Preparation method of gadadotec acid meglumine, product obtained by preparation method and detection method of gadadotec acid meglumine

Abstract

The invention discloses a preparation method of gadotec acid meglumine. The gadotec acid meglumine is prepared by taking DOTA, gadolinium oxide and meglumine as raw materials. Wherein the related substances in the DOTA meet the following conditions in percentage by mass: less than or equal to 0.05% of impurity RM, and / or less than or equal to 0.05% of impurity P01, less than or equal to 0.05% of impurity P02, less than or equal to 0.05% of impurity P03, less than or equal to 0.05% of impurity P04 and less than or equal to 0.5% of total impurities. The invention also relates to the bulk drug prepared by the preparation method and a high performance liquid chromatography detection method thereof. On the basis of deep research, according to consideration factors such as the importance degree of each quality index and / or the difficulty degree of removing one or some impurities, key process conditions or parameters for preparing gadadotec acid meglumine are finally found out and determined; product quality management and / or control of the production source and even the whole process of the gadadotec acid meglumine bulk drug are / is really realized and strengthened, and the medication safety of vast patients is better guaranteed.

Description

Technical Field

[0001] This invention belongs to the technical field of nuclear magnetic resonance diagnostic reagents (contrast agents), specifically relating to a method for preparing gadotyl ether meglumine, the product obtained by the preparation method, and a method for detecting the product. Background Technology

[0002] The Pharmacopoeia of the People's Republic of China (2020 Edition) clearly states that impurities are a key quality attribute of pharmaceuticals, which can affect the safety and efficacy of the product; it is necessary to strengthen the qualitative and quantitative research on impurities in chemical drugs, and to control known and unknown impurities separately. Impurities in pharmaceutical quality standards refer to impurities introduced into pharmaceuticals produced according to processes and raw materials approved by the National Medical Products Administration in accordance with law, either by the manufacturing process or raw materials, or impurities generated during storage.

[0003] For active pharmaceutical ingredients (APIs), it is necessary to control both the purity (active ingredient) of the API product and the limits of impurities in the API in order to meet the requirements for drug safety and efficacy (see: Pharmacopoeia of the People's Republic of China (2020 Edition), Part IV).

[0004] Specifically regarding gadoteric meglumine, it is also necessary to adhere to my country's development strategy of "improving drug quality, ensuring drug safety, and serving drug regulation," and strengthen the management and control of product quality at the source of raw material production and throughout the entire process.

[0005] Gadolinium meglumine, chemical name: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid gadolinium meglumine, is an MRI diagnostic reagent (contrast agent). It possesses high kinetic and thermodynamic stability and is widely used in diagnostic techniques for various diseases, including cardiovascular diseases and vascular tumors. References: CN 106220580A, CN 113527222 A, CN113925976 A, CN 115869426 A, CN 115916761A, etc.

[0006] If gadotate meglumine is to be used as a contrast agent, its purity must be high enough and the level of impurities in the product must be strictly controlled to be low enough, especially impurities such as free gadolinium. This is because impurities such as free gadolinium, if retained in the product, can cause side effects and are therefore considered unsafe for human use. Relevant pharmaceutical regulatory agencies may therefore not approve the sale and / or use of the product.

[0007] In order to meet the high requirements for gadoteric acid meglumine drugs and / or the approval or regulatory requirements of administrative departments, it is necessary to further strengthen the product quality management and / or control of gadoteric acid meglumine raw material production source and even the whole process, so as to better protect the medication safety of patients.

[0008] In view of this, the present invention is hereby proposed. Summary of the Invention

[0009] To address the problems and / or deficiencies in existing technologies, the present invention aims to provide a method for preparing gadoteric acid meglumine, the resulting product, and a detection method. Unlike existing technologies (e.g., CN 106220580A), which employ purification methods to manage and / or control the quality of gadoteric acid meglumine raw materials, this invention, based on in-depth research into the sources and / or causes of impurities in gadoteric acid meglumine raw materials and injection solutions, and considering factors such as the importance of various quality indicators and / or the ease of removing one or more impurities, ultimately identifies and determines the key process conditions or parameters for preparing gadoteric acid meglumine. This truly realizes and strengthens product quality management and / or control at the source and throughout the entire production process of gadoteric acid meglumine raw materials, better ensuring medication safety for patients.

[0010] This invention provides a method for preparing gadoteric acid meglumine, using DOTA, gadolinium oxide, and meglumine as raw materials; wherein, the relevant substances in the DOTA meet the following conditions: by mass percentage, impurity RM≤0.05%, and / or, impurity PO1≤0.05%, impurity PO2≤0.05%, impurity PO3≤0.05%, impurity PO4≤0.05%, and total impurities≤0.5%;

[0011] The impurity RM and impurities PO1 to PO4 have the following structures respectively:

[0012]

[0013] Furthermore,

[0014] In any of the above technical solutions (preparation method of gadotyl ether meglumine), the relevant substances in the DOTA meet the following conditions: by mass percentage, impurity RM ≤ 0.02% or not detected, and / or, impurity PO1 ≤ 0.02% or not detected, and / or, impurity PO2 ≤ 0.01% or not detected, and / or, impurity PO3 ≤ 0.01% or not detected, and / or, impurity PO4 ≤ 0.02% or not detected;

