WO2019153220A1 - 双环铂药物检测方法 - Google Patents

双环铂药物检测方法 Download PDF

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WO2019153220A1
WO2019153220A1 PCT/CN2018/075926 CN2018075926W WO2019153220A1 WO 2019153220 A1 WO2019153220 A1 WO 2019153220A1 CN 2018075926 W CN2018075926 W CN 2018075926W WO 2019153220 A1 WO2019153220 A1 WO 2019153220A1
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drug
carboplatin
diffraction
content
platinum
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PCT/CN2018/075926
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English (en)
French (fr)
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杨旭清
张灵敏
孙雪南
于红艳
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北京索普兴大医药研究有限公司
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Priority to PCT/CN2018/075926 priority Critical patent/WO2019153220A1/zh
Priority to CN201880000702.6A priority patent/CN108780053A/zh
Publication of WO2019153220A1 publication Critical patent/WO2019153220A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • G01N23/207—Diffractometry using detectors, e.g. using a probe in a central position and one or more displaceable detectors in circumferential positions
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2223/00—Investigating materials by wave or particle radiation
    • G01N2223/05—Investigating materials by wave or particle radiation by diffraction, scatter or reflection
    • G01N2223/056—Investigating materials by wave or particle radiation by diffraction, scatter or reflection diffraction
    • G01N2223/0566—Investigating materials by wave or particle radiation by diffraction, scatter or reflection diffraction analysing diffraction pattern

Definitions

  • the invention relates to a medicine detecting method, in particular to a method for detecting a medicine using bicycloplatin as an active ingredient.
  • Dicycloplatin is a relatively stable supramolecular compound composed of carboplatin and cyclobutanedioic acid through four hydrogen bonds. Its chemical structure is 1,1-cyclobutanedicarboxylic acid, diammine platinum (II). Is a 1,1-cyclobutane dicarboxylic acid diaminoplatin (II)] complex. Studies have shown that bicycloplatinum is a new generation of supramolecular anticancer drugs with broad spectrum, high efficiency, low toxicity, low drug resistance, low cross-resistance and good penetrability. For example, the invention patent disclosed in CN1311183A has carried out acute toxicity, pharmacodynamic experiments and clinical tests on bicycloplatin.
  • bicyclo platinum is not only low in toxicity but also high in anticancer activity, and is suitable for cancer, head and neck cancer, nasopharyngeal carcinoma, and breast.
  • Cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, intestinal cancer, lymphoma, etc. have significant effects. At present, there are no reports on the relevant methods for effective qualitative and/or quantitative determination of bicycloplatinum.
  • the invention provides a method for detecting a drug using bicycloplatin as an active ingredient, which is used for effective qualitative and/or quantitative analysis of bicycloplatinum.
  • the demonstration of the clinical efficacy of bicycloplatin as a new generation of supramolecular anticancer drugs provides a basis for its promotion and application. To realize the industrial production of the drug, it is indispensable to establish a relevant quality inspection and monitoring system.
  • the supramolecular structure of bicycloplatin is derived from the hydrogen bonding between carboplatin and cyclobutanedioic acid in the molecule.
  • LC-MS liquid chromatography-mass spectrometry
  • CZE capillary electrophoresis
  • the art is still attempting to detect them using different methods and/or standards in order to obtain a good method for identifying bicyclic platinum and, for example, carboplatin.
  • the invention patent publication CN104122280A discloses a method for detecting a bicyclic platinum drug.
  • the patent indicates that if the X-ray powder diffraction pattern of the drug has a diffraction peak at a 2 ⁇ angle of 10.3-10.7° and a diffraction peak at a 2 ⁇ angle of 11.3-11.7°, it indicates that the drug contains bicycloplatinum.
  • the diffraction peak at 11.3-11.7 ° is a characteristic peak of carboplatin.
  • the inventors have surprisingly found that in the preparation of bicycloplatinic drugs in multiple batches, diffraction peaks at a 2 theta angle of 10.3-10.7° do not appear in the X-ray powder diffraction pattern of some batches of bicycloplatinum. That is to say, the stability of the diffraction peak at 10.3-10.7° is not satisfactory. Therefore, for bicycloplatinum drugs, it is particularly important to select a suitable characteristic peak that can be identified. If the selected characteristic peaks do not have good reproducibility, it may bring illusion to the qualitative and/or quantitative analysis of bicycloplatin in the drug.
  • the inventors analyzed the X-ray powder diffraction pattern of a plurality of batches of the bicyclic platinum drug to expect to find a diffraction peak more suitable as a characteristic peak of the bicycloplatinum drug.
  • the inventors have found that the diffraction peak at a ⁇ -angle of 7.4-7.8° and at 15.0-15.4° is also a characteristic peak of a bicyclo platinum drug, but is more a diffraction peak at a 10.3-10.7° angle than the 2 ⁇ angle. For stable appearance, it is suitable as a characteristic peak for identifying a bicyclic platinum drug.
  • the present invention provides a method for detecting a drug comprising bicycloplatin as an active ingredient, the detection method comprising:
  • the drug contains bicyclo platinum. .
  • XRPD X-ray powder diffraction analysis
  • the 2 ⁇ angle is one, two or three (about 7.6°, 10.5°, and 15.2) at 7.4-7.8°, 10.3-10.7°, and 15.0-15.4°.
