Preparation method of Resmetirom crystal form I and quantitative detection method of Resmetirom crystal form I

Abstract

The invention provides a preparation method of a Resmetirom crystal form I and a quantitative detection method of the Resmetirom crystal form I. The invention specifically provides a detection method of the Resmerom crystal form I. The detection method comprises the following steps: carrying out X-ray powder diffraction on a composition containing the Resmerom crystal form I; the composition comprises an active ingredient and a pharmaceutic adjuvant, wherein the active ingredient comprises a Resmetirom crystal form I; and calculating the mass content of the crystal form I in the active component according to the following formula: wt% = A * (100 * (IAA / (IAA + k * IDA)-B, wherein A ranges from 100 to 104, and B ranges from 1.0 to 1.4. The detection method provided by the invention is high in accuracy and strong in operability, and the preparation method provided by the invention is high in yield, good in purity, convenient and fast.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemical refining. Specifically, it relates to a preparation method and a quantitative detection method of Resmetirom polymorph I. Background Art

[0002] On March 15, 2024, the drug Resmetirom developed by Madrigal Pharmaceuticals was approved by the FDA for the treatment of adult patients with metabolic dysfunction-associated steatohepatitis (MASH, formerly known as NASH), which is the world's first approved MASH drug.

[0003]

[0004] The original research company disclosed Resmetirom polymorph I and its preparation method in patent WO2014043706A. Among them, it is not easy to directly obtain high-purity polymorph I using solvates, but it often needs to be converted into MIBK solvate, and then polymorph I is obtained from the MIBK solvate, with complex operations.

[0005] In patent WO2020010068A1, it was disclosed that Resmetirom can easily form corresponding solvates in different solvents, and a total of 16 solvate polymorphs were obtained. It is difficult to obtain the solvent-free polymorph of Resmetirom. Patent WO2021063367A1 disclosed a Resmetirom polymorph CSI. This patent also mentioned that after more than 300 experiments, most of the products obtained were solvates, indicating that the preparation of the anhydrous polymorph I is not easily achieved by conventional methods in this field.

[0006] Generally, the polymorph of a drug determines its physicochemical properties such as stability, solubility, and bioavailability, which are important factors directly affecting the clinical efficacy and safety of the drug. However, if the conditions are not properly controlled during the production and storage of the drug, it is easy to occur polymorph transformation and degradation products. Therefore, only qualitative research on the polymorph of the drug can no longer meet the requirements. Moreover, in pharmaceutical preparations, excipient components will have a great interference on the quantitative research of the active ingredient. To ensure the efficacy and safety of the drug, it is of great importance to determine the content of the effective polymorph in the raw material drug or preparation, and appropriate methods are needed to quantitatively analyze the polymorphs. Summary of the Invention

[0007] To solve the above technical problems, the present invention provides a preparation method and a quantitative detection method of Resmetirom polymorph I. The preparation method provided by the present invention has a high yield and high purity, and the detection method provided by the present invention is convenient, fast, and has good accuracy.

[0008] The present invention solves the above technical problems through the following solutions.

[0009] The present invention provides a method for detecting Resmetirom polymorph I, which comprises the following steps: subjecting a composition containing Resmetirom polymorph I to X-ray powder diffraction;

[0010] The composition contains an active ingredient and a pharmaceutical excipient, and the active ingredient contains Resmetirom polymorph I;

[0011] Calculate the mass content of polymorph I according to the following formula:

[0012] wt% = A × (100 × (I AA ÷ (I AA + k × I DA ) - B;

[0013] wherein, A is 100 - 104, and B is 1.0 - 1.4;

[0014] I AA is the sum of the peak areas in the regions of 10.26 ± 0.2° to 10.62 ± 0.2° and / or 18.67 ± 0.2° to 18.88 ± 0.2° of the X-ray powder diffraction pattern of Resmetirom polymorph I represented by the 2θ angle using Cu-Kα radiation;

[0015] I DA is the sum of the peak areas in the region of 5.36 ± 0.2° to 6.14 ± 0.2°, or in the regions of 5.36 ± 0.2° to 6.14 ± 0.2°, 9.03 ± 0.2° to 9.35 ± 0.2° and 11.75 ± 0.2° to 11.90 ± 0.2° of the X-ray powder diffraction pattern of Resmetirom dihydrate represented by the 2θ angle using Cu-Kα radiation;

[0016] k is I 0 AA / I 0 DA where I 0 AA is the sum of the areas of the characteristic peaks in the X-ray powder diffraction pattern of a composition in which the active ingredient is Resmetirom polymorph I (i.e., the mass percentage of Resmetirom polymorph I in the active ingredient is 100%) represented by the 2θ angle using Cu-Kα radiation, I 0 DAFor a composition with the active ingredient being Resmetirom dihydrate (i.e., the mass percentage of Resmetirom dihydrate in the active ingredient is 100%), the sum of the areas of the characteristic peaks in the X-ray powder diffraction pattern expressed in terms of 2θ angle using Cu-Kα radiation;

[0017] wt% is the mass percentage of Resmetirom polymorph I in the active ingredient.

[0018] In one embodiment, the active ingredient further comprises Resmetirom dihydrate.

[0019] In one embodiment, the composition consists of the active ingredient and the pharmaceutical excipient, wherein the active ingredient consists of the Resmetirom polymorph I and the Resmetirom dihydrate.

[0020] In the present invention, the composition containing Resmetirom polymorph I is in the form of a material that can be routinely subjected to X-ray powder diffraction in the art, such as being ground into powder form.

[0021] In one embodiment, the X-ray powder diffraction pattern of the Resmetirom dihydrate expressed in terms of 2θ angle using Cu-Kα radiation has diffraction peaks at 5.9±0.2°, 9.5±0.2°, 11.8±0.2°, 12.6±0.2°, 13.2±0.2°, 14.6±0.2° and 25.4±0.2°.

[0022] Preferably, the thermogravimetric analysis curve of the Resmetirom dihydrate shows a weight loss of 7.54% from 25±3°C to 150±3°C.

[0023] More preferably, the X-ray powder diffraction pattern of the Resmetirom dihydrate expressed in terms of 2θ angle using Cu-Kα radiation is substantially as Figure 1 shown; and / or, the thermogravimetric analysis curve of the Resmetirom dihydrate is substantially as Figure 2 shown.

[0024] In one embodiment, the pharmaceutical excipient comprises one or more of a filler, a disintegrant, a diluent and a glidant. Preferably, the filler is, for example, lactose, the diluent is, for example, microcrystalline cellulose, the glidant is, for example, magnesium stearate, and the disintegrant is, for example, croscarmellose sodium.

[0025] In one embodiment, in the composition, the X-ray powder diffraction pattern of Resmetirom polymorph I using Cu-Kα radiation and expressed in 2θ angle has diffraction peaks at 10.5±0.2°, 18.7±0.2°, 22.9±0.2°, 23.6±0.2° and 24.7±0.2°. Preferably, the X-ray powder diffraction pattern of Resmetirom polymorph I using Cu-Kα radiation and expressed in 2θ angle further has diffraction peaks at 8.2±0.2°, 11.2±0.2°, 15.7±0.2°, 16.4±0.2°, 17.7±0.2°, 30.0±0.2° and 32.2±0.2°.

[0026] In one embodiment, in the composition, the mass percentage of Resmetirom polymorph I in the active ingredient is 3%-100%, such as 5%, 20%, 30% or 70%.

[0027] In one embodiment, A is 102-