[0015] And / or, the relevant substances in the DOTA are determined according to RS detection method I;

[0016] in,

[0017] The chromatographic conditions for RS detection method I include:

[0018] Chromatographic column: C18 column or equivalent column; preferably, the chromatographic column is a Kromasil 100-5-C18 column;

[0019] And / or, the chromatographic column has the following specifications: 4.6 mm × 250 mm, 5 μm;

[0020] And / or, column temperature: 15℃~45℃ (e.g.: 20℃, 25℃, 28℃, 30℃, 32℃, 35℃, 40℃, 42℃, 45℃, etc.); preferably, the column temperature is 35℃~40℃, more preferably 36℃;

[0021] And / or, the injection volume is 0.5 μl to 25 μl (e.g., injection volumes of 1 μl, 2 μl, 3 μl, 4 μl, 5 μl, 6 μl, 7 μl, 8 μl, 9 μl, 10 μl, 15 μl, 20 μl, 25 μl, etc.); preferably, the injection volume is 8 μl to 12 μl, more preferably 10 μl;

[0022] And / or, flow rate: 0.1 ml / min to 2 ml / min (e.g., flow rates of 0.5 ml / min, 0.6 ml / min, 0.7 ml / min, 0.8 ml / min, 0.9 ml / min, 1.0 ml / min, 1.2 ml / min, 1.5 ml / min, etc.); preferably, the flow rate is 1.0 ml / min to 1.5 ml / min, more preferably 1.0 ml / min;

[0023] And / or, the detection wavelength is 180nm to 220nm (e.g., detection wavelengths of 185nm, 190nm, 195nm, 200nm, 205nm, 210nm, 215nm, etc.); preferably, the detection wavelength is 200nm;

[0024] And / or, mobile phase A: an aqueous solution of 0.01 mol / L potassium dihydrogen phosphate containing 0.01 mol / L sodium heptanesulfonate, with a pH of 2.2 ± 0.2; mobile phase B: acetonitrile;

[0025] Perform gradient elution according to the following procedure:

[0026]

[0027]

[0028] More preferably, the RS detection method I uses the following methods for quantification: principal component self-comparison with correction factor, principal component self-comparison without correction factor, internal standard method, external standard method, or area normalization method; even more preferably, the RS detection method I uses the principal component self-comparison with correction factor for quantification.

[0029] Furthermore,

[0030] In any of the above technical solutions (the preparation method of gadoteric acid meglumine),

[0031] The gadolinium oxide conforms to the Chinese national standard GB / T 2526-2020 and the following conditions: praseodymium oxide ≤ 2 ppm, and / or europium oxide ≤ 5 ppm, and / or terbium oxide ≤ 5 ppm, and / or thulium oxide ≤ 2 ppm, and / or lutetium oxide ≤ 2 ppm;

[0032] And / or, by mass percentage, the meglumine complies with the provisions of the 2020 edition of the Chinese Pharmacopoeia, Part II, and the reducing substances therein are ≤0.05%;

[0033] Preferably, the gadolinium oxide is selected from gadolinium oxide of grade Gd2O3-4N5 or Gd2O3-5N.

[0034] Furthermore,

[0035] In any of the above technical solutions (preparation method of gadotyl ether meglumine), the preparation method includes the following steps:

[0036] DOTA, gadolinium oxide and meglumine were reacted in a solvent. After the reaction was completed, the resulting reaction solution was decolorized, filtered, and the solvent was removed from the filtrate. Then, a recrystallization step was optionally included to obtain gadotonic acid meglumine.

[0037] The control method for ending the reaction is as follows: at the end of the reaction and / or after the reaction is completed, the DOTA content in the reaction solution is 0.015wt% to 0.15wt%, and / or the pH value of the reaction solution is <6.3;

[0038] Preferably, at the end of the reaction and / or after the reaction is completed, the DOTA content in the reaction solution is 0.02 wt% to 0.09 wt%.

[0039] More preferably, at the end of the reaction and / or after the reaction is completed, the content of DOTA in the reaction solution is 0.03wt% to 0.07wt%.

[0040] Furthermore,

[0041] In any of the above technical solutions (the preparation method of gadoteric acid meglumine),

[0042] Based on the amount of gadolinium oxide per mole, the amount of DOTA used is 2.001 mol to 2.1 mol, and the amount of meglumine used is 1.9 mol to 2.0 mol.

[0043] And / or, based on gadolinium oxide per kilogram, the amount of solvent used in the reaction is 9 kg to 15 kg;

[0044] And / or, the reaction temperature is 55°C to 92°C;

[0045] And / or, the order of the reactions is: DOTA reacts with gadolinium oxide to generate gadotonic acid, and then reacts with meglumine;

[0046] Preferably, the reaction temperature of DOTA with gadolinium oxide is 85℃~90℃, and the reaction temperature of gadotiamic acid with meglumine is 60℃~75℃.

[0047] Furthermore,

[0048] In any of the above technical solutions (preparation method of gadotyl meglumine), the solvent for the reaction is water or pharmaceutically acceptable water; and / or, the solvent for recrystallization is water and / or an alcohol solvent, wherein the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-pentanol and its isomers, propylene glycol, butanediol, glycerol, and benzyl alcohol; and / or, the method for decolorizing the reaction solution is to add activated carbon to the reaction solution;

[0049] Preferably, the alcohol solvent is selected from methanol and isopropanol.

