Method for detecting albendazole crystal form content

Abstract

The invention discloses a method for detecting the crystal form content of albendazole. According to the method, an infrared paste method is adopted, an albendazole sample to be detected, an albendazole crystal form I reference substance and an albendazole crystal form II reference substance are uniformly mixed into paste in an agate mortar by using liquid paraffin, the sample paste is filled into a liquid pool, the liquid paraffin is used for preparing a blank, an infrared spectrometer is used for collecting an instrument background, and the liquid paraffin is used for detecting the albendazole crystal form I reference substance and the albendazole crystal form II reference substance. And then carrying out absorbance collection on the sample and the reference substance. The method has the advantages of simplicity and convenience in operation, high analysis speed, high sensitivity, good repeatability, accurate and reliable data and the like.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical and chemical technology, and specifically to a method for detecting the content of albendazole crystal forms. Background Technology

[0002] Albendazole is a broad-spectrum anthelmintic of the imidazole derivative class. It was discovered in 1972 by the Animal Health Laboratory of GlaxoSmithKline. Albendazole is listed in the Essential Medicines List and is one of the most important essential health medications. Its structural formula is as follows:

[0003]

[0004] Polymorphism, also known as "isomorphism," refers to the existence of two or more crystalline forms of a solid chemical drug. Polymorphism is prevalent in solid-state pharmaceuticals. Although drugs with different crystalline forms are chemically identical, variations in molecular arrangement, conformation, and crystallization solvents can lead to significant differences in solubility, bioavailability, stability, and safety, directly impacting clinical efficacy and drug quality. Therefore, research on drug polymorphism is crucial, and identifying the dominant pharmaceutical crystalline form is essential for ensuring stable drug quality and clinical efficacy.

[0005] According to Pranzo MB et al., albendazole exhibits polymorphism, and a different crystal form (Crystal II) can be obtained by recrystallization from methanol and dimethylformamide (DMF), which is different from the commercially available active pharmaceutical ingredient (Crystal I).

[0006] X-ray diffraction testing is time-consuming, generally requiring more than 30 minutes; it presents challenges in detecting low-concentration phases, as the diffraction peaks of a phase in a sample may be masked by noise or overlap with the main phase peaks if the content of a certain phase is too low (e.g., <5%); it also presents difficulties in distinguishing similar structures, as phases with similar lattice parameters may produce overlapping peaks; X-ray diffraction equipment is relatively expensive, increasing the burden on enterprises; and the X-rays emitted during testing pose safety hazards. Summary of the Invention

[0007] The purpose of this invention is to provide a method for detecting albendazole crystal form content that is simple to operate, has a short testing time, good repeatability, and accurate and reliable data, in order to address the various shortcomings of the above-mentioned detection methods.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] (1) Sample preparation:

[0010] A. Preparation of reference standards: Weigh 2-10 mg of albendazole crystal form II reference standard and 40-48 mg of crystal form I reference standard into an agate mortar, add 0.3 ml of liquid paraffin, mix evenly into a paste, and fill the sample paste into a liquid pool with a thickness of 0.2 mm.

[0011] B. Sample preparation: Weigh 30.5-50 mg of sample into an agate mortar, add 0.3 ml of liquid paraffin, mix well into a paste, and fill the sample paste into a liquid pool with a thickness of 0.2 mm.

[0012] (2) Sample testing:

[0013] A blank was prepared using liquid paraffin to collect instrument background data; absorbance was collected for both samples and reference standards under the following conditions and parameters:

[0014] A. Instrument conditions and parameters:

[0015] Scanning range: 200-8000cm -1 Resolution: 0.1-10cm -1 Scan count: 16-64 times; Window used in liquid cell: KBr sheet, diameter 10-60mm, thickness 2-10mm; Teflon sheet used in liquid cell: diameter 10-50mm, thickness 0.20 / 0.40mm.

