Method for detecting crystallinity of a solid formulation of apalutamide

Abstract

The present application relates to the technical field of drug detection, and in particular to a method for detecting crystallinity of apalutamide solid preparation. The method for detecting crystallinity of apalutamide solid preparation uses differential scanning calorimetry for detection, and comprises the following steps: (1) determining the peak area of a standard sample; (2) determining the peak area of an apalutamide solid preparation sample; (3) comparing the peak areas of the sample and the standard sample, and calculating the crystallinity of the sample; the standard sample comprises amorphous apalutamide and crystalline apalutamide. The detection method of the present application is convenient for sample preparation, and the measured crystallinity has high sensitivity, with a detection limit of 1%, and can be used for quality control during production and storage of apalutamide solid preparation.

Description

Technical Field

[0001] This invention relates to the field of drug detection technology, and in particular to a method for detecting the crystallinity of apalutamide solid dosage form. Background Technology

[0002] Drug crystal form is one of the important factors affecting drug quality. To ensure the efficacy and safety of drugs, qualitative analysis of crystal form alone is no longer sufficient to meet the requirements of research and production. At present, quantitative analysis of the crystal form of active pharmaceutical ingredients plays a very important role in the research and development and production of crystalline drugs.

[0003] Apalutamide is an androgen receptor (AR) inhibitor developed by the University of California. It was approved by the FDA in February 2018 for the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). The original manufacturer of apalutamide tablets uses near-infrared spectroscopy (NIRS) to quantitatively detect crystallinity.

[0004] Quantitative analysis using near-infrared spectroscopy primarily employs chemometric methods to extract near-infrared spectral information related to sample content, establishing relevant mathematical correction models. These models then predict the content or properties of unknown components. The chemometric methods used to establish these correction models include discriminant analysis (DA), principal component analysis (PCA), partial least squares (PLS), topological methods (TP), artificial neural networks (ANN), multiple linear regression (MLR), and the OSC-PLS method combining support vector machine (SVM) and partial least squares. To increase the resolution between adjacent peaks, first-order or second-order derivative processing is often performed on the NIRS spectra before data calculation. Furthermore, spectral preprocessing techniques such as standard normal variable transformation (SNV) and multivariate scattering correction (MSC) can more effectively reduce scattering effects caused by differences in sample particle size. Additionally, introducing chemometric models such as multiple linear regression (MLR), principal component analysis (PCA), and PLS are also methods to address these issues. A significant feature of NIRS is its rapid analysis speed. Its speed allows it to not only identify different crystal forms of active ingredients, but also to detect the purity of crystal forms in active pharmaceutical ingredients and formulations.

[0005] However, existing technologies using NIRS for quantitative detection of apalutamide crystallinity suffer from problems such as low sensitivity, difficulty in modeling, and poor repeatability.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The purpose of this invention is to provide a method for detecting the crystallinity of apalutamide solid dosage form, which has high sensitivity and good repeatability.

[0008] To achieve the above-mentioned objectives of this invention, this invention provides a method for detecting the crystallinity of apalutamide solid dosage form, which uses differential scanning calorimetry and includes the following steps:

[0009] (1) Determine the peak area of ​​the standard;

[0010] (2) Determine the peak area of ​​the apaltamethasone solid dosage form sample;

[0011] (3) Compare the peak areas of the sample and the standard, and calculate the crystallinity of the sample;

[0012] The standards include amorphous apalutamide and crystalline apalutamide.

[0013] Furthermore, the amorphous apalutamide comprises apalutamide and a dispersant.

[0014] Furthermore, in the amorphous apaltadamine, the mass ratio of apaltadamine to the dispersant is 1:(1-5).

[0015] Furthermore, the dispersant comprises at least one of the following: ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, HPMC acetate succinate, polyvinyl acetate phthalate, polymethacrylate, polyethylene glycol, polypropylene glycol, poloxamer, soluplus, polyvinylpyrrolidone, copovidone, and vinylpyrrolidone-vinyl acetate copolymer.

[0016] Furthermore, in the standard, the mass of the crystalline apalutamide is 1% to 18% of the mass of the amorphous apalutamide.

[0017] Furthermore, the apaltamethasone solid dosage form is obtained by spray drying or hot melt extrusion granulation.

[0018] Furthermore, the apalutamide solid dosage form includes at least one of powder, granules, tablets, capsules, pellets, and films.

[0019] Furthermore, in the differential scanning calorimetry, the temperature is 20–280°C, and more specifically 25–250°C.

[0020] Furthermore, in the differential scanning calorimetry, the heating rate is 8–12 °C / min.