[0050] This invention also provides a gadoteric acid meglumine raw material that meets the following quality standards:

[0051] Based on anhydrous content, gadotiacid content ranges from 72.0 wt% to 76.4 wt%, and meglumine content ranges from 24.6 wt% to 26.6 wt%.

[0052] And / or, the free gadolinium content is ≤0.002wt%;

[0053] And / or, the DOTA content is 0.01wt% to 0.1wt%;

[0054] And / or, heavy metal content ≤10ppm;

[0055] And / or, the content of related substance RS01 is ≤0.05wt%, which has the following structure:

[0056]

[0057] Preferably, the gadoteric acid meglumine raw material is prepared by any of the preceding methods.

[0058] This invention also provides a high-performance liquid chromatography (HPLC) method for the detection of gadoteric acid meglumine raw material, wherein the chromatographic conditions include:

[0059] Chromatographic column: C18 column or equivalent column, using phenyl-bonded silica gel as packing material; preferably, the column is a Waters Xbridge Phenyl column, and / or the column specifications are: 4.6 mm × 250 mm, 3.5 μm;

[0060] Mobile phase A: 0.04 mol / L to 0.05 mol / L potassium dihydrogen phosphate aqueous solution with a pH of 3.0 ± 0.2; preferably, the pH of mobile phase A is adjusted to 3.0 ± 0.2 with phosphoric acid.

[0061] Mobile phase B: A mixed solution of acetonitrile and mobile phase A in a volume ratio of 10:90;

[0062] Perform gradient elution according to the following procedure:

[0063] Time / min Mobile phase A / %, volume percentage Mobile phase B / %, volume percentage 0 96 4 5 96 4 25 0 100

[0064] Detection wavelength: 180nm~220nm (e.g., detection wavelengths of 185nm, 190nm, 195nm, 200nm, 205nm, 210nm, 215nm, etc.); preferably, the detection wavelength is 195nm;

[0065] Preferably,

[0066] Column temperature: 15℃~45℃ (e.g., 20℃, 25℃, 28℃, 30℃, 32℃, 35℃, 40℃, 42℃, 45℃, etc.); more preferably, the column temperature is 25℃~35℃; even more preferably 30℃;

[0067] And / or, the injection volume is 0.5 μl to 25 μl (e.g., injection volumes of 1 μl, 2 μl, 3 μl, 4 μl, 5 μl, 6 μl, 7 μl, 8 μl, 9 μl, 10 μl, 15 μl, 20 μl, 25 μl, etc.); more preferably, the injection volume is 8 μl to 12 μl; even more preferably, it is 10 μl;

[0068] And / or, flow rate: 0.1 ml / min to 2 ml / min (e.g., flow rates of 0.5 ml / min, 0.6 ml / min, 0.7 ml / min, 0.8 ml / min, 0.9 ml / min, 1.0 ml / min, 1.2 ml / min, 1.5 ml / min, etc.); more preferably, the flow rate is 0.5 ml / min to 1 ml / min; even more preferably, 0.6 ml / min.

[0069] Furthermore,

[0070] In any of the above technical solutions (high performance liquid chromatography detection method of gadotate meglumine raw material), the test solution of the high performance liquid chromatography detection method is prepared by dissolving gadotate meglumine raw material or the aforementioned gadotate meglumine raw material in water.

[0071] The reference solution of the high performance liquid chromatography detection method is prepared by dissolving the related substance RS01 reference standard in water;

[0072] The related substance RS01 has the following structure:

[0073]

[0074] And / or, the high performance liquid chromatography detection method is a qualitative or quantitative detection; preferably, the quantitative detection is to calculate the content of related substances RS01 in gadotate meglumine raw material by peak area using the external standard method.

[0075] as well as,

[0076] The present invention also provides a gadoteric meglumine injection, comprising gadoteric meglumine raw material, water for injection and one or more pharmaceutically acceptable excipients, wherein the gadoteric meglumine raw material is the gadoteric meglumine raw material described above.

[0077] The beneficial effects of this invention are mainly in the following aspects:

[0078] (1) The preparation method of gadotate meglumine of the present invention is different from the inventive concept of the prior art. Based on in-depth research on the source and / or cause of impurities of gadotate meglumine, and considering factors such as the importance of various quality indicators and / or the ease of removing one or more impurities, the key process conditions or parameters for preparing gadotate meglumine are finally identified and determined.

[0079] (2) The preparation method of gadotate meglumine of the present invention has mild reaction conditions, good safety, and is easy to operate and / or control. The product has high yield, high purity, low energy consumption, and low cost, making it more suitable for industrial production. It truly realizes and strengthens the product quality management and / or control of the source and the entire process of gadotate meglumine raw material production, and better protects the medication safety of patients.