  • Having a diffraction peak at °) may indicate the presence of bicycloplatin, and the physical mixture of cyclosuccinic acid, carboplatin, succinic acid, and carboplatin has no diffraction peaks at these points; moreover, the prepared bicyclic ring is known in the art.
  • Platinum drugs are often mixed with carboplatin raw material impurities.
  • the 2 ⁇ angle of 11.3-11.7° does not have a diffraction peak, and it can also indicate the presence of bicycloplatinum, carboplatin and ring.
  • the physical mixture of succinic acid and carboplatin has a diffraction peak there. Therefore, X-ray powder diffraction analysis is particularly capable of qualitatively detecting a powdery drug containing bicycloplatinum, such as a bicyclic platinum drug substance.
  • bicycloplatinum for example, a bicyclic platinum injection
  • detection conditions for example, liquid chromatography analysis, etc.
  • the bicyclic platinum in the bicyclic platinum solution is effectively qualitatively detected, for example, it cannot be distinguished from the mixed solution of carboplatin and succinic acid.
  • the invention provides a method for detecting a drug using bicycloplatin as an active ingredient, and the detection method comprises:
  • the drug contains bicyclo platinum. .
  • the invention also provides a method for detecting a drug using bicycloplatin as an active ingredient, the detection method comprising:
  • the drug contains bicycloplatinum and does not contain carboplatin.
  • the drug contains bicyclo platinum. And does not contain carboplatin; if the first diffraction pattern has a diffraction peak at a 2 ⁇ angle of 15.0-15.4°, and the 2 ⁇ angle has a diffraction peak at 11.3-11.7°, the drug contains bicycloplatinum and does not Contains carboplatin.
  • the drug to be detected may be a bicyclo platinum injection, and the detection method thus further comprises lyophilizing the drug to prepare a bicyclo platinum drug powder.
  • X-ray powder diffraction analysis can be performed on the bicycloplatinum powder.
  • the above detection method according to the present invention wherein if the 2 ⁇ angle in the first diffraction pattern is 7.4-7.8°, 10.3-10.7°, and 15.0-15.4°, one, two or three, and 2 ⁇ angle
  • the diffraction method has a diffraction peak at 11.3-11.7°, and the detection method may further include:
  • X-ray powder diffraction analysis is carried out by mixing a bicyclo platinum standard with carboplatin to obtain a second diffraction pattern, wherein the mass percentage of carboplatin in the mixed powder is X%;
  • An integrated intensity A 11 of the diffraction peak at a 2 ⁇ angle of 7.4-7.8° and/or an integrated intensity A 12 of a diffraction peak at 15.0-15.4°, and a 2 ⁇ angle of 11.3-11.7°, respectively, are obtained in the first diffraction pattern.
  • the detection method of the present invention further comprises quantitatively detecting a drug having bicycloplatin as an active ingredient, that is,
  • the bicyclo platinum raw material is prepared as a solution or diluted with a bicyclo platinum injection, and subjected to reversed-phase high performance liquid chromatography, and the solution of 0.025-0.999 mg/mL carboplatin and 0.101-3.99 mg/mL cyclosuccinic acid solution is used.
  • the standard solution determines the mass content of carboplatin and cyclosuccinic acid in the bicyclo platinum injection, respectively.
  • the mass concentration of the bicyclic platinum in the solution or the diluted bicyclo platinum injection is 1 mg/mL, and the 0.7 mg/mL carboplatin solution and the 0.3 mg/mL cyclosuccinic acid solution are used as standards. Solution.
  • the determination of the mass content can be carried out by an external standard method.
  • the reversed-phase high performance liquid chromatography was carried out, and 0.037-2.7 mmol/L of carboplatin solution and 0.7-27.8 mmol/L of cyclosuccinic acid solution were used as the solution.
  • a standard solution is used to determine the molar content of carboplatin and cyclosuccinic acid in the bicyclo platinum injection and the molar ratio of carboplatin to cyclosuccinic acid, respectively.
  • the molar concentration of the bicyclic platinum in the solution or the diluted bicyclic platinum injection was 2 mmol/L, and a 2 mmol/L carboplatin solution and a 2 mmol/L cyclosuccinic acid solution were used as a standard solution.
  • the method for detecting a drug containing bicycloplatin as an active ingredient provided by the invention can qualitatively and/or quantitatively analyze bicycloplatinum in a drug, which can eliminate the illusion caused by other measuring methods, and truly and intuitively treat the double ring Platinum is effectively measured, and the content of impurities in the drug can be effectively measured, thereby facilitating quality control of the bicyclic platinum drug.
  • Example 1 is an X-ray powder diffraction pattern of Sample I in Example 1 of the present invention.
  • Example 2 is an X-ray powder diffraction pattern of Sample II in Example 1 of the present invention.
  • Example 3 is an X-ray powder diffraction pattern of Sample 1 in Example 1 of the present invention.
  • Figure 5 is an X-ray powder diffraction pattern of Sample 3 in Example 1 of the present invention.
  • Figure 6 is an X-ray powder diffraction pattern of Sample 4 in Example 1 of the present invention.
  • Figure 7 is an X-ray powder diffraction pattern of Sample 5 in Example 1 of the present invention.
  • Figure 8 is an X-ray powder diffraction pattern of Sample 6 in Example 1 of the present invention.
  • Figure 9 is an X-ray powder diffraction pattern of Sample 7 in Example 1 of the present invention.