[0021] Another aspect of the present invention provides a method for detecting the crystallinity of apalutamide tablets, comprising the following steps:

[0022] (A) Differential scanning calorimetry was used to detect at least two standards with different crystallinity and to determine the peak area;

[0023] (B) Using the peak area and crystallinity of the standard as the abscissa and ordinate respectively, a standard working curve is obtained by fitting.

[0024] (C) The apalutamide tablet sample was tested using the differential scanning calorimetry method, and the peak area of ​​the sample was substituted into the standard working curve to calculate the crystallinity of the apalutamide tablet.

[0025] The standard includes amorphous apalutamide and crystalline apalutamide.

[0026] Furthermore, the amorphous apalutamide is dispersed in a dispersant.

[0027] Furthermore, in the amorphous apaltadamine, the mass ratio of apaltadamine to the dispersant is 1:(1-5).

[0028] Furthermore, in the differential scanning calorimetry, the temperature is 20–280°C, and more specifically 25–250°C.

[0029] Furthermore, in the differential scanning calorimetry, the heating rate is 8–12 °C / min.

[0030] Furthermore, in the differential scanning calorimetry, the flow rate of nitrogen gas is 40–90 mL / min, such as 75–85 mL / min.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] This invention provides a method for testing the crystallinity of apalutamide solid dosage forms. The method is simple, easy to operate, and more stable. It can be used for various solid dosage forms. Sample preparation is convenient, and the measured crystallinity has high sensitivity with a detection limit of 1%. The method can be used for quality control during the production and storage of apalutamide solid dosage forms, ensuring efficacy and safety in clinical use. Attached Figure Description

[0033] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0034] Figure 1 This is the DSC chart of the blank excipient in the specificity test of the experimental example of the present invention;

[0035] Figure 2The DSC chart of spiked test sample 1 in the system suitability test of the experimental example of the present invention;

[0036] Figure 3 The DSC chart of spiked test sample 2 in the system suitability test of the experimental example of the present invention;

[0037] Figure 4 The DSC plot of the linear experiment of the present invention;

[0038] Figure 5 This is the working curve in the linear experiment of the experimental example of the present invention;

[0039] Figure 6 DSC curve of the 1% crystallinity standard provided in Experimental Example 5 of this invention;

[0040] Figure 7 This is a DSC chart of the test sample in Example 2 of the present invention. Detailed Implementation

[0041] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall be followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0042] The "apaltadamine raw material" mentioned in this invention refers to the raw material used to produce apaltadamine preparations, which is apaltadamine in crystalline form.

[0043] This invention discloses a method for detecting the crystallinity of apalutamide solid dosage form, which uses differential scanning calorimetry and includes the following steps:

[0044] (1) Determine the peak area of ​​the standard;

[0045] (2) Determine the peak area of ​​apalutamide solid dosage form samples;

[0046] (3) Compare the peak areas of the sample and the standard, and calculate the crystallinity of the sample;

[0047] The standards include amorphous apalutamide and crystalline apalutamide.

[0048] In some embodiments of the present invention, the standard of the present invention includes crystalline apalutamide. The crystal form of the crystalline apalutamide is the same as that of the solid dosage form API. Crystalline apalutamide is used directly as the standard, and the amount of crystalline apalutamide used in the standard is set according to the specified content of crystallinity of the solid dosage form. The standard has at least two points, and the values ​​of the two points cover the content of crystallinity of the solid dosage form. The number of standards can be 3, 4, 5 or 6. The peak area of ​​the standards is used as the abscissa, and the crystallinity is used as the ordinate. A working curve is calculated, the peak area of ​​the obtained apalutamide fixed dosage form sample is measured, and the crystallinity of the sample is calculated based on the working curve obtained from the peak area of ​​the standards.

[0049] In other embodiments of the invention, the standard of the invention comprises amorphous apalutamide and crystalline apalutamide. The amorphous apalutamide comprises crystalline apalutamide and a dispersant. In this processing method, crystalline apalutamide is added to amorphous apalutamide; wherein the preparation of amorphous apalutamide comprises: mixing crystalline apalutamide and a dispersant in a proportionate manner, and then granulating by spray drying or hot melt extrusion to obtain amorphous apalutamide.

[0050] In some embodiments, the mass ratio of apalutamide to dispersant in the amorphous apalutamide is 1:(1-5). Further, the mass ratio of apalutamide to dispersant is 1:1, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5. Further, the dispersant may include at least one of: ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, HPMC acetate succinate, polyvinyl acetate phthalate, polymethacrylate, polyethylene glycol, polypropylene glycol, poloxamer, soluplus, polyvinylpyrrolidone, copovidone, and vinylpyrrolidone-vinyl acetate copolymer.