[0080] also,

[0081] The high-performance liquid chromatography (HPLC) method for detecting gadotate meglumine raw material provided by this invention has no significant interference between the detected chromatographic peaks, high resolution, and accurate and reliable detection results. It meets the relevant regulations and / or requirements for methodological validation such as accuracy and precision, and can more effectively monitor and ensure the quality of the product. It can better protect the product quality and / or safety of its downstream pharmaceutical preparations (such as injections), and has good economic and social value. Attached Figure Description

[0082] Figure 1 This is a representative HPLC chromatogram for the determination of gadoteric acid in Example 2.

[0083] Figure 2 This is a representative HPLC chromatogram for the determination of meglumine in Example 2.

[0084] Figure 3 This is a representative HPLC chromatogram of DOTA determined in Example 2.

[0085] Figure 4 This is a representative HPLC chromatogram of the related substance RS01 determined in Example 2. Detailed Implementation

[0086] The present invention will now be clearly and completely described in conjunction with specific embodiments. Those skilled in the art will understand that the embodiments described below are some, but not all, embodiments of the present invention, and are only used to illustrate the present invention, and should not be regarded as a limitation on the scope of protection of the present invention.

[0087] In the embodiments of the present invention, experiments without specific conditions are conducted according to conventional conditions in the art or conditions recommended by the manufacturer. The reagents and instruments used, unless otherwise specified, are all conventional products that can be purchased commercially.

[0088] Unless otherwise specified, all percentages used in this invention are mass percentages.

[0089] Regarding the definitions of terms used in this invention, unless otherwise stated, the initial definitions provided herein apply to the term throughout the text; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and / or context.

[0090] Chinese patent applications CN 202010318397.4 (Invention title: A method for preparing gadotate meglumine; Application date: April 21, 2020) and CN 202010669147.5 (Invention title: A gadotate meglumine injection and its preparation method; Application date: July 13, 2020) are incorporated herein by reference in their entirety.

[0091] Example 1

[0092] Impurities are a key quality attribute of pharmaceuticals, which can affect the safety and efficacy of the product (among pharmaceutical impurities, organic impurities with chemical structures similar to or related to the active ingredient are usually referred to as related substances).

[0093] Typically, the main components of DOTA (chemical name: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; purchased or prepared in-house) include:

[0094]

[0095] Among them, impurity RM is the raw material impurity, impurity P01 is the trisubstituted product impurity, impurities P02 and P03 are the disubstituted product impurities, and impurity P04 is the monosubstituted product impurity (the target product is: the tetrasubstituted product DOTA).

[0096] The following high-performance liquid chromatography (HPLC) method was used to detect DOTA (complying with the method validation requirements of the 2020 edition of the Chinese Pharmacopoeia) (denoted as: RS detection method I), and the specific conditions are shown in Table 1 below:

[0097] Table 1. HPLC conditions for detecting related substances in DOTA

[0098]

[0099]

[0100] Test solution: Weigh 260 mg of the test sample (i.e., the DOTA to be tested), place it in a 10 ml volumetric flask, add diluent (mobile phase A - mobile phase B = 95:5, volume ratio) to dissolve and dilute to the mark, mix well, and the solution is ready.

[0101] The contents of related substances (the limits of quantitation for impurities RM, PO1, PO2, PO3, and PO4 are 0.02%, 0.005%, 0.01%, 0.01%, and 0.02%, respectively) were calculated using the principal component self-comparison method with correction factors (calculated based on peak area, refer to: 2020 edition of Chinese Pharmacopoeia, Part IV; in addition, other methods such as the principal component self-comparison method without correction factors, internal standard method, external standard method, and area normalization method can also be used).

[0102] The test results of a batch of DOTA (purity 95.32%) for a certain process optimization / screening were as follows: impurity RM content was 0.02%, impurity PO1 content was 0.47%, impurity PO2 content was 3.58%, impurity PO3 content was 0.01%, and impurity PO4 content was 0.04%.

[0103] The test results for another batch of DOTA (purity 98.77%) under the process optimization / screening method were as follows: impurity RM was not detected, impurity PO1 content was 0.12%, impurity PO2 content was 0.81%, impurity PO3 was not detected, and impurity PO4 content was 0.01%.

[0104] The test results for the preferred batch of DOTA (purity > 99.50%) are as follows: impurity RM was not detected, impurity P01 content was 0.02%, impurity P02 was not detected, impurity P03 was not detected, and impurity P04 was not detected.

[0105] In order to truly implement my country's development strategy of "improving drug quality, ensuring drug safety, and serving drug regulation", the quality control checkpoint will be moved forward, and the quality management and / or control of drugs (including but not limited to raw materials) at the source of production and throughout the entire process will be strengthened (see: 2020 edition of the Chinese Pharmacopoeia).

[0106] Meanwhile, based on the actual research and development situation, the quality management and / or control standards for DOTA preparation of gadotyl ether meglumine are determined as follows: impurity RM≤0.05%, impurity PO1≤0.05%, impurity PO2≤0.05%, impurity PO3≤0.05%, impurity PO4≤0.05%; total impurities≤0.5% (purity≥99.5%).

[0107] If purchased or self-prepared DOTA does not meet the aforementioned quality management and / or control standards, it can be purified by methods described in patent documents such as CN 112574131A and CN 108264491A (e.g., using ethanol and water as purification solvents). After meeting the quality management and / or control standards, it can be used as a raw material for preparing gadotidine meglumine.

