Quantitative determination method for two impurities of basic lanthanum carbonate in lanthanum carbonate octahydrate bulk drug

Abstract

The invention relates to the technical field of lanthanum carbonate determination, in particular to a quantitative determination method for two impurities of basic lanthanum carbonate in a lanthanum carbonate octahydrate bulk drug. The two impurities of basic lanthanum carbonate are a basic lanthanum carbonate crystal form I and a basic lanthanum carbonate crystal form II, and the determination method comprises the following steps: determining quantitative characteristic peaks of the two impurities of basic lanthanum carbonate by using an XRPD method, mixing the two impurities of basic lanthanum carbonate and lanthanum carbonate octahydrate to prepare mixed powder, detecting the mixed powder by using the XRPD method, and determining diffraction data of the two impurities of basic lanthanum carbonate. The method is good in linear relation, low in detection limit, high in sensitivity and easy to operate.

Description

Technical Field

[0001] The invention relates to the technical field of lanthanum carbonate determination, and in particular to a method for quantitatively determining two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate raw material. Background Art

[0002] Drug crystal form is one of the important properties of small molecule chemical drugs, and is closely related to the physical and chemical properties of the drug and the efficacy and toxicity of the final product. For drug molecules with the same chemical structure, different crystal forms have different crystal structures and lattice energies, so they have different physical and chemical properties in the solid state (such as solubility, stability, mechanical properties, etc.), and they are also closely related to the performance in drug production and process development, such as powder properties, impurity removal ability, process scalability, etc.

[0003] The above-mentioned factors are directly related to the bioavailability, effectiveness and safety of drugs. Therefore, the study of drug crystal forms, especially the quantitative analysis of impurity crystal forms, plays a vital role in ensuring the quality of drugs.

[0004] Commonly used crystal quantitative analysis techniques include X-ray powder diffraction technology, Raman technology, infrared technology, solid-state nuclear magnetic resonance technology, etc. Among them, X-ray powder diffraction technology (XRPD) is the most widely used technology, which has the characteristics of relatively simple operation, reliable data results, and high quantitative detection sensitivity.

[0005] Based on the prior art, the present invention aims to develop an XRPD analysis method suitable for the quantitative analysis of two impurity crystal forms in lanthanum carbonate octahydrate raw materials. Lanthanum carbonate octahydrate (a form of lanthanum carbonate hydrate) is a non-calcium, non-aluminum phosphate binder that can be used to treat hyperphosphatemia. Hyperphosphatemia is one of the complications of chronic renal failure, and 80% of renal dialysis patients suffer from this disease. Two crystalline impurities, hydroxy lanthanum carbonate I and hydroxy lanthanum carbonate II, are often produced in hydrated lanthanum carbonate. Patent applications with application numbers CN201810584092.0 and CN201910428450.3 have both disclosed them. Therefore, a more convenient and reliable method for quantifying and detecting crystal forms is needed, which is also convenient for better controlling the content of impurity crystals in hydrated lanthanum carbonate.

[0006] There is a lack of a reliable technical analysis method for the quantitative analysis of two crystal impurities in lanthanum carbonate octahydrate. In the prior art, the detection of these two crystal impurities requires the assistance of internal standards, which increases the complexity and difficulty of the operation, limits the universality of the method, and the sensitivity needs to be improved. In similar varieties such as lanthanum carbonate or lanthanum carbonate tetrahydrate, although there is an XRPD method, it is not suitable for the exclusive use of lanthanum carbonate octahydrate, and the method is complicated and the operation is cumbersome. The present invention aims to develop a simple and efficient crystal quantitative analysis method for the quantitative analysis of two crystal impurities in the variety of lanthanum carbonate octahydrate for quality control of the variety. Summary of the invention

[0007] In view of the above-mentioned defects, the object of the present invention is to provide a method for quantitatively determining two impurity lanthanum carbonate hydroxides in lanthanum carbonate octahydrate raw materials.

[0008] In order to achieve the above-mentioned object and other related objects, the present invention provides the following technical solutions: A method for quantitatively determining two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate raw material, wherein the two impurity lanthanum carbonate hydroxides are lanthanum carbonate hydroxide crystal form I and lanthanum carbonate hydroxide crystal form II, comprising the following steps: The XRPD method was used to determine the quantitative characteristic peaks of two impurity lanthanum carbonate hydroxides. The two impurity lanthanum carbonate hydroxides and lanthanum carbonate octahydrate are mixed to prepare a mixed powder, and the mixed powder is detected by the XRPD method to obtain the diffraction data of the two impurity lanthanum carbonate hydroxides.

[0009] Furthermore, the conditions for detecting mixed powder by XRPD method include: X-ray power 40KV, 40mA; scanning angle range 17°~21°; step length 0.02°; step time 10s; scanning mode Continuous PSD fast; X-ray source: Cu palladium Kα ray (Kα1:λ=1.54060 Å, Kα2:λ=1.54439 Å).