[0051] The ratio of apatamide to dispersant in the amorphous apatamide in the standard is the same as the ratio in the solid dosage form to be tested. The standard has at least two points; the mass of amorphous apatamide at each point is accurately weighed. The ratio of the mass of added crystalline apatamide to the mass of amorphous apatamide is the crystallinity of apatamide in each standard. Differential scanning calorimetry (DSC) is used to detect each standard, with the peak area as the x-axis and crystallinity as the y-axis, to obtain a working curve. The same DSC is then used to detect the solid dosage form to obtain the corresponding peak area, which is then substituted into the working curve to obtain the corresponding crystallinity.

[0052] In other embodiments, the amorphous apalutamide in the standard comprises apalutamide, a dispersant, and other excipients used in the preparation of apalutamide solid dosage forms.

[0053] In other embodiments of the present invention, the standard includes amorphous apalutamide and crystalline apalutamide, wherein the amorphous apalutamide in the standard is the solid dosage form to be tested. The solid dosage form to be tested in the present invention can be apalutamide tablets or a controlled apalutamide solid dosage form, such as uncoated tablets, unfilled capsule powder, etc., where the morphology of the apalutamide solid dosage form requiring monitoring of crystallinity is crucial. The corresponding solid dosage form is ground, weighed, and then crystalline apalutamide is added to obtain the standard. The ratio of the mass of crystalline apalutamide to the mass of amorphous apalutamide is the degree of crystallinity.

[0054] In this invention, apaltamethasone solid formulation is obtained by spray drying or hot melt extrusion granulation.

[0055] Other excipients in solid dosage forms include, but are not limited to, at least one of disintegrants, fillers, gliding agents, and lubricants.

[0056] In this invention, the number of standard samples is as follows: there are at least two standard samples. There can be two, three, four, five, or six standard samples, with five being the preferred number.

[0057] In this invention, the crystallinity of the standard product spans the standard range for the crystallinity of apalutamide solid dosage form; that is, the region between the maximum and minimum crystallinity values ​​corresponding to the standard product covers the standard specified for the crystallinity of apalutamide. Furthermore, the peak area of ​​the standard product is normalized.

[0058] In this invention, the mass of crystalline apalutamide in the standard is 1% to 18% of the mass of amorphous apalutamide. In different embodiments, the mass of crystalline apalutamide in the standard can be at least two of the following: 1%, 2%, 3%, 5%, 8%, 10%, 12%, 15%, and 18% of the mass of amorphous apalutamide, and must span the standard range for the crystallinity of apalutamide solid dosage form. The number of standards selected is adapted to the working curve, and at least two standards are selected. Regardless of whether they are within the crystallinity range disclosed in this invention, the standard processing method using this method falls within the scope of protection of this invention.

[0059] In this invention, the instrument used for detection is a differential scanning calorimeter (DSC), protected by nitrogen, and the injection volume of the standard is 2.0–10.0 mg. More specifically, the injection volume is 3.0–10.0 mg. The DSC test mode is linear temperature ramp.

[0060] In this invention, the flow rate of nitrogen is 40–90 mL / min. Further, the flow rate of nitrogen can be a range of 40 mL / min, 50 mL / min, 60 mL / min, 70 mL / min, 80 mL / min, 90 mL / min, or any combination thereof.

[0061] In this invention, the instrument's temperature range can cover the melting point of the apalutamide crystal form used in solid dosage forms, specifically 20–280°C, and more specifically 25–250°C. The temperature range can be set according to the type of crystal form; for example, the melting point of the active pharmaceutical ingredient used in solid dosage forms of apalutamide is 192–195°C.

[0062] In this invention, the heating rate of the instrument is 8–12 °C / min. In different embodiments, the heating rate of the instrument can be 8 °C / min, 9 °C / min, 10 °C / min, 11 °C / min, 12 °C / min, or any combination thereof.

[0063] In this invention, apalutamide solid dosage forms include at least one of powder, granules, tablets, capsules, pellets, and films.

[0064] In this invention, the standard is amorphous apalutamide, and a certain proportion of crystalline apalutamide is added using the spiking method.

[0065] In this invention, there are at least two standard samples. The range of mass percentages of crystalline apalutamide to amorphous apalutamide in these two standard samples covers the standard for the crystallinity of apalutamide.