[0108] also,

[0109] Based on the same considerations and combined with the actual research and development situation, the quality management and / or control standards for gadolinium oxide (Gd2O3) used in the preparation of gadotium tertrate meglumine are determined as follows: praseodymium oxide (Pr6O3) 11 ≤2ppm, europium oxide (Eu2O3) ≤5ppm, terbium oxide (Tb4O7) ≤5ppm, thulium oxide (Tm2O3) ≤2ppm, lutetium oxide (Lu2O3) ≤2ppm, for example, gadolinium oxide of grades Gd2O3-4N5 or Gd2O3-5N is used as a raw material for the preparation of gadotyl ether meglumine (National Standard: GB / T 2526-2020).

[0110] Furthermore, the quality management and / or control standards for meglumine (CAS No.: 6284-40-8) used to prepare gadotyl ether meglumine are determined to be: in accordance with the provisions and requirements of Part II of the 2020 edition of the Chinese Pharmacopoeia, with a tightened limit of: reducing substances ≤0.05%.

[0111] Example 2

[0112] The main raw materials used in the preparation of gadoteric acid meglumine are as follows:

[0113] ①DOTA: Tested, all indicators meet the quality management and / or control standards (impurity RM≤0.05%, impurity P01≤0.05%, impurity P02≤0.05%, impurity P03≤0.05%, impurity P04≤0.05%; total impurities≤0.5% (purity≥99.5%));

[0114] ② Gadolinium oxide (Gd2O3): Gd2O3-4N5 grade gadolinium oxide was selected. Testing showed that all indicators met the quality management and / or control standards (Pr6O3). 11 Europium oxide (Eu₂O₃) ≤ 2ppm, terbium oxide (Tb₄O₇) ≤ 5ppm, thulium oxide (Tm₂O₃) ≤ 2ppm, lutetium oxide (Lu₂O₃) ≤ 2ppm;

[0115] ③Meglumine: All indicators meet the requirements of the 2020 edition of the Chinese Pharmacopoeia, Part II. The reducing substances were tested and found to be ≤0.05%.

[0116] 36.05 kg (approximately 2.04 equivalents) of DOTA and 15.686 kg (1 equivalent) of gadolinium oxide were dissolved in 153.06 kg of purified water. The solution was heated to 85°C–90°C and stirred until dissolved. The solution was then cooled to approximately 70°C (e.g., ±5°C), and 16.725 kg (approximately 1.96 equivalents) of meglumine was added. The solution was stirred until dissolved. The reaction was checked for completeness (the DOTA content in the reaction solution was approximately 0.02 wt%–0.09 wt%, preferably 0.03 wt%–0.07 wt%). Activated carbon (e.g., 1.75 kg–3.5 kg) was added for decolorization. The solution was filtered, and the solvent was evaporated to obtain the crude product. The crude product was then processed according to CN 113527222. Recrystallization was performed using the method described in paragraph

[0054] of Example 1: Gadotate meglumine raw material was obtained by recrystallization with alcohol solvents (methanol and isopropanol), which was a white or off-white solid with a yield in the range of 90% to 99.6% and a purity ≥99%.

[0117] The following test methods have been verified to comply with the provisions and requirements for methodological validation in the 2020 edition of the Chinese Pharmacopoeia.

[0118] 2.1 Content determination

[0119] (1) Gadolinium

[0120] The determination was performed according to high performance liquid chromatography (General Chapter 0512, Part IV, 2020 edition of the Chinese Pharmacopoeia).

[0121] Test solution: Take this product (gadolinium meglumine to be tested), dissolve and dilute it with water to a solution containing about 1.0 mg per 1 ml.

[0122] Reference solution: Accurately weigh gadoteric acid meglumine reference standard, dissolve and dilute with water to a solution containing approximately 1.0 mg per ml.

[0123] Chromatographic conditions:

[0124] Column (with phenyl-bonded silica gel as packing material): Waters Xbridge Phenyl (4.6 mm × 250 mm, 3.5 μm), or a column with equivalent performance;

[0125] Mobile phase A: 0.04 mol / L potassium dihydrogen phosphate aqueous solution (adjusted to pH 3.0 ± 0.2 with phosphoric acid);

[0126] Mobile phase B: Acetonitrile - Mobile phase A = 10:90 (volume ratio);

[0127] Mobile phase A - Mobile phase B = 60:40 (volume ratio) isocratic elution;

[0128] Flow rate: 0.6 ml / min;

[0129] Column temperature: 35℃;

[0130] Detection wavelength: 200nm;

[0131] Injection volume: 10 μl.

[0132] System applicability requirements: The theoretical plate number calculated based on the gadoteric acid peak should be no less than 3000, and the tailing factor should be no greater than 2.0.

[0133] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms; calculate the gadoteric acid content by peak area using the external standard method. Determine the representative HPLC chromatogram of a batch of gadoteric acid meglumine product after accelerated stability testing or long-term stability testing, such as... Figure 1 As shown, the retention time of gadolinium trioxide is approximately 7.76 min.

[0134] Multiple batches of test results show that, calculated on anhydrous basis, the gadotia content of gadotia meglumine raw material is 72.0% to 76.4% (w / w), or it can also be written as 72.0wt% to 76.4wt%, which meets the product quality standard requirements for gadotia meglumine raw material.