[0010] Furthermore, the conditions for determining the quantitative characteristic peaks of the two impurity lanthanum carbonates by XRPD method include: X-ray power 40KV, 40mA; scanning angle range 3°~45°; step length 0.02°; step time 0.1s; scanning mode Continuous PSDfast; X-ray source: Cu palladium Kα ray (Kα1:λ=1.54060 Å, Kα2:λ=1.54439 Å).

[0011] Furthermore, the quantitative characteristic peaks of the two impurity lanthanum carbonate hydroxides are: 17.8° is selected as the quantitative characteristic peak of lanthanum carbonate hydroxide form I, and 20.5° is selected as the quantitative characteristic peak of lanthanum carbonate hydroxide form II.

[0012] Furthermore, when the mixed powder is prepared, the mass of the lanthanum carbonate hydroxide crystal form I accounts for 0.5%-5% of the total mass of the mixed powder, and the mass of the lanthanum carbonate hydroxide crystal form II accounts for 0.3%-3% of the total mass of the mixed powder.

[0013] Furthermore, the diffraction data includes diffraction net intensity and signal-to-noise ratio. A standard curve is drawn with the concentration of lanthanum carbonate hydroxide form I or lanthanum carbonate hydroxide form II as the abscissa and the net intensity ratio of lanthanum carbonate hydroxide form I or lanthanum carbonate hydroxide form II as the ordinate to obtain a linear equation.

[0014] Furthermore, it was determined that the detection limit of lanthanum carbonate hydroxide form I was 0.5%, and the detection limit of lanthanum carbonate hydroxide form II was 0.3%.

[0015] Furthermore, the signal-to-noise ratios of lanthanum carbonate hydroxide forms I and II are 11 and 5, respectively.

[0016] The beneficial effects of the present invention are: 1. The method of the present invention fills the gap in the quantitative analysis method of impurity crystals of lanthanum carbonate octahydrate.

[0017] 2. The method of the present invention is simple, efficient, easy to operate, and does not require an internal standard.

[0018] 3. The method of the present invention has good linear relationship, low detection limit and high sensitivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0020] Figure 1 It is the X-ray powder diffraction pattern in Example 1 of the present invention; it should be noted that, in the figure, Form I is Form I of lanthanum carbonate hydrate, and Form II is Form II of lanthanum carbonate hydrate.

[0021] Figure 2 It is the X-ray powder diffraction pattern in Example 2 of the present invention; it should be noted that, in the figure, about 17.8° is the quantitative characteristic peak of lanthanum carbonate hydroxide form I, and about 20.5° is the quantitative characteristic peak of lanthanum carbonate hydroxide form II.

[0022] Figure 3 This is a standard curve diagram of the lanthanum carbonate hydroxide form I in Example 2 of the present invention.

[0023] Figure 4 This is a standard curve diagram of the lanthanum carbonate hydroxide form II in Example 2 of the present invention. DETAILED DESCRIPTION

[0024] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] Unless otherwise specified, the instruments and samples used in the examples can be easily obtained from commercial companies, some of which are shown in Table 1 below.

[0026] Table 1

[0027] The following is a method for quantitative determination of two impurities, lanthanum carbonate hydroxide, in lanthanum carbonate octahydrate raw material.

[0028] Example 1 Identification and selection of quantitative characteristic peaks of two crystalline impurities (lanthanum carbonate basic form I and lanthanum carbonate basic form II): The X-ray powder diffraction (XRPD) method was used to collect spectra of lanthanum carbonate octahydrate API and two crystalline impurities (lanthanum carbonate hydroxide form I and lanthanum carbonate hydroxide form II), respectively, to identify and confirm the quantitative characteristic peaks of the two crystalline impurities, and to preliminarily evaluate the feasibility of method development.

[0029] The specific parameters of this method are shown in Table 2 below: Table 2

[0030] Test results reference Figure 1 , 17.8° was selected as the reference peak of lanthanum carbonate hydroxide form I, and 20.5° was selected as the reference peak of lanthanum carbonate hydroxide form II.

[0031] Example 2 Preparation of mixed powders with different proportions of impurities of different crystal forms and investigation of the linearity and sensitivity of the method: The specific steps for preparing and testing the double mixed powder of lanthanum carbonate basic form I and lanthanum carbonate basic form II are as follows: According to Table 3, lanthanum carbonate hydroxide crystal form I, lanthanum carbonate hydroxide crystal form II, and lanthanum carbonate octahydrate were weighed and mixed evenly. After mixing, vortexed for 10 minutes to obtain 8% bicrystalline mixed powder. An appropriate amount of 8% bicrystalline mixed powder was taken and continued to be mixed with lanthanum carbonate octahydrate and diluted step by step. Three different mixed powders were obtained, specifically mixed powder 1, mixed powder 2, and mixed powder 3. Then the mixed powder was placed on a sample plate with zero background for sample preparation.