[0066] For apalutamide solid dosage form testing, the sample preparation method involves taking the solid dosage form, grinding it into powder, and then measuring the sample. Alternatively, uncoated tablets or unfilled capsule powder from the formulation process can be used for testing.

[0067] This invention also discloses a method for detecting the crystallinity of apalutamide tablets, comprising the following steps:

[0068] (A) Differential scanning calorimetry was used to detect at least two standards with different crystallinity and to determine the peak area;

[0069] (B) Using the peak area and crystallinity of the standard as the x and y axes respectively, a standard working curve is obtained by fitting.

[0070] (C) Differential scanning calorimetry was used to detect the apalutamide tablet samples. The peak area of ​​the samples was substituted into the standard working curve to calculate the crystallinity of the apalutamide tablets.

[0071] Furthermore, the method for detecting the crystallinity of apalutamide tablets includes the following steps:

[0072] (a) DSC analysis was performed on apalutamide tablets to obtain the DSC curve;

[0073] (b) Obtain the peak area based on the DSC curve; substitute the peak area into the standard working curve of crystallinity-peak area to calculate the crystallinity of apalutamide tablets;

[0074] The method for obtaining the standard working curve includes: using DSC to detect at least two standards with different crystallinity and measuring the peak area;

[0075] A standard working curve was obtained by fitting the peak area of ​​the standard sample to the x-axis and the crystallinity to the y-axis.

[0076] The standard preparation method includes: taking the sample to be tested, grinding it, weighing the sample, adding crystalline apalutamide, mixing thoroughly, accurately weighing the mixed powder, and injecting it for measurement. The crystal form of the crystalline apalutamide corresponds to the crystal form in the sample to be tested. At least two points should be prepared according to the requirements of the working curve, and the crystallinity range of the standard should cover the crystallinity limit range of apalutamide tablets. The working curve can be prepared at 2, 3, 4, 5, or 6 points, with 5 points being optimal.

[0077] The DSC detection conditions include: under nitrogen protection, a test temperature range covering the melting point of the apalutamide crystal form used in solid dosage forms, specifically 20–280°C in this invention, and more specifically 25–250°C. The heating rate is 8–12°C / min, and in different embodiments, the instrument's heating rate can be 8°C / min, 9°C / min, 10°C / min, 11°C / min, 12°C / min, or any combination thereof.

[0078] This invention employs differential scanning calorimetry (DSC), utilizing the thermal effect generated during the melting of apalutamide crystals. A linear relationship exists between the thermal change in this process and the quality of the crystal form. By measuring the melting peak area of ​​the standard, the content of the drug's crystal form can be quantitatively analyzed using a standard curve method, thereby achieving the test of crystallinity. The ratio of the mass of crystalline apalutamide to the mass of the sample to be tested is taken as the crystallinity. Different proportions of crystalline apalutamide in the standard result in different crystallinities, thus obtaining the working curve.

[0079] This invention provides a novel method for detecting the crystallinity of apalutamide tablets. The method is convenient to prepare, has high sensitivity in crystallinity measurement, and a detection limit of 1%. This method can be used for quality control during the production and storage of apalutamide tablets, ensuring efficacy and safety in clinical use.

[0080] In practice, a conventional differential scanning calorimeter can be used for DSC testing, which improves the universality of the method.

[0081] In the embodiments of the present invention, selecting a suitable heating rate and temperature range can further improve the linear correlation between melting enthalpy and crystallinity, improve the accuracy of detection results, and ensure sensitivity.

[0082] In a specific embodiment of the present invention, the correlation coefficient r of the standard working curve is ≥0.990, and the Y-axis intercept percentage is ≤5%.

[0083] By adjusting the test method of this invention, the correlation and Y-axis intercept percentage of the standard working curve can be guaranteed to meet the above conditions, thus satisfying the system applicability requirements. The Y-axis intercept percentage refers to (Y-axis intercept / response at 100% concentration) × 100%.

[0084] In a specific embodiment of the present invention, the crystallinity of apalutamide in the apalutamide standard is 1% to 18%. Further, the crystallinity of apalutamide in the apalutamide standard is 1%, 2%, 3%, 5%, 8%, 10% and 12%, 15%, 18%, respectively.

[0085] In practice, the crystallinity of apalutamide in the standard samples can be selected within the range of 1% to 12%. Selecting apalutamide series of standards with crystallinities of 1%, 3%, 5%, 8%, 10%, and 12% further ensures sufficiently high correlation and a sufficiently low Y-axis intercept percentage in the standard working curve, improving detection accuracy. The apalutamide tablet crystallinity detection method of this invention exhibits good accuracy within the range of 1% to 10%, better reflecting the crystallinity of the apalutamide test sample and better ensuring the efficacy and safety of the apalutamide drug. The crystallinity of the working curve can be precisely quantitatively analyzed.