[0016] Furthermore, the instrument conditions and parameters are optimized as follows: Scanning range: 300-6000 cm -1 Resolution: 0.1-3cm -1 Number of scans: 22-38.

[0017] B. Formula for calculating the content of albendazole crystal form II:

[0018]

[0019] As = First-order differential absorbance difference of the sample

[0020] Ar = First-order differential absorbance difference of the reference standard

[0021] Cs = Concentration of the paraffin paste in the sample, mg / ml

[0022] Cr = Concentration of the paraffin paste of the reference standard, mg / ml

[0023] M = Crystal form II content of the reference standard, %

[0024] Choosing an infrared detector as the instrument for detecting albendazole crystal form solves the accuracy problem of using X-ray diffraction for crystal form detection, improving the precision from 5% to 2%; it also shortens the detection time from over 30 minutes to 15 minutes; the infrared detector is widely applicable within the company, avoiding the need for outsourcing X-ray diffraction testing and solving the problem of third-party testing results not being sufficient for product release; the infrared detector shows good linearity in detecting albendazole crystal form content within the investigated range, proving that the detection method is feasible. Attached Figure Description

[0025] Figure 1 The infrared spectrum of albendazole crystal form reference standard.

[0026] Figure 2 This is a line graph showing the difference between the content of albendazole crystal form II and the first-order differential absorbance value.

[0027] Figure 3 The X-ray diffraction results are for different crystal forms. Detailed Implementation

[0028] The present invention will be described in detail below through specific embodiments. These embodiments are used to explain the present invention, but not to limit it.

[0029] Method validation was performed using specificity, linearity, accuracy, robustness, intermediate precision, and repeatability tests.

[0030] Example 1

[0031] 1. Measurement conditions and parameters:

[0032] Scanning range: 400-4000cm -1

[0033] Resolution: 5cm -1

[0034] Number of scans: 16

[0035] Window used in the liquid cell: KBr plate, 30mm in diameter, 5mm thick

[0036] Teflon sheets used in the liquid tank: 30mm in diameter, 0.20mm thick.

[0037] 2. Specificity test:

[0038] (1) Preparation of reference sample:

[0039] Accurately weigh 50 mg of albendazole crystal form I reference standard and albendazole crystal form II reference standard into an agate mortar, accurately transfer 0.3 ml of liquid paraffin into it, and mix well into a paste.

[0040] (2) Operation steps:

[0041] The sample paste was placed into a liquid cell with a thickness of 0.2 mm, and the absorbance of the sample was scanned.

[0042] (3) The test results are as follows:

[0043] The highest wavenumber after first-order differential of crystal form II Lowest wavenumber after first derivative of crystal form II <![CDATA[589cm -1 ]]> <![CDATA[587cm -1 ]]>

[0044] 3. Linearity test:

[0045] (1) Sample preparation:

[0046] According to the requirements in the table below, accurately weigh 50 mg of albendazole crystal form I and crystal form II reference standards into an agate mortar, accurately transfer 0.3 ml of liquid paraffin into it, and mix thoroughly to form a paste. Pour the sample paste into a liquid reservoir with a thickness of 0.2 mm.

[0047] Sample I％ II% 1 98 2 2 95 5 3 90 10 4 80 20 5 50 50

[0048] (2) Operation steps:

[0049] After preheating and equilibrating the instrument, measure each of the above standard samples according to the method requirements and record the spectrum.

[0050] Sequence: Prepare a blank using liquid paraffin to collect instrument background data; collect samples.

[0051]

[0052] 4. Accuracy test:

[0053] (1) Sample preparation:

[0054] A: Preparation of reference standard: Accurately weigh 5 mg of albendazole II crystal form and 45 mg of albendazole I crystal form into an agate mortar, accurately transfer 0.3 ml of liquid paraffin into it, mix evenly into a paste, fill the sample paste into a liquid cell with a thickness of 0.2 mm, and perform absorbance scanning.