[0032] Table 3

[0033] The mixed powder was tested, and the specific test parameters are shown in Table 4: Table 4

[0034] The test results are shown in Table 5. Figure 2-Figure 4 As shown: Table 5

[0035] It should be noted that net intensity (Net Intensity) = total diffraction intensity (Intensity) - baseline intensity.

[0036] A standard curve is drawn with the concentration of lanthanum carbonate hydroxide form I or lanthanum carbonate hydroxide form II as the abscissa and the net intensity of lanthanum carbonate hydroxide form I or lanthanum carbonate hydroxide form II as the ordinate to obtain a linear equation.

[0037] Combined with Table 5, Figure 2-Figure 4 In the detection methods of the prior art, the signal-to-noise ratio is generally only 3 or 2, while the signal-to-noise ratio of the present invention can reach 11 or 5, indicating that the determination method of the present invention has a strong ability to distinguish and identify the diffraction peaks of the sample, has high sensitivity, and can be used for quantitative determination. Moreover, the detection limit of the determination method of the present invention for hydroxycarbonate lanthanum form I is 0.5%, and the detection limit for hydroxycarbonate lanthanum form II is 0.3%, with a high overall sensitivity, and can be used for the quantitative study of the crystal forms of two crystal forms of impurities in octahydrate lanthanum carbonate bulk drug.

[0038] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for quantitatively determining two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate bulk drug, wherein the two impurity lanthanum carbonate hydroxides are lanthanum carbonate hydroxide crystal form I and lanthanum carbonate hydroxide crystal form II, characterized in that: The steps include: The XRPD method was used to determine the quantitative characteristic peaks of two impurity lanthanum carbonate hydroxides. The two impurity lanthanum carbonate hydroxides and lanthanum carbonate octahydrate are mixed to prepare a mixed powder, and the mixed powder is detected by the XRPD method to obtain the diffraction data of the two impurity lanthanum carbonate hydroxides.

2. The quantitative determination method of two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate bulk drug according to claim 1, characterized in that: The conditions for XRPD detection of mixed powder include: X-ray power: 40KV, 40mA; scanning angle range: 17°~21°; step length: 0.02°; step time: 10s; scanning mode: Continuous PSD fast; X-ray source: Cu palladium Kα ray, Kα1:λ=1.54060 Å, Kα2:λ=1.54439 Å.

3. The method for quantitative determination of two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate bulk drug according to claim 1, characterized in that: The conditions for determining the quantitative characteristic peaks of two impurity lanthanum carbonate by XRPD method include: X-ray power: 40KV, 40mA; scanning angle range: 3°~45°; step length: 0.02°; step time: 0.1s; scanning mode: ContinuousPSD fast; X-ray source: Cu palladium Kα ray, Kα1:λ=1.54060 Å, Kα2:λ=1.54439 Å.

4. The method for quantitative determination of two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate bulk drug according to claim 1, characterized in that: The quantitative characteristic peaks of the two impurity lanthanum carbonate hydroxides are: 17.8° is selected as the quantitative characteristic peak of lanthanum carbonate hydroxide form I, and 20.5° is selected as the quantitative characteristic peak of lanthanum carbonate hydroxide form II.

5. The method for quantitative determination of two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate bulk drug according to claim 1, characterized in that: When the mixed powder is prepared, the mass of the lanthanum carbonate hydroxide crystal form I accounts for 0.5%-5% of the total mass of the mixed powder, and the mass of the lanthanum carbonate hydroxide crystal form II accounts for 0.3%-3% of the total mass of the mixed powder.

6. The method for quantitative determination of two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate bulk drug according to claim 1, characterized in that: The diffraction data include diffraction net intensity and signal-to-noise ratio. A standard curve is drawn with the concentration of lanthanum carbonate hydroxide form I or lanthanum carbonate hydroxide form II as the abscissa and the net intensity ratio of lanthanum carbonate hydroxide form I or lanthanum carbonate hydroxide form II as the ordinate to obtain a linear equation.

7. The method for quantitative determination of two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate bulk drug according to claim 1, characterized in that: The detection limit of lanthanum carbonate hydroxide form I was determined to be 0.5%, and the detection limit of lanthanum carbonate hydroxide form II was 0.3%.

8. The method for quantitative determination of two impurity lanthanum carbonate hydroxides in a lanthanum carbonate octahydrate bulk drug according to claim 6, characterized in that: The signal-to-noise ratio of lanthanum carbonate hydroxide form I is 11, and the signal-to-noise ratio of lanthanum carbonate hydroxide form II is 5.

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