[0135] (2) Meglumine

[0136] The determination was performed according to high performance liquid chromatography (General Chapter 0512, Part IV, 2020 edition of the Chinese Pharmacopoeia).

[0137] Test solution: Take this product (gadolinium meglumine to be tested), dissolve and dilute it with water to a solution containing approximately 4.0 mg per 1 ml.

[0138] Reference solution: Weigh the meglumine reference standard accurately, dissolve and dilute it with water to prepare a solution containing approximately 1.0 mg of meglumine per ml.

[0139] Chromatographic conditions:

[0140] Chromatographic column (with sulfonic acid cation exchange bonded silica gel as packing material): CAPCELL PAK SCX (4.6 mm × 150 mm, 5 μm), or a column with equivalent performance;

[0141] Mobile phase: water-trifluoroacetic acid-formic acid = 100:0.05:0.3 (volume ratio) isocratic elution;

[0142] Flow rate: 1.0 ml / min;

[0143] Column temperature: 35℃;

[0144] Differential refractive index detector (temperature: 35℃);

[0145] Injection volume: 10 μl.

[0146] System applicability requirements: The theoretical plate number calculated based on the meglumine peak should be no less than 3000, and the tailing factor should be no greater than 1.5.

[0147] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms; calculate the results by peak area using the external standard method. A representative HPLC chromatogram of a batch of gadotyl meglumine product or meglumine after accelerated testing is shown below. Figure 2 As shown, the retention time of meglumine is approximately 12.12 min.

[0148] Multiple batches of test results show that, calculated on anhydrous basis, the gadoteric acid meglumine raw material contains 24.6% to 26.6% (w / w), or 24.6 wt% to 26.6 wt%, which meets the product quality standard requirements for gadoteric acid meglumine raw material.

[0149] 2.2 Determination of Free Gadolinium

[0150] Take approximately 7.54 g of this product (gadolinium meglumine to be tested), dissolve it in 30 ml of water, add 10 ml of acetate buffer (take 100 ml of 0.1 mol / L acetic acid, add 200 ml of 0.1 mol / L sodium acetate solution, mix well, and adjust the pH to 4.8–5.2 with 0.1 mol / L acetic acid or 0.1 mol / L sodium acetate solution), add 1 drop of pyridine and 10 drops of 0.1% xylenol orange solution. The solution should be yellow; if it is red, titrate with disodium ethylenediaminetetraacetate titrant (0.002 mol / L) until the solution changes from red to yellow.

[0151] Test results showed that the free gadolinium content of gadotate meglumine raw material was ≤0.002wt%, which met the product quality standard requirements for gadotate meglumine raw material.

[0152] 2.3 DOTA Measurement

[0153] The determination was performed according to high performance liquid chromatography (General Chapter 0512, Part IV, 2020 edition of the Chinese Pharmacopoeia).

[0154] Test solution: Take an appropriate amount of this product (gadolinium meglumine to be tested), dissolve and dilute it with water to make a solution containing about 20 mg of the test product per 1 ml.

[0155] Reference solution: Take an appropriate amount of DOTA reference standard, accurately weigh it, dissolve it in water and dilute it to a solution containing about 20 μg (DOTA) per 1 ml.

[0156] Chromatographic conditions:

[0157] Chromatographic column (using octadecylsilane-bonded silica gel as packing material): Kromasil 100-5-C18 (4.6 mm × 250 mm, 5 μm), or a column with equivalent performance;

[0158] Mobile phase A: 0.02 mol / L phosphate buffer (dissolve 2.72 g of potassium dihydrogen phosphate and 2.02 g of sodium heptanesulfonate in 1000 ml of water, and adjust the pH to 2.2 ± 0.2 with phosphoric acid);

[0159] Mobile phase B: Acetonitrile;

[0160] Perform gradient elution as shown in Table 2 below;

[0161] Table 2. Gradient elution procedure for DOTA determination

[0162]

[0163]

[0164] Flow rate: 1.0 ml / min;

[0165] Column temperature: 30℃;

[0166] Detection wavelength: 200nm;

[0167] Injection volume: 10 μl.

[0168] System applicability requirements: The theoretical number of plates calculated based on the DOTA peak should be no less than 3000, and the tailing factor should be no greater than 1.5.

[0169] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms; calculate the peak area using the external standard method. Determine the representative HPLC chromatogram of a batch of gadotyl diglucamine product or after accelerated testing, such as... Figure 3 As shown, the retention time for DOTA is approximately 15.383 minutes.

[0170] Test results showed that the DOTA content of gadoteric acid meglumine raw material was in the range of 0.01wt% to 0.1wt%, which met the product quality standard requirements for gadoteric acid meglumine raw material.

[0171] 2.4 Heavy Metal Determination

[0172] Take 2.0g of this product (gadoteryl meglumine to be tested) and test it according to the method (2020 edition of Chinese Pharmacopoeia, Part IV, General Chapter 0821, Method II).

[0173] The test results showed that the heavy metal content of gadoteric acid meglumine raw material was ≤10ppm (i.e., not more than 10 parts per million), which meets the product quality standard requirements for gadoteric acid meglumine raw material.