[0055] B: Sample Preparation: According to the requirements in the table below, accurately weigh a total of 50 mg of albendazole I crystal form and albendazole II crystal form reference standards into an agate mortar, accurately transfer 0.3 ml of liquid paraffin into it, and mix thoroughly to form a paste. Pour the sample paste into a liquid cell with a thickness of 0.2 mm and perform absorbance scanning.

[0056] Sample ％I %II 1 98 2 2 98 2 3 98 2 4 90 10 5 90 10 6 90 10 7 50 50 8 50 50 9 50 50

[0057] (2) Operation steps:

[0058] After preheating and equilibrating the instrument, perform absorbance scanning on each of the above standard samples according to the method requirements and record the spectrum.

[0059] Sequence: Prepare a blank using liquid paraffin to collect instrument background data; collect samples.

[0060]

[0061] 5. Repeatability test:

[0062] (1) Sample preparation:

[0063] A: Preparation of reference standard: Accurately weigh 5 mg of albendazole II crystal form and 45 mg of albendazole I crystal form into an agate mortar, accurately transfer 0.3 ml of liquid paraffin into it, mix evenly into a paste, fill the sample paste into a liquid cell with a thickness of 0.2 mm, and perform absorbance scanning.

[0064] B: Sample preparation: Take a batch of uniform albendazole sample, weigh 50 mg into an agate mortar, accurately transfer 0.3 ml of liquid paraffin into it, and mix well to form a paste. Pour the sample paste into a liquid cell with a thickness of 0.2 mm, and scan the absorbance of the sample.

[0065] (2) Operation steps:

[0066] After preheating and balancing the instrument and confirming that it is working properly, perform the measurement according to the method requirements and record the spectrum.

[0067] Sequence: Prepare a blank using liquid paraffin to collect instrument background data; collect samples.

[0068]

[0069] 6. Intermediate precision test:

[0070] (1) Sample preparation:

[0071] A: Preparation of reference standard: Accurately weigh 5 mg of albendazole II crystal form and 45 mg of albendazole I crystal form into an agate mortar, accurately transfer 0.3 ml of liquid paraffin into it, mix evenly into a paste, fill the sample paste into a liquid cell with a thickness of 0.2 mm, and perform absorbance scanning.

[0072] B: Sample preparation: Take a batch of uniform albendazole sample, weigh 50 mg into an agate mortar, accurately transfer 0.3 ml of liquid paraffin into it, and mix well to form a paste. Pour the sample paste into a liquid cell with a thickness of 0.2 mm, and scan the absorbance of the sample.

[0073] (3) Operation steps:

[0074] One laboratory technician shall determine each of the six parallel samples in each batch according to the prescribed method. Another laboratory technician shall prepare and determine the six parallel samples in the same batch on a different day, according to the prescribed method.

[0075] After preheating and balancing the instrument and confirming that it is working properly, perform the measurement according to the method requirements and record the spectrum.

[0076] Sequence: Prepare a blank using liquid paraffin to collect instrument background data; collect samples.

[0077]

[0078] 7. Durability test:

[0079] (1) Sample preparation:

[0080] (2) Weigh different masses of albendazole samples into an agate mortar as required, accurately transfer 0.3 ml of liquid paraffin into the mortar, and mix thoroughly to form a paste. Place the sample paste into a liquid cell with a thickness of 0.2 mm and perform absorbance scanning.

[0081] (3) Operation steps:

[0082] After preheating and equilibrating the instrument and confirming that it is working properly, perform the measurements according to the method requirements and record the spectra. The sequence is as follows: prepare a blank using liquid paraffin to collect instrument background data; then collect the sample.

[0083]

[0084]

[0085] 8. Albendazole crystal form test:

[0086] The albendazole crystal content was detected using an infrared detector and the infrared paste method.