  • Figure 10 is an X-ray powder diffraction pattern of dicyclo platinum added with 1.0% carboplatin in Example 2 of the present invention.
  • Example 11 is an X-ray powder diffraction pattern of a bicycloplatin supplemented with 2.0% carboplatin according to Example 2 of the present invention.
  • Figure 12 is an X-ray powder diffraction pattern of a 3.0% carboplatin-added bicycloplatin according to Example 2 of the present invention.
  • Scanning mode ⁇ /2 ⁇ scanning; DS divergence slit 1.2mm, cable slit 2.5mm;
  • the XRPD pattern of Sample I shows a complete bicyclic platinum diffraction peak, including diffraction peaks at 2 ⁇ angles of 7.58°, 10.51°, and 15.12°.
  • the inventors have unexpectedly found that the XRPD pattern shown by the same preparation method and crystallization conditions and the like has a diffraction peak with a 2 ⁇ angle of 7.68° and 15.24°, but does not show 10.3-10.7°. The diffraction peak at the place.
  • the inventors conducted multi-batch bicyclic platinum sample synthesis and performed XRPD determination on the obtained sample.
  • XRPD measurement of a total of 35 batches of bicyclic platinum samples a total of 7 samples were found to have no diffraction peaks at 10.3-10.7° in the XRPD pattern.
  • the synthetic preparation of the seven samples shown is the same as described above, and the crystallization conditions and grinding conditions of each sample are as follows:
  • Sample serial number Crystallization condition Grinding situation Sample 1 Stirring at 2-8 ° C for 4 hours 1 minute Sample 2 Static crystallization at 2-8 ° C, 15 days 2 minutes Sample 3 Crystallization at 2-8 ° C for 30 days 2 minutes Sample 4 Stirring at 2-8 ° C for 4 hours no Sample 5 Stirring at 2-8 ° C for 4 hours 2 minutes Sample 6 Crystallization at 2-8 ° C for 30 days no Sample 7 Crystallization at 2-8 ° C for 30 days 2 minutes
  • the XRPD pattern measured by the sample 1 has diffraction peaks with a 2 ⁇ angle of 7.629° and 15.198°, but does not show a diffraction peak at 10.3-10.7°.
  • Tables 2 and 3 below show the peaks and intensities detected by the XRPD patterns (see Figures 4 to 5) measured by Samples 2 and 3, respectively:
  • the XRPD pattern parameters of samples 4 to 7 are not shown in detail herein, and the XRPD pattern data of samples 4 to 7 can be seen in FIGS. 6 to 9.
  • the diffraction peak at 10.3-10.7° can be used as a characteristic peak for identifying bicycloplatin, the peak does not have good reproducibility.
  • the presence of 20% of the bicyclic platinum sample did not show a diffraction peak at 10.3-10.7.
  • the inventors have found that, in contrast, the characteristic peaks at 7.4-7.8° and 15.0-15.4° of bicyclo platinum have better reproducibility and are suitable as characteristic peaks for identifying bicyclic platinum.
  • the impurity carboplatin has a diffraction peak at a 2 ⁇ angle of 11.3-11.7° in the XRPD pattern, and the bicycloplatinum pure product has no diffraction peak there.
  • the carboplatin content can be determined from the peak area ratio of the characteristic peaks of carboplatin and bicycloplatinum.
  • the peak height of the diffraction peak at 10.3-10.7° is much lower than the peak height at 7.4-7.8° and 15.0-15.4°, 10.3-
  • the peak area of the diffraction peak at 10.7° is also much smaller than the peak area of the diffraction peak at 7.4-7.8° and 15.0-15.4°. It can be reasonably inferred that the peak area of the diffraction peak at 10.3-10.7° is greatly affected by noise.
  • the peak area of the diffraction peak at 7.4-7.8° and 15.0-15.4° is compared with the peak area of the diffraction peak at 10.3-10.7°. More accurate results.
  • a 21 The integrated intensity of the diffraction peak at a 2 ⁇ angle of 7.4-7.8° in the diffraction pattern is denoted as A 21
  • a 22 the integrated intensity of the diffraction peak at a 2 ⁇ angle of 15.0-15.4° is denoted as A 22
  • the angle of 2 ⁇ is 11.3-11.7°
  • a 23 The integrated intensity of the diffraction peak is denoted as A 23 .
  • a 21 /A 23 of the sample AC were calculated to be 760.8, 256.4, and 80.3, respectively, and A 22 /A 23 were 276.5, 34.5, and 13.6, respectively.
  • the XRPD measurement was carried out on the bicyclic platinum drug substance, and the integrated intensity of the diffraction peak at a 2 ⁇ angle of 7.4-7.8° in the diffraction pattern was recorded as A 11 , and the integrated intensity of the diffraction peak at a 2 ⁇ angle of 15.0-15.4° was recorded as The integrated intensity of the diffraction peak at A 12 , 2 ⁇ angle of 11.3-11.7° is denoted as A 13 , and A 11 /A 13 and A 12 /A 13 are calculated, and the carboplatin content of each sample and its corresponding A 21 are calculated. /A 23 and A 22 /A 23 were used as a reference to determine the content of carboplatin in the bicyclic platinum drug substance.
  • the carboplatin content in the above sample is not limited to the values shown in the above examples, as long as the sample can be detected by XRPD diffraction pattern.