[0174] 2.5 Determination of related substances

[0175] The determination was performed according to the high performance liquid chromatography method (General Chapter 0512, Part IV of the 2020 Chinese Pharmacopoeia) (denoted as: RS detection method II).

[0176] Test solution: Take this product (gadolinium meglumine to be tested), dissolve and dilute it with water to a solution containing approximately 20 mg per 1 ml.

[0177] Reference solution: Accurately weigh the relevant substance RS01 reference standard, dissolve and dilute it with water to a solution containing approximately 10 μg per ml.

[0178]

[0179] (Mainly generated by the reaction of impurity PO1 in DOTA with gadolinium oxide)

[0180] Chromatographic conditions:

[0181] Column (with phenyl-bonded silica gel as packing material): Waters Xbridge Phenyl (4.6 mm × 250 mm, 3.5 μm), or a column with equivalent performance;

[0182] Mobile phase A: 0.04 mol / L potassium dihydrogen phosphate aqueous solution (adjusted to pH 3.0 ± 0.2 with phosphoric acid);

[0183] Mobile phase B: Acetonitrile - Mobile phase A = 10:90 (volume ratio);

[0184] Perform gradient elution as shown in Table 3 below;

[0185] Table 3. Gradient elution procedures for the determination of related substances

[0186] Time (min) Mobile phase A (%, volume percentage) Mobile phase B (%, volume percentage) 0 96 4 5 96 4 25 0 100 30 0 100 31 96 4 50 96 4

[0187] Flow rate: 0.6 ml / min;

[0188] Column temperature: 30℃;

[0189] Detection wavelength: 195nm;

[0190] Injection volume: 10 μl.

[0191] System suitability requirements: The theoretical plate number, calculated based on the RS01 peak of the relevant substances, should be no less than 3000, and the tailing factor should be no greater than 1.5.

[0192] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms; calculate the results by peak area using the external standard method. This method involves determining representative HPLC chromatograms of related substances from a batch of unpurified gadotyl meglumine product or after accelerated testing, such as... Figure 4 As shown, the retention time of related substance RS01 is approximately 17.93 min.

[0193] The test results showed that the content of related substances RS01 in gadotate meglumine raw material was ≤0.05wt%, which met the product quality standard requirements for gadotate meglumine raw material.

[0194] Example 3

[0195] Using gadoteric acid meglumine (e.g., the gadoteric acid meglumine prepared in Example 2) that meets the quality standard requirements (① gadoteric acid content of 72.0wt% to 76.4wt%; ② meglumine content of 24.6wt% to 26.6wt%; ③ free gadolinium content ≤0.002wt%; ④ DOTA content of 0.01wt% to 0.1wt%; ⑤ heavy metal content ≤10ppm; ⑥ related substance RSO1 content ≤0.05wt%; etc.) as the active pharmaceutical ingredient, gadoteric acid meglumine injection was prepared according to the method described in the example of CN 202010669147.5.

[0196] The obtained gadoteric acid meglumine injection meets the quality requirements of "i. gadoteric acid content of 26.53% to 29.33% g / ml; ii. meglumine content of 9.27% ​​to 10.25% g / ml; iii. free gadolinium content of ≤0.005% g / ml; iv. free acid (DOTA) content of 0.005% to 0.05% g / ml", exhibiting good stability and complying with the import drug registration standards and relevant provisions of the Chinese Pharmacopoeia. This facilitates its transportation and / or storage, better ensuring that the drug does not deteriorate or become ineffective within its shelf life. It truly embodies my country's development strategy of "improving drug quality, ensuring medication safety, and serving drug regulation," and better protects the medication safety of patients.

[0197] Of course, the present invention can also have other various embodiments. Without departing from the spirit and essence of the present invention, those skilled in the art can make various corresponding changes and / or modifications according to the present invention, and these corresponding changes and / or modifications should all fall within the protection scope of the appended claims.

Claims

1. A method for preparing gadoteric acid meglumine, characterized in that, Gadolinium methylamine was prepared from DOTA, gadolinium oxide, and meglumine; wherein the related substances in the DOTA met the following conditions: by mass percentage, impurity RM ≤ 0.05%, and / or, impurity PO1 ≤ 0.05%, impurity PO2 ≤ 0.05%, impurity PO3 ≤ 0.05%, impurity PO4 ≤ 0.05%, and total impurities ≤ 0.5%; The impurity RM and impurities PO1 to PO4 have the following structures respectively:

2. The preparation method according to claim 1, characterized in that, The relevant substances in the DOTA meet the following conditions: by mass percentage, impurity RM ≤ 0.02% or undetectable, and / or, impurity P01 ≤ 0.02% or undetectable, and / or, impurity P02 ≤ 0.01% or undetectable, and / or, impurity P03 ≤ 0.01% or undetectable, and / or, impurity P04 ≤ 0.02% or undetectable; And / or, the relevant substances in the DOTA are determined according to RS detection method I.

