℃ at a rate of 3℃ / min, pressure limit 25 bar, react for 10 min, and break the Si-Pd / Al-Pd bond; Step 3: add 3 mL of H2O2, heat to 180±5℃ at a rate of 2℃ / min, pressure limit 40 bar, and heat for 15 min until the solution is clear; Step 4: after cooling, add 0.5 mL of 1% AuCl3 solution, dilute to 50 mL with ultrapure water, and the ultrapure water resistance value is >18.2 MΩ.

[0018] DRC-ICP-MS detection (DRC-ICP-MS is configured as follows) The cone interface of the DRC-ICP-MS detection device is a Pt shielded cone; The internal standard system of the DRC-ICP-MS detection device is configured to add Rh and Ir online 115 In / 193 Ir / 187 Re corrects signal drift and matrix suppression; DRC uses He collision mode (KED) with a He flow of 4-6 mL / min or NH3 reaction mode with a flow of 0.3-0.5 mL / min; The atomizer of the DRC-ICP-MS detection device is a PFA hydrogen fluoride acid-resistant atomizer compatible with HF digestion solution.

[0019] The DRC-ICP-MS detection device is set to enable mass shift for oxide / ammonium elements, Se (ammonium shift to m / z=94), Pd (oxide shift to m / z=122).

[0020] The RPq value of the DRC-ICP-MS device is set to As / P for light elements, RPq=0.3-0.5; and Pd / Cd for heavy metals, RPq=0.6-0.7; The DRC-ICP-MS device set as above detects the sample reagent obtained in S1, and the quantification limit of Pd is ≤0.01 μg / g, with a recovery rate of 90-110% (spiked concentration 0.1 μg / g); As in NH3 mode 40 Ar 35 The elimination rate of Cl+ interference is ≥99%.

[0021] The data obtained according to the above configuration of equipment and detection scheme are as follows: element Average concentration (μg / g, ppm) Concentration RSD (%) Average signal strength (cps) As 0.15 5.2 12500 Cd ＜0.05 -- 850 Hg ＜0.03 -- 420 Pb 0.22 4.8 18300 Pd 0.85 3.1 65000 Ni 0.35 6.0 9700 Co 0.12 7.5 5300 Cu 0.60 4.0 22100 Fe 2.80 8.2 105000 It will be obvious to a person skilled in the art that the application is not limited to the details of the foregoing exemplary embodiments and can be implemented in other concrete forms without departing from the spirit or essential characteristics of the application. The embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the application being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. The markers in the claims are not to be construed as limiting the claims involved.

[0022] Furthermore, it should be understood that although the description is made on the basis of the embodiments, not every embodiment contains only one independent technical solution, and the description manner of the specification is only for the sake of clarity, and a person skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be properly combined to form other embodiments which can be understood by a person skilled in the art.

Claims

1. a detection method for elemental impurities in dabigatran etcxilate bulk drug, it is characterized in that The following steps are involved: S1. High-precision sample pretreatment Dynamic gradient microwave digestion: Accurately weigh an appropriate amount of dabigatran etexilate mesylate API, perform HNO3 / H2O2 pre-reaction, HF / HClO4 complex breaking, and H2O2 incremental oxidation in sequence; add a gold stabilizer to inhibit palladium volatilization; and then adjust to volume with ultrapure water. S2. DRC-ICP-MS Detection DRC was performed in He collision mode (KED) with a He flow rate of 4–6 mL / min or NH 3 reaction mode of 0.3–0.5 mL / min; The internal standard system of the DRC-ICP-MS detection device is configured to add 115 In / 193 Ir / 187 Re correction for signal drift and matrix suppression; RPq value of the DRC-ICP-MS device, the cell voltage difference is set to light elements As / P, RPq = 0.3-0.5; heavy metals Pd / Cd, RPq = 0.6-0.7; The sample reagent obtained in S1 was detected by the DRC-ICP-MS device set up as above.

2. the detection method of elemental impurities in a kind of dabigatran etcxilate bulk drug according to claim 1, is characterized in that: The gold stabilizer used in step S1 is a 1 wt % gold chloride AuCl 3 solution.

3. the detection method of elemental impurities in a kind of dabigatran etcxilate bulk drug according to claim 1, is characterized in that: In the HNO3 / H2O2 pre-reaction, HF / HClO4 complex breaking, and H2O2 incremental oxidation, the volume ratio of nitric acid to hydrogen peroxide in the HNO3 / H2O2 pre-reaction is 5:1, the volume ratio of HF / HClO4 complex breaking is 4:1, and the volume ratio of H2O2 increment to nitric acid and HF in the H2O2 incremental oxidation is 5:3:

2.

4. the detection method of elemental impurities in a kind of dabigatran etcxilate bulk drug according to claim 1, is characterized in that: The atomizer of the DRC-ICP-MS detection device is a PFA hydrofluoric acid-resistant atomizer, which is compatible with HF digestion solution, and the cone interface of the DRC-ICP-MS detection device is a Pt shielding cone.

5. the detection method of elemental impurities in a kind of dabigatran etcxilate bulk drug according to claim 1, is characterized in that: The light elements As / P include As, Si, P, Ge, Ni, Cr, etc., and include Pd, Cd, Hg, Pt, etc.

6. the detection method of elemental impurities in a kind of dabigatran etcxilate bulk drug according to claim 1, is characterized in that: The DRC-ICP-MS detection apparatus is configured to enable mass shifting for elements that form oxides / amides.

7. the detection method of elemental impurities in a kind of dabigatran etcxilate bulk drug according to claim 1, is characterized in that: The dynamic gradient microwave digestion is carried out in a closed microwave digestion system.

8. the detection method of elemental impurities in a kind of dabigatran etcxilate crude drug according to claim 7, is characterized in that: The hydrogen peroxide is a 30 wt% aqueous solution.

9. the detection method of elemental impurities in a kind of dabigatran etcxilate bulk drug according to claim 7, is characterized in that: The hydrofluoric acid is a 49 wt % aqueous solution.

10. the detection method of elemental impurities in a kind of dabigatran etcxilate bulk drug according to claim 7, is characterized in that: The perchloric acid is a 70 wt% aqueous solution.