  • the carboplatin content (for example, the carboplatin content in the sample is ⁇ 0.1%), then A 21 /A 23 and A 22 /A 23 may be any other value, and the value can be used as a reference to determine the carboplatin in the bicyclic platinum drug substance. content.

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Abstract

一种以双环铂为有效成分的药物的检测方法，所述检测方法包括：对所述药物进行X射线粉末衍射分析获得第一衍射图谱，确认所述第一衍射图谱中2θ角为7.4-7.8°处、15.0-15.4°处和/或11.3-11.7°处是否具有衍射峰，若所述第一衍射图谱中2θ角为7.4-7.8°处和15.0-15.4°处中的一处或两处具有衍射峰，和/或2θ角为11.3-11.7°处不具有衍射峰，则所述药物中含有双环铂。该方法能够对含有双环铂的药物及其中杂质进行有效的定性和/或定量分析。

Description

双环铂药物检测方法 技术领域
本发明涉及一种药物检测方法，特别涉及一种以双环铂为有效成分的药物的检测方法。
背景技术
双环铂(Dicycloplatin)是由卡铂与环丁烷二酸通过四个氢键组成的相对稳定的超分子化合物，其化学结构为1,1-环丁烷二羧酸，二氨配铂(Ⅱ)合1,1-环丁烷二羧酸(Bis-[1,1-cyclobutane dicarboxylic acid diaminoplatin(Ⅱ)]complex)。研究表明双环铂具有广谱、高效、低毒、低耐药、低交叉耐药以及穿透性好等特点，是新一代超分子抗癌药物。例如，公开号为CN1311183A的发明专利对双环铂进行了急毒、药效实验及临床检验，结果表明双环铂不仅低毒而且抗癌活性高，对泌生癌、头颈癌、鼻咽癌、乳腺癌、肺癌、肝癌、胰腺癌、胃癌、肠癌、淋巴癌等均有显著疗效。目前，尚无对双环铂进行有效定性和/或定量的相关方法报道。
发明内容
本发明提供一种以双环铂为有效成分的药物的检测方法，用于对双环铂进行有效的定性和/或定量分析。
双环铂作为新一代超分子抗癌药物的临床功效的证明为其推广应用提供了基础，为实现该药物的工业化生产，建立相关的质量检测和监控体系不可或缺。双环铂的超分子结构来自分子中卡铂与环丁烷二酸之间的氢键结合，由于双环铂的这种超分子结构特性，采用液相色谱-质谱联用法(LC-MS)、流动注射-质谱分析、红外光谱分析、毛细管电泳(CZE)等多数测试方法均无法对以双环铂为有效成分的药物中的双环铂进行精确地定性，测定结果容易出现假象。
基于对双环铂药物成分检测的困难，本领域仍在尝试采用不同的方式和/或标准对其进行检测，以期望获得良好的鉴别双环铂与例如卡铂的方法。特 别地，公开号为CN104122280A的发明专利公开了一种对双环铂药物的检测方法。其中，该专利指出若药物的X射线粉末衍射图谱中2θ角为10.3-10.7°处具有衍射峰和2θ角为11.3-11.7°处不具有衍射峰，指示药物中含有双环铂。其中，11.3-11.7°处的衍射峰为卡铂的特征峰。然而，本发明人出人意料地发现，在多批次制备双环铂药物时，一些批次的双环铂的X射线粉末衍射图谱中并不出现2θ角为10.3-10.7°处的衍射峰。也就是说，10.3-10.7°处的衍射峰的稳定性不理想。因此，对于双环铂药物而言，选择合适的能够对其鉴别的特征峰尤为重要。若选定的特征峰不具有良好的重现性，可能对药物中的双环铂的定性和/或定量分析带来假象。对此，本发明人对多批次双环铂药物的X射线粉末衍射图谱进行分析，以期望找到更适合作为双环铂药物特征峰的衍射峰。经比对，本发明人发现2θ角为7.4-7.8°处、15.0-15.4°处的衍射峰同样为双环铂药物的特征峰，但是相比于2θ角为10.3-10.7°处的衍射峰更为稳定出现，适合作为鉴定双环铂药物的特征峰。
因此，本发明提供了一种以双环铂为有效成分的药物的检测方法，所述检测方法包括：
对所述药物进行X射线粉末衍射分析，获得第一衍射图谱；
确认所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处和15.0-15.4°处是否具有衍射峰；
若所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处和15.0-15.4°处中的一处、两处或三处具有衍射峰，则所述药物中含有双环铂。
本发明人发现，采用X射线粉末衍射分析(XRPD)能够有效地对双环铂进行定性分析。其中，室温得到的衍射图谱中，2θ角为7.4-7.8°处、10.3-10.7°处和15.0-15.4°处中的一处、两处或三处(约7.6°处、10.5°处和15.2°处)具有衍射峰可以表明双环铂存在，而环丁二酸、卡铂、环丁二酸和卡铂的物理混合物在这些处均不具有衍射峰；此外，本领域已知制备得到的双环铂药物常常混有卡铂原料杂质，对于由此制备的双环铂药物而言，2θ角为11.3-11.7°处(约11.55°处)不具有衍射峰也可以表明双环铂存在，卡铂、环丁二酸和卡铂的物理混合物在该处均具有衍射峰。因此，X射线粉末衍射分析尤其能够对粉末状的含有双环铂的药物进行定性检测，例如双环铂原料 药。