[0087] Serial Number Sample batch number Crystal form II content / % 1 68321001 3.6％ 2 68321002 4.3％ 3 68321003 3.8％ 4 68316001 4.8％ 5 68316002 5.2％ 6 68316003 5.6％

[0088] Example 2

[0089] 1. Measurement conditions and parameters:

[0090] Scanning range: 200-1000cm -1

[0091] Resolution: 0.5cm -1

[0092] Number of scans: 16

[0093] Window used in the liquid cell: KBr plate, 30mm in diameter, 5mm thick

[0094] Teflon sheets used in the liquid tank: 30mm in diameter, 0.20mm thick.

[0095] 2. Specificity, linearity, accuracy, robustness, intermediate precision, and repeatability tests; the method for detecting albendazole crystal form content is the same as in Example 1.

[0096] Example 3

[0097] 1. Measurement conditions and parameters:

[0098] Scanning range: 300-6000cm -1

[0099] Resolution: 0.2cm -1

[0100] Number of scans: 64

[0101] Window used in the liquid cell: KBr plate, 30mm in diameter, 5mm thick

[0102] Teflon sheets used in the liquid tank: 30mm in diameter, 0.20mm thick.

[0103] 2. Specificity, linearity, accuracy, robustness, intermediate precision, and repeatability tests; the method for detecting albendazole crystal form content is the same as in Example 1.

[0104] Example 4

[0105] 1. Measurement conditions and parameters:

[0106] Scanning range: 200-8000cm -1

[0107] Resolution: 1cm -1

[0108] Number of scans: 32

[0109] Window used in the liquid cell: KBr plate, 30mm in diameter, 5mm thick

[0110] Teflon sheets used in the liquid tank: 30mm in diameter, 0.20mm thick.

[0111] 2. Specificity, linearity, accuracy, robustness, intermediate precision, and repeatability tests; the method for detecting albendazole crystal form content is the same as in Example 1.

[0112] These are merely preferred embodiments of the present invention, and the scope of protection of the present invention is not limited to the above embodiments. All technical solutions falling within the scope of the present invention's concept are within the scope of protection of the present invention. It should be noted that for those skilled in the art, improvements and modifications made without departing from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. A method for detecting the content of albendazole crystal forms, characterized in that, The detection method includes the following steps: (1) Sample preparation: The sample preparation includes the following steps: A. Preparation of reference standards: Weigh 2-10 mg of albendazole crystal form II reference standard and 40-48 mg of crystal form I reference standard into an agate mortar, add 0.3 ml of liquid paraffin, mix evenly into a paste, and fill the sample paste into a liquid pool with a thickness of 0.2 mm. B. Sample preparation: Weigh 30-50 mg of sample into an agate mortar, add 0.3 ml of liquid paraffin, mix well into a paste, and fill the sample paste into a liquid pool with a thickness of 0.2 mm. (2) Sample testing: A blank was prepared using liquid paraffin to collect instrument background data; absorbance of the sample and reference standard was collected; infrared spectrometer detection conditions and parameters are as follows: A. Instrument conditions and parameters: Scanning range: 200-8000cm -1 Resolution: 0.1-10cm -1 Number of scans: 16-64 Window used in liquid tanks: KBr plate, diameter 10-60mm, thickness 2-10mm Teflon sheets used in liquid tanks: diameter 10-50mm, thickness 0.20 / 0.40mm B. Formula for calculating the content of albendazole crystal form II: As = First-order differential absorbance difference of the sample Ar = First differential absorbance difference of the reference standard Cs = Concentration of the paraffin paste in the sample, mg / ml Cr = Concentration of the paraffin paste of the reference standard, mg / ml M = Crystal form II content of the reference standard, %.

2. The method for detecting the content of albendazole crystal form according to claim 1, characterized in that: The scanning range of the infrared spectrometer is 300-6000 cm⁻¹. -1 .

3. The method for detecting the content of albendazole crystal form according to claim 1, characterized in that: The resolution of the infrared spectrometer is 0.1-3 cm. -1 .

4. The method for detecting the content of albendazole crystal form according to claim 1, characterized in that: The infrared spectrometer scans 22-38 times.

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