[0086] In some embodiments, the crystallinity of apalutamide in the standard can be selected within the range of 5% to 15%, and a series of apalutamide standards with crystallinity of 5%, 8%, 10%, 12%, and 15% are selected. The crystallinity requirement for apalutamide tablets is ≤10%. The working curve range covers the limits of the standard, so that the standard limit is located in the middle of the working curve.

[0087] In a specific embodiment of the present invention, the apalutamide standard includes amorphous apalutamide and crystalline apalutamide. Further, the preparation of the apalutamide standard includes: obtaining apalutamide tablets or apalutamide extract tablets, grinding them, and adding a certain amount of crystalline apalutamide according to the crystallinity set in the working curve, thereby preparing a standard with the corresponding crystallinity.

[0088] In a specific embodiment of the present invention, the preparation of the apalutamide tablet test sample includes: grinding the apalutamide tablet to be tested into a fine powder. Further, 3 to 5 portions of the test sample are prepared in parallel, tested separately, and the corresponding crystallinity is calculated, and the average value is taken.

[0089] The preparation method of apalutamide tablets of the present invention is simple to operate, requiring only routine grinding of the sample to be tested, which simplifies the operation and improves convenience.

[0090] In a specific embodiment of the present invention, the detection method further includes: using the same DSC detection conditions, obtaining DSC curves for 50% spiked test samples and 80% spiked test samples, and calculating the recovery rate; if the crystallinity recovery rate of each spiked test sample is within the range of 95% to 105%, then the standard working curve is applicable to the crystallinity calculation of the current test sample; if the crystallinity recovery rate of each spiked test sample exceeds the range of 95% to 105%, then the standard working curve is re-established.

[0091] Before calculating the crystallinity of the test sample, this invention verifies the applicability of the standard working curve. When the conditions are met, the standard working curve can be used to calculate the crystallinity of the current test sample; when the conditions are not met, the standard working curve is re-established to ensure the accuracy of the test results.

[0092] In a specific embodiment of the present invention, the preparation of the 50% spiked test sample includes: mixing apalutamide raw material and blank excipient evenly to obtain a mixture with a crystallinity of 5%; the preparation of the 80% spiked test sample includes: mixing apalutamide raw material and blank excipient evenly to obtain a mixture with a crystallinity of 8%.

[0093] In practice, when preparing spiked test samples, apalutamide raw material and blank excipients are weighed in proportion, placed in an aluminum foil bag, and shaken thoroughly to ensure that the materials are fully and evenly dispersed.

[0094] The blank excipients include at least one of the following: dispersant, disintegrant, filler, flow aid, and lubricant. The dispersant is at least one of the following: ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, HPMC acetate succinate, polyvinyl acetate phthalate, polymethacrylate, polyethylene glycol, polypropylene glycol, poloxamer, soluplus, polyvinylpyrrolidone, copovidone, and vinylpyrrolidone-vinyl acetate copolymer.

[0095] Blank excipients also include a combination of microcrystalline cellulose (MCC), croscarmellose sodium (CC-Na), colloidal silica (SiO2), and magnesium stearate. Blank excipients have no effect on this method.

[0096] In a specific embodiment of the present invention, the flow rate of nitrogen gas in DSC detection is 40–90 mL / min.

[0097] In different implementations, the flow rate of nitrogen gas in DSC detection can be 40 mL / min, 50 mL / min, 60 mL / min, 70 mL / min, 80 mL / min, 90 L / min or any combination thereof, preferably 80 mL / min.

[0098] In a specific embodiment of the present invention, the sample amount used in DSC detection is 2.0–10.0 mg. Further, the injection volume is 3.0–10.0 mg, and more specifically, 3–6 mg.

[0099] In different implementation methods, the sample dosage in DSC detection can be a range of 3 mg, 3.2 mg, 3.5 mg, 3.8 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, or any combination thereof. Here, sample dosage refers to the amount of test sample added, or the amount of spiked test sample, or the amount of working samples in the apalutamide standard series.

[0100] In a specific embodiment of the present invention, an open aluminum crucible is used to hold the sample to be tested in DSC detection.

[0101] In some embodiments of this invention, the amorphous apalutamide used was purchased from Janssen Pharmaceuticals under the brand name Ansenke (60mg / tablet, batch number NIJOO1). The differential scanning calorimeter used in this invention was manufactured by Mettler and model DSC1.