对于含有双环铂的溶液(例如双环铂针剂)，本发明人发现多数的检测条件(例如液相色谱分析等)会破坏双环铂分子内氢键，使其无法以超分子的形式存在，因此无法有效地对双环铂溶液中的双环铂进行定性检测，例如无法将其与卡铂和环丁二酸的混合溶液区分开。
本发明提供了一种以双环铂为有效成分的药物的检测方法，所述检测方法包括：
对所述药物进行X射线粉末衍射分析，获得第一衍射图谱；
确认所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处和15.0-15.4°处是否具有衍射峰；
若所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处和15.0-15.4°处中的一处、两处或三处具有衍射峰，则所述药物中含有双环铂。
本发明还提供了一种以双环铂为有效成分的药物的检测方法，所述检测方法包括：
对所述药物进行X射线粉末衍射分析，获得第一衍射图谱；
确认所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处、15.0-15.4°处和/或11.3-11.7°处是否具有衍射峰；
若所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处和15.0-15.4°处中的一处、两处或三处具有衍射峰，并且2θ角为11.3-11.7°处不具有衍射峰，则所述药物中含有双环铂且不含有卡铂。
在本发明的检测方法中，若所述第一衍射图谱中2θ角为7.4-7.8°处具有衍射峰，并且2θ角为11.3-11.7°处不具有衍射峰，则所述药物中含有双环铂且不含有卡铂；若所述第一衍射图谱中2θ角为15.0-15.4°处具有衍射峰，并且2θ角为11.3-11.7°处不具有衍射峰，则所述药物中含有双环铂且不含有卡铂。
在本发明的检测方法中，待检测药物可为双环铂针剂，所述检测方法因此还包括对所述药物进行冻干处理，从而制得双环铂药粉。X射线粉末衍射分析可针对所述双环铂药粉进行。
根据本发明的上述检测方法，其中若所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处和15.0-15.4°处中的一处、两处或三处以及2θ角为11.3-11.7° 处均具有衍射峰，则所述检测方法还可包括：
将双环铂标准品与卡铂制成混合粉末进行X射线粉末衍射分析，获得第二衍射图谱，所述混合粉末中卡铂的质量百分含量为X％；
分别获得所述第一衍射图谱中2θ角为7.4-7.8°处的衍射峰的积分强度A 11和/或15.0-15.4°处的衍射峰的积分强度A 12，以及2θ角为11.3-11.7°处的衍射峰的积分强度A 13，并且分别获得所述第二衍射图谱中2θ角为7.4-7.8°处的衍射峰的积分强度A 21和/或15.0-15.4°处的衍射峰的积分强度A 22，以及2θ角为11.3-11.7°处的衍射峰的积分强度A 23，计算A 11/A 13与A 21/A 23和/或A 12/A 13与A 22/A 23；
若A 11/A 13≥A 21/A 23，则所述药物中卡铂的含量≤X％，若A 11/A 13<A 21/A 23，则所述药物中卡铂的含量＞X％；
若A 12/A 13≥A 22/A 23，则所述药物中卡铂的含量≤X％，若A 12/A 13<A 22/A 23，则所述药物中卡铂的含量＞X％。
在本发明的检测方法中，若A 11/A 13≥760.8，则双环铂原料药中卡铂的含量≤1.0％；若A 11/A 13<760.8，则双环铂原料药中卡铂的含量＞1.0％。
在本发明的检测方法中，若A 11/A 13≥256.4，则双环铂原料药中卡铂的含量≤2.0％；若A 11/A 13<256.4，则双环铂原料药中卡铂的含量＞2.0％。
在本发明的检测方法中，若A 11/A 13≥80.3，则双环铂原料药中卡铂的含量≤3.0％；若A 11/A 13<80.3，则双环铂原料药中卡铂的含量＞3.0％。
在本发明的检测方法中，若A 12/A 13≥276.5，则双环铂原料药中卡铂的含量≤1.0％；若A 12/A 13<276.5，则双环铂原料药中卡铂的含量＞1.0％。
在本发明的检测方法中，若A 12/A 13≥34.5，则双环铂原料药中卡铂的含量≤2.0％；若A 12/A 13<34.5，则双环铂原料药中卡铂的含量＞2.0％。
在本发明的检测方法中，若A 12/A 13≥13.6，则双环铂原料药中卡铂的含量≤3.0％；若A 12/A 13<13.6，则双环铂原料药中卡铂的含量＞3.0％。
进一步地，本发明的检测方法还包括对以双环铂为有效成分的药物进行定量检测，即：
将双环铂原料药制成溶液后或双环铂针剂稀释后进行反相高效液相色谱检测，同时以0.025-0.999mg/mL的卡铂溶液和0.101-3.99mg/mL的环丁二酸 溶液作为标准溶液，分别确定所述双环铂针剂中卡铂和环丁二酸的质量含量。