3. The preparation method according to claim 1 or 2, characterized in that, The gadolinium oxide conforms to the Chinese national standard GB / T 2526-2020 and the following conditions: praseodymium oxide ≤ 2 ppm, and / or europium oxide ≤ 5 ppm, and / or terbium oxide ≤ 5 ppm, and / or thulium oxide ≤ 2 ppm, and / or lutetium oxide ≤ 2 ppm; And / or, by mass percentage, the meglumine complies with the provisions of the 2020 edition of the Chinese Pharmacopoeia, Part II, and the reducing substances therein are ≤0.05%; Preferably, the gadolinium oxide is selected from gadolinium oxide of grade Gd2O3-4N5 or Gd2O3-5N.

4. The preparation method according to any one of claims 1-3, characterized in that, The preparation method includes the following steps: DOTA, gadolinium oxide and meglumine were reacted in a solvent. After the reaction was completed, the resulting reaction solution was decolorized, filtered, and the solvent was removed from the filtrate. Then, a recrystallization step was optionally included to obtain gadotonic acid meglumine. The control method for ending the reaction is as follows: at the end of the reaction and / or after the reaction is completed, the DOTA content in the reaction solution is 0.015wt% to 0.15wt%, and / or the pH value of the reaction solution is <6.3; Preferably, at the end of the reaction and / or after the reaction is completed, the DOTA content in the reaction solution is 0.02 wt% to 0.09 wt%. More preferably, at the end of the reaction and / or after the reaction is completed, the content of DOTA in the reaction solution is 0.03wt% to 0.07wt%.

5. The preparation method according to claim 4, characterized in that, Based on the amount of gadolinium oxide per mole, the amount of DOTA used is 2.001 mol to 2.1 mol, and the amount of meglumine used is 1.9 mol to 2.0 mol. And / or, based on gadolinium oxide per kilogram, the amount of solvent used in the reaction is 9 kg to 15 kg; And / or, the reaction temperature is 55°C to 92°C; And / or, the order of the reactions is: DOTA reacts with gadolinium oxide to generate gadotonic acid, and then reacts with meglumine; Preferably, the reaction temperature of DOTA with gadolinium oxide is 85℃~90℃, and the reaction temperature of gadotiamic acid with meglumine is 60℃~75℃.

6. The preparation method according to claim 4, characterized in that, The solvent for the reaction is water or pharmaceutically acceptable water; and / or, the solvent for the recrystallization is water and / or an alcohol solvent selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, n-pentanol and its isomers, propylene glycol, butanediol, glycerol, and benzyl alcohol; and / or, the method for decolorizing the reaction solution is to add activated carbon to the reaction solution. Preferably, the alcohol solvent is selected from methanol and isopropanol.

7. A gadoteric acid meglumine raw material, characterized in that, The gadotate meglumine raw material meets the following quality standards: Based on anhydrous content, gadotiacid content ranges from 72.0 wt% to 76.4 wt%, and meglumine content ranges from 24.6 wt% to 26.6 wt%. And / or, the free gadolinium content is ≤0.002wt%; And / or, the DOTA content is 0.01wt% to 0.1wt%; And / or, heavy metal content ≤10ppm; And / or, the content of related substance RS01 is ≤0.05wt%, which has the following structure: Preferably, the gadoteric acid meglumine raw material is prepared by the preparation method according to any one of claims 1 to 6.

8. A high-performance liquid chromatography method for the detection of gadoteric acid meglumine raw material, characterized in that, The chromatographic conditions of the high-performance liquid chromatography detection method include: Chromatographic column: C18 column or equivalent column, using phenyl-bonded silica gel as packing material; preferably, the column is a Waters Xbridge Phenyl column, and / or the column specifications are: 4.6 mm × 250 mm, 3.5 μm; Mobile phase A: 0.04 mol / L to 0.05 mol / L potassium dihydrogen phosphate aqueous solution with a pH of 3.0 ± 0.2; preferably, the pH of mobile phase A is adjusted to 3.0 ± 0.2 with phosphoric acid. Mobile phase B: A mixed solution of acetonitrile and mobile phase A in a volume ratio of 10:90; Perform gradient elution according to the following procedure: Detection wavelength: 180nm~220nm; preferably, the detection wavelength is 195nm; Preferably, Column temperature: 15℃~45℃; more preferably, the column temperature is 25℃~35℃; And / or, the injection volume is 0.5 μl to 25 μl; more preferably, the injection volume is 8 μl to 12 μl; And / or, the flow rate is 0.1 ml / min to 2 ml / min; more preferably, the flow rate is 0.5 ml / min to 1 ml / min.

9. The high-performance liquid chromatography detection method according to claim 8, characterized in that, The test solution of the high performance liquid chromatography detection method is prepared by dissolving gadotate meglumine raw material or gadotate meglumine raw material as described in claim 7 in water; The reference solution of the high performance liquid chromatography detection method is prepared by dissolving the related substance RS01 reference standard in water; The related substance RS01 has the following structure: And / or, the high performance liquid chromatography detection method is a qualitative or quantitative detection; preferably, the quantitative detection is to calculate the content of related substances RS01 in gadotate meglumine raw material by peak area using the external standard method.

10. A gadoteric acid meglumine injection, comprising gadoteric acid meglumine active pharmaceutical ingredient, water for injection, and one or more pharmaceutically acceptable excipients, characterized in that, The gadoteric acid meglumine raw material is the gadoteric acid meglumine raw material as described in claim 7.

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