[0102] The verification test used apalutamide tablets from Hisun Pharmaceuticals, batch number: 22304081.

[0103] The experimental conditions used are shown in Table 1.

[0104] Table 1 Instrument Conditions

[0105] Crucible type Open aluminum crucible Testing atmosphere Nitrogen Flow rate 80mL / min Test mode linear heating Start temperature 25℃ End temperature 250℃ heating rate 10℃ / min Testing dosage 4.0–6.0 mg

[0106] Experimental Example 1

[0107] Exclusivity

[0108] 1. Sample preparation:

[0109] Blank excipient: Accurately weigh 3.93 mg of blank excipient (same as commercially available Ansenco excipients) fine powder, place it in an open aluminum crucible, and seal it.

[0110] Test sample: Take 10 apaltadamine tablets, grind them into a fine powder using an agate mortar and pestle, accurately weigh 5.05 mg of the fine powder, place it in an open aluminum crucible, and seal it.

[0111] Spiked test sample (equivalent to 10% crystallinity sample): Take 10 apaltadamine tablets, grind them finely with an agate mortar, accurately weigh 60.53 mg of apaltadamine raw material (crystal form), place them in the same agate mortar, grind for 2 minutes, transfer the entire amount to an aluminum foil bag, and shake thoroughly to mix evenly.

[0112] 2. Measurement Method

[0113] Referring to the testing conditions in Table 1, blank excipients, test samples, and spiked test samples were injected for testing, and the DSC curves were recorded.

[0114] Figure 1 The DSC curve is for a blank excipient. From... Figure 1 It can be seen that blank excipients do not interfere with crystallinity testing.

[0115] Experimental Example 2

[0116] System Applicability

[0117] 1. Sample preparation:

[0118] Spiked Sample 1 (equivalent to 2% crystallinity sample): Take 10 apalutamide tablets, grind them finely in an agate mortar, accurately weigh 12.50 mg of apalutamide raw material, place them in the same agate mortar, grind for 2 minutes, transfer the entire amount to an aluminum foil bag, and shake thoroughly to mix evenly. Perform three parallel tests, accurately weighing the above spiked sample 1 at 5.01 mg, 4.91 mg, and 4.83 mg respectively, and place them in open aluminum crucibles and seal them.

[0119] Spiked Sample 2 (equivalent to 5% crystallinity sample): Take 10 apalutamide tablets, grind them finely in an agate mortar, accurately weigh 30.63 mg of apalutamide raw material (crystal form B), place them in the same agate mortar, grind for 2 minutes, transfer the entire amount to an aluminum foil bag, and shake thoroughly to mix evenly. Perform 6 parallel tests, accurately weighing the above spiked sample 2: 5.03 mg, 5.27 mg, 5.31 mg, 4.96 mg, 4.95 mg, and 5.14 mg respectively, and place them in open aluminum crucibles and seal them.

[0120] 2. Measurement Method

[0121] Referring to the detection conditions in Table 1, spiked sample 1 and spiked sample 2 were injected and tested respectively, and the DSC curves were recorded.

[0122] The DSC curve of spiked test sample 1 is as follows: Figure 2 As shown; the DSC curve of spiked sample 2 is as follows. Figure 3 As shown in Tables 2 and 3, these are the system applicability verification results.

[0123] Table 2 System Applicability Verification Results

[0124]

[0125]

[0126] Table 3 System Applicability Verification Results II

[0127]

[0128] Experimental Example 3

[0129] Experimental Example 3-1

[0130] Linearity and Range 1

[0131] (1) Prepare different linear test samples according to Table 4; wherein, the preparation method refers to the test results of spiked test sample 2 under the System Suitability Validation item.

[0132] Table 4 Composition of linear test sample

[0133]

[0134] The composition and specifications of apalutamide tablets are the same as in Example 1.

[0135] The linearity verification results are shown in Table 5, and the DSC curves and linear graphs are shown below. Figure 4 and Figure 5 As shown.

[0136] Table 5. Linearity Validation Results

[0137]

[0138]

[0139] Experimental Example 3-2

[0140] Linearity and Range 2

[0141] The operation method is the same as "Linearity and Range 1". The apalutamide tablets used are uncoated tablets, and the dispersant is HPMCAS. The mass ratio of apalutamide to HPMCAS is 1:3.

[0142] In the linear verification results, the peak areas corresponding to crystallinity of 5.4%, 7.9%, 10%, 11.9%, and 15.1% were 0.35, 0.5, 0.67, 0.81, and 1.08, respectively. The linear equation was: y = 13.141x + 1.0981, with a correlation coefficient r = 0.9980.