进一步地，使所述溶液或稀释后的所述双环铂针剂中双环铂的质量浓度为1mg/mL，并且以0.7mg/mL的卡铂溶液和0.3mg/mL的环丁二酸溶液作为标准溶液。所述质量含量的确定可以通过外标法进行。
本发明还可以采用其它定量检测方法，例如：
将双环铂原料药制成溶液后或双环铂针剂稀释后进行反相高效液相色谱检测，同时以0.067-2.7mmol/L的卡铂溶液和0.7-27.8mmol/L的环丁二酸溶液作为标准溶液，分别确定所述双环铂针剂中卡铂和环丁二酸的摩尔含量以及卡铂与环丁二酸的摩尔比。
进一步地，使所述溶液或稀释后的所述双环铂针剂中双环铂的摩尔浓度为2mmol/L，并且以2mmol/L的卡铂溶液和2mmol/L的环丁二酸溶液作为标准溶液。
本发明所提供的以双环铂为有效成分的药物的检测方法，能够对药物中的双环铂进行定性和/或定量分析，其能够排除其它测定方法所带来的假象，真实且直观地对双环铂进行有效地测定，能够对药物中的杂质含量进行有效地测定，从而有利于双环铂药物的质量控制。
附图说明
图1为本发明实施例1中样品I的X射线粉末衍射图谱；
图2为本发明实施例1中样品II的X射线粉末衍射图谱；
图3为本发明实施例1中样品1的X射线粉末衍射图谱；
图4为本发明实施例1中样品2的X射线粉末衍射图谱；
图5为本发明实施例1中样品3的X射线粉末衍射图谱；
图6为本发明实施例1中样品4的X射线粉末衍射图谱；
图7为本发明实施例1中样品5的X射线粉末衍射图谱；
图8为本发明实施例1中样品6的X射线粉末衍射图谱；
图9为本发明实施例1中样品7的X射线粉末衍射图谱；
图10为本发明实施例2中添加1.0％卡铂的双环铂的X射线粉末衍射图 谱；
图11为本发明实施例2的添加2.0％卡铂的双环铂的X射线粉末衍射图谱；
图12为本发明实施例2的添加3.0％卡铂的双环铂的X射线粉末衍射图谱。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将结合本发明的附图和实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1X射线粉末衍射(XRPD)分析
一、仪器和条件
X射线粉末衍射仪：Aeries；
透射：CuKα辐射，石墨单色器，管压40kV，管流40mA；
扫描方式：θ/2θ扫描；DS发散狭缝1.2mm，索拉狭缝2.5mm；
2θ扫描范围：5-40°；扫描速度：40/min；步长：0.02°/step。
二、XRPD分析
本发明人参照授权公告号为CN1121380C的专利中描述的方法制备双环铂，完成反应后在2-8℃静置结晶15天，经过滤、洗涤、干燥后获得双环铂纯品。以此方法分别制得两个批次的双环铂样品I和样品II。分别取部分样品I和样品II，各研磨2分钟，并在室温下进行XRPD测定。所得XRPD谱图结果如图1、图2以及下表(仅示出了2-Theta(°)在20之前的衍射峰及强度)所示。
Figure PCTCN2018075926-appb-000001
Figure PCTCN2018075926-appb-000002
由上表可以看出，样品I的XRPD图谱显示出了完整的双环铂衍射峰，包括2θ角为7.58°处、10.51°处和15.12°处等的衍射峰。然而，本发明人出人意料地发现，以同样制备方法和结晶条件等获得的样品II所显示的XRPD图谱中虽然存在2θ角为7.68°、15.24°的衍射峰，但是却未显示出10.3-10.7°处的衍射峰。
为了进一步了解这一现象出现的可能性，本发明人进行了多批次的双环铂样品合成，并对所得样品进行XRPD测定。在对共计35个批次的双环铂样品的XRPD测定中，共发现7个样品的XRPD图谱中不显示10.3-10.7°处的衍射峰。所示7个样品的合成制备与前述相同，各样品结晶条件及研磨情况如下所示：
样品编号 结晶条件 研磨情况
样品1 2-8℃搅拌结晶，4小时 1分钟
样品2 2-8℃静置结晶，15天 2分钟
样品3 2-8℃静置结晶，30天 2分钟
样品4 2-8℃搅拌结晶，4小时 无
样品5 2-8℃搅拌结晶，4小时 2分钟
样品6 2-8℃静置结晶，30天 无
样品7 2-8℃静置结晶，30天 2分钟
其余显示10.3-10.7°处的衍射峰的28个样品覆盖了相似结晶条件(2-8℃下静置结晶15天或30天，或者2-8℃搅拌结晶4小时)和研磨情况(无研磨、1分钟、2分钟)，在此未详细示出。结合来看，似乎所制备得到的双环铂样品是否显示10.3-10.7°处的衍射峰并无规律，而是存在一定程度的偶然性。即，在对不同批次的双环铂纯品进行XRPD测定中，一些批次的双环铂纯品并不 显示出完整的衍射峰。
样品1至7的衍射图谱分别如图3至图9所示。具体而言，由样品1测得的XRPD图谱(参见图3)所检测出的峰及强度如下表1所示：
表1
Figure PCTCN2018075926-appb-000003
可见，由样品1测得的XRPD图谱中存在2θ角为7.629°、15.198°的衍射峰，但未显示出10.3-10.7°处的衍射峰。同样，以下表2、表3分别示出由样品2和样品3测得的XRPD图谱(参见图4至图5)所检测出的峰及强度：
表2
Figure PCTCN2018075926-appb-000004
Figure PCTCN2018075926-appb-000005
表3
Figure PCTCN2018075926-appb-000006
Figure PCTCN2018075926-appb-000007
在此未详细示出样品4至7的XRPD图谱参数，样品4至7的XRPD图谱数据可参见图6至图9。
根据以上各批次样品的XRPD测定结果可知，虽然10.3-10.7°处的衍射峰可作为鉴别双环铂的特征峰，但是该峰并不具有良好的重现性。在本发明人进行的共35个批次的样品中，存在20％的双环铂样品并不显示10.3-10.7°处的衍射峰。发明人研究发现，相比之下，双环铂7.4-7.8°处和15.0-15.4°处的特征峰具有更好的重现性，适合作为鉴别双环铂的特征峰。
实施例2药物杂质分析
如前所述，杂质卡铂在XRPD图谱中2θ角为11.3-11.7°处具有衍射峰，而双环铂纯品在该处无衍射峰。在卡铂与双环铂的混合物的XRPD图谱中，可根据卡铂与双环铂特征峰的峰面积比来判断其中卡铂含量。
取3份双环铂纯品，向各份中分别精密添加1.0％、2.0％和3.0％的卡铂，轻微研细混合均匀，分别制成样品A、样品B和样品C。
将上述样品A-C分别进行XRPD测定，衍射图谱如图10-12所示，图10-12相应的XRPD谱图参数列出如下：
表4
Figure PCTCN2018075926-appb-000008
表5
Figure PCTCN2018075926-appb-000009
表6
Figure PCTCN2018075926-appb-000010
根据上述谱图及相应参数可以看出，在双环铂的XRPD谱图中，10.3-10.7°处的衍射峰的峰高远低于7.4-7.8°处和15.0-15.4°处的峰高，10.3-10.7°处衍射峰的峰面积也远小于7.4-7.8°处和15.0-15.4°处衍射峰的峰面积。可以合理推断，10.3-10.7°处的衍射峰的峰面积受到噪音影响较大。若以峰面积判断卡铂与双环铂的混合物中卡铂的含量，选用7.4-7.8°处和15.0-15.4°处衍射 峰的峰面积会相比于10.3-10.7°处衍射峰的峰面积得到更准确的结果。
将衍射图谱中2θ角为7.4-7.8°处的衍射峰的积分强度记作A 21，2θ角为15.0-15.4°处的衍射峰的积分强度记作A 22，2θ角为11.3-11.7°处的衍射峰的积分强度记作A 23。经计算，样品A-C的A 21/A 23分别为760.8、256.4和80.3，A 22/A 23分别为276.5、34.5和13.6。
对双环铂原料药进行XRPD测定，并将其衍射图谱中2θ角为7.4-7.8°处的衍射峰的积分强度记作A 11，2θ角为15.0-15.4°处的衍射峰的积分强度记作A 12，2θ角为11.3-11.7°处的衍射峰的积分强度记作A 13，计算A 11/A 13和A 12/A 13，并通过各样品的卡铂含量及其相对应的A 21/A 23和A 22/A 23作为参照来确定双环铂原料药中卡铂的含量。
即，若A 11/A 13≥760.8，则双环铂原料药中卡铂的含量≤1.0％，若A 11/A 13<760.8，则双环铂原料药中卡铂的含量＞1.0％；进一步地，若A 11/A 13≥256.4，则双环铂原料药中卡铂的含量≤2.0％，若A 11/A 13<256.4，则双环铂原料药中卡铂的含量＞2.0％；再进一步地，若A 11/A 13≥80.3，则双环铂原料药中卡铂的含量≤3.0％，若A 11/A 13<80.3，则双环铂原料药中卡铂的含量＞3.0％。
同样，若A 12/A 13≥276.5，则双环铂原料药中卡铂的含量≤1.0％，若A 12/A 13<276.5，则双环铂原料药中卡铂的含量＞1.0％；进一步地，若A 12/A 13≥34.5，则双环铂原料药中卡铂的含量≤2.0％，若A 12/A 13<34.5，则双环铂原料药中卡铂的含量＞2.0％；再进一步地，若A 12/A 13≥13.6，则双环铂原料药中卡铂的含量≤3.0％，若A 12/A 13<13.6，则双环铂原料药中卡铂的含量＞3.0％。
本实施例仅示例了如何对双环铂原料药中的卡铂含量进行定量检测，然而上述样品中的卡铂含量并不局限于上述所示例的数值，只要能够添加通过XRPD衍射图谱检测出样品中的卡铂含量(例如样品中卡铂含量≥0.1％)，则A 21/A 23和A 22/A 23可以是其它任意数值，并且可以该数值作为参照来确定双环铂原料药中的卡铂含量。
以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全 部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。

Claims (12)

  1. 一种以双环铂为有效成分的药物的检测方法，所述检测方法包括：
    对所述药物进行X射线粉末衍射分析，获得第一衍射图谱；
    确认所述第一衍射图谱中2θ角为7.4-7.8°处、15.0-15.4°处和/或11.3-11.7°处是否具有衍射峰；
    若所述第一衍射图谱中2θ角为7.4-7.8°处和15.0-15.4°处中的一处或两处具有衍射峰，和/或2θ角为11.3-11.7°处不具有衍射峰，则所述药物中含有双环铂。
  2. 一种以双环铂为有效成分的药物的检测方法，所述检测方法包括：
    对所述药物进行X射线粉末衍射分析，获得第一衍射图谱；
    确认所述第一衍射图谱中2θ角为7.4-7.8°处、15.0-15.4°处和/或11.3-11.7°处是否具有衍射峰；
    若所述第一衍射图谱中2θ角为7.4-7.8°处和15.0-15.4°处中的一处或两处具有衍射峰，并且2θ角为11.3-11.7°处不具有衍射峰，则所述药物中含有双环铂且不含有卡铂。
  3. 一种以双环铂为有效成分的药物的检测方法，所述检测方法包括：
    对所述药物进行X射线粉末衍射分析，获得第一衍射图谱；
    确认所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处、15.0-15.4°处和/或11.3-11.7°处是否具有衍射峰；
    若所述第一衍射图谱中2θ角为7.4-7.8°处、10.3-10.7°处和15.0-15.4°处中的两处或三处具有衍射峰，并且2θ角为11.3-11.7°处不具有衍射峰，则所述药物中含有双环铂且不含有卡铂。
  4. 根据权利要求1至3中任一项所述的检测方法，其中所述药物为双环铂针剂，所述检测方法还包括对所述药物进行冻干处理或减压干燥处理，制得双环铂药粉，所述X射线粉末衍射分析针对所述双环铂药粉进行。
  5. 根据权利要求1至3中任一项所述的检测方法，其中若所述第一衍射 图谱中2θ角为7.4-7.8°处和15.0-15.4°处中的一处或两处以及2θ角为11.3-11.7°处具有衍射峰，则所述检测方法还包括：
    将双环铂标准品与卡铂制成混合粉末进行X射线粉末衍射分析，获得第二衍射图谱，所述混合粉末中卡铂的质量百分含量为X％；
    分别获得所述第一衍射图谱中2θ角为7.4-7.8°处的衍射峰的积分强度A 11和/或15.0-15.4°处的衍射峰的积分强度A 12，以及2θ角为11.3-11.7°处的衍射峰的积分强度A 13，并且分别获得所述第二衍射图谱中2θ角为7.4-7.8°处的衍射峰的积分强度A 21和/或15.0-15.4°处的衍射峰的积分强度A 22，以及2θ角为11.3-11.7°处的衍射峰的积分强度A 23，计算A 11/A 13与A 21/A 23和/或A 12/A 13与A 22/A 23；
    若A 11/A 13≥A 21/A 23，则所述药物中卡铂的含量≤X％，若A 11/A 13<A 21/A 23，则所述药物中卡铂的含量＞X％；
    若A 12/A 13≥A 22/A 23，则所述药物中卡铂的含量≤X％，若A 12/A 13<A 22/A 23，则所述药物中卡铂的含量＞X％。
  6. 根据权利要求5所述的检测方法，其中若A 11/A 13≥760.8，则双环铂原料药中卡铂的含量≤1.0％；若A 11/A 13<760.8，则双环铂原料药中卡铂的含量＞1.0％。
  7. 根据权利要求5所述的检测方法，其中若A 11/A 13≥256.4，则双环铂原料药中卡铂的含量≤2.0％；若A 11/A 13<256.4，则双环铂原料药中卡铂的含量＞2.0％。
  8. 根据权利要求5所述的检测方法，其中若A 11/A 13≥80.3，则双环铂原料药中卡铂的含量≤3.0％；若A 11/A 13<80.3，则双环铂原料药中卡铂的含量＞3.0％。
  9. 根据权利要求5所述的检测方法，其中若A 12/A 13≥276.5，则双环铂原料药中卡铂的含量≤1.0％；若A 12/A 13<276.5，则双环铂原料药中卡铂的含量＞1.0％。
  10. 根据权利要求5所述的检测方法，其中若A 12/A 13≥34.5，则双环铂原料药中卡铂的含量≤2.0％；若A 12/A 13<34.5，则双环铂原料药中卡铂的含量＞2.0％。
  11. 根据权利要求5所述的检测方法，其中若A 12/A 13≥13.6，则双环铂原料药中卡铂的含量≤3.0％；若A 12/A 13<13.6，则双环铂原料药中卡铂的含量＞3.0％。
  12. 一种对双环铂药物中的卡铂杂质的定量方法，所述定量方法包括：
    对所述药物进行X射线粉末衍射分析，获得第一衍射图谱；
    将双环铂标准品与卡铂制成混合粉末进行X射线粉末衍射分析，获得第二衍射图谱，所述混合粉末中卡铂的质量百分含量为X％；
    分别获得所述第一衍射图谱中2θ角为7.4-7.8°处的衍射峰的积分强度A 11和/或15.0-15.4°处的衍射峰的积分强度A 12，以及2θ角为11.3-11.7°处的衍射峰的积分强度A 13，并且分别获得所述第二衍射图谱中2θ角为7.4-7.8°处的衍射峰的积分强度A 21和/或15.0-15.4°处的衍射峰的积分强度A 22，以及2θ角为11.3-11.7°处的衍射峰的积分强度A 23，计算A 11/A 13与A 21/A 23和/或A 12/A 13与A 22/A 23；
    若A 11/A 13≥A 21/A 23，则所述药物中卡铂的含量≤X％，若A 11/A 13<A 21/A 23，则所述药物中卡铂的含量＞X％；
    若A 12/A 13≥A 22/A 23，则所述药物中卡铂的含量≤X％，若A 12/A 13<A 22/A 23，则所述药物中卡铂的含量＞X％。
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