[0143] Experimental Example 3-3

[0144] Linearity and Range 3

[0145] The operation method is the same as "Linearity and Range 1". The apalutamide tablets used are uncoated tablets, and the dispersant is HPMCAS. The mass ratio of apalutamide to HPMCAS is 1:3.5.

[0146] In the linear verification results, the peak areas corresponding to crystallinity of 5.2%, 8%, 10%, 12.2%, and 15.1% were 0.34, 0.51, 0.67, 0.82, and 1.08, respectively. The linear equation was: y = 13.322x + 0.9876, with a correlation coefficient r = 0.9973.

[0147] Experimental Example 3-4

[0148] Linearity and Range 4

[0149] The operation method is the same as "Linearity and Range 1". The apalutamide tablets used are uncoated tablets, and the dispersant is HPMCAS. The mass ratio of apalutamide to HPMCAS is 1:2.5.

[0150] In the linear verification results, the linear equation is: y = 13.264x + 0.9673, and the correlation coefficient r = 0.9966.

[0151] Experiment Example 4

[0152] Repeatability

[0153] The spiked sample prepared under the "Specificity" validation item was used as the spiked sample under the "Reproducibility" validation item. Six parallel tests were performed. The spiked samples were accurately weighed separately: 4.93 mg, 5.21 mg, 5.12 mg, 5.30 mg, 5.00 mg, and 5.17 mg, and placed in separate open aluminum crucibles, then sealed.

[0154] Referring to the detection conditions in Table 1, the above-mentioned spiked test samples were injected sequentially, and the experimental results were recorded as shown in Table 6. The RSD of the peak area in the six spiked test samples was calculated.

[0155] Table 6 Repeatability verification results

[0156]

[0157] The recovery rate was calculated based on the previous results, and the test results are shown in Table 7.

[0158] Table 7. Recovery Rate Validation Results

[0159]

[0160] Recovery rate = Measured crystallinity (%) / Actual crystallinity (%) × 100%;

[0161] Actual crystallinity = mass of apaltadamine raw material crystal form / mass of apaltadamine tablets × 100%;

[0162] The measured crystallinity (%) was calculated using the linear formula in Experiment 3-1.

[0163] Experimental Example 5

[0164] Detection limit

[0165] 1. Sample preparation

[0166] 10% spiked test sample (equivalent to 1% crystallinity sample): same linear 10% spiked test sample preparation.

[0167] 2. Measurement Method

[0168] Referring to the detection conditions in Table 1, take 10% spiked test sample and test 6 times consecutively, and record the DSC curve.

[0169] 3. Acceptable Standards

[0170] In the detection limit test results, the RSD of the enthalpy of fusion for 6 consecutive tests was ≤10.0%.

[0171] 4. Results

[0172] The test results are shown in Table 8.

[0173] Table 8 Detection Limits

[0174]

[0175] The DSC curve of the 1% crystallinity standard is shown below. Figure 6 .

[0176] Example 1

[0177] This embodiment provides a method for detecting the crystallinity of apalutamide tablets, including the following steps:

[0178] (1) Prepare a series of apalutamide standard working samples with different crystallinity contents according to Table 9; wherein, the preparation method of the apalutamide standard series working samples includes: placing each ground material in an aluminum foil bag according to the proportion and shaking to mix thoroughly.

[0179] Table 9. Composition of working samples in the apalutamide standard series with different crystallinities.

[0180]

[0181]

[0182] Among them, apalutamide tablets are apalutamide tablets (Haizheng Pharmaceutical, batch number: 22304081).

[0183] Specifically, the method for preparing a 10% crystallinity standard is as follows: Take 10 apalutamide tablets, grind them in an agate mortar, add 60.53 mg of precisely weighed apalutamide raw material to the same mortar, grind for 2 minutes, transfer the entire amount to a foil bag, and shake thoroughly to mix evenly.

[0184] Standard series working samples of other crystallinities were prepared in the same manner according to the proportions in Table 9.

[0185] (2) Preparation of test samples: Take 10 tablets of apaltadamine (Haizheng Pharmaceutical, batch number: 22304081) to be tested, grind them into fine powder, take about 4.0 to 6.0 mg of fine powder, weigh it accurately, place it in an open aluminum crucible, and seal it; to obtain 6 test samples.

[0186] (3) Take the above apaltadamine standards and test samples and perform DSC detection according to the DSC detection conditions in Table 1, and record the DSC curve information.

[0187] (4) Based on the DSC of apalutamide standard, the melting peak area of ​​apalutamide in the working samples of the apalutamide standard series was obtained respectively; with the peak area of ​​apalutamide in the working samples of the apalutamide standard series as the abscissa and the corresponding crystallinity (%) as the ordinate, linear regression was performed to obtain the linear equation and correlation coefficient; the linear equation is: y = 14.05x + 0.097, and the correlation coefficient R 2 =0.9959.

[0188] The melting peak areas of apalutamide in 6 test samples were obtained, and substituted into the above linear equation to calculate the crystallinity of the 6 test samples. The average value was taken as the test value.

[0189] No peak area was detected in the test sample.

[0190] Example 2

[0191] This embodiment refers to the detection method of Embodiment 1, with the difference being:

[0192] For the preparation method of standard products, refer to Linearity and Range 1;

[0193] Sample preparation: Take 10 apalutamide tablets, grind them into a fine powder using an agate mortar and pestle, and accurately weigh 5.16 mg;

[0194] The DSC curve of the test sample is shown below. Figure 7 As shown in the image, no detectable substance was found.

[0195] Example 3

[0196] This embodiment refers to the detection method of Embodiment 1, with the difference being:

[0197] For the preparation method of standard products, refer to Linearity and Range 3;

[0198] Sample preparation: Take 10 apaltadine tablets (uncoated tablets prepared according to the patent application with publication number CN106999431A, wherein the dispersant is HPMCAS and the mass ratio of apaltadine to HPMCAS is 1:3.5), grind them into a fine powder with an agate mortar, and accurately weigh 5.62 mg.

[0199] The DSC testing conditions are shown in Table 1. Not detected.

[0200] Example 4

[0201] This embodiment refers to the detection method of Embodiment 1, with the difference being:

[0202] The preparation method of the standard is referenced in Linearity and Range 1; the standard is Ansenco, and the crystalline apaltamethasone is the corresponding crystal form.

[0203] Sample preparation: Take 10 apalutamide tablets (Ansenke), grind them into a fine powder using an agate mortar, and accurately weigh 5.62 mg;

[0204] The DSC testing conditions are shown in Table 1. Not detected.

[0205] The results above show that the method for detecting the crystallinity of apalutamide tablets of the present invention is convenient for sample preparation, highly sensitive, and has a detection limit of 1%. It can be used for quality control during drug production and storage, and ensure the efficacy and safety in clinical use.

[0206] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for detecting the crystallinity of apalutamide solid dosage form, characterized in that, Includes the following steps: (A) Differential scanning calorimetry is used to test at least two standards with different crystallinity and to determine the melting peak area of ​​the standards; (B) Using the melting peak area and crystallinity of the standard as the abscissa and ordinate respectively, a standard working curve is obtained by fitting. (C) The differential scanning calorimetry method is used to detect the apaltadamine solid dosage form sample to be tested. The melting peak area of ​​the sample is substituted into the standard working curve to calculate the crystallinity of the apaltadamine solid dosage form to be tested. The standard comprises amorphous apalutamide and crystalline apalutamide; wherein the mass of the crystalline apalutamide is 1% to 18% of the mass of the amorphous apalutamide. The amorphous apalutamide in the standard includes apalutamide and a dispersant; during the differential scanning calorimetry detection, the nitrogen flow rate is 75~85 mL / min, a linear heating mode is adopted, starting from 25℃ and increasing to 250℃ at a rate of 10℃ / min, and the detection amount of the standard or sample is 4.0~6.0 mg.

2. The method for detecting the crystallinity of apalutamide solid dosage form according to claim 1, characterized in that, In the amorphous apaltadamine in the standard, the mass ratio of apaltadamine to the dispersant is 1:(1-5).

3. The method for detecting the crystallinity of apalutamide solid dosage form according to claim 1, characterized in that, The dispersant comprises at least one of the following: ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, HPMC acetate succinate, polyvinyl acetate phthalate, polymethyl methacrylate, polyethylene glycol, polypropylene glycol, poloxamer, soluplus, polyvinylpyrrolidone, copolyvinylpyrrolidone, and vinylpyrrolidone-vinyl acetate copolymer.

4. The method for detecting the crystallinity of apalutamide solid dosage form according to claim 1, characterized in that, The apaltadamine solid dosage form is obtained by spray drying or hot melt extrusion granulation; the apaltadamine solid dosage form includes at least one of powder, granules, tablets, capsules, pellets and films.

5. The method for detecting the crystallinity of apalutamide solid dosage form according to claim 2, characterized in that, The amorphous apalutamide in the standard is apalutamide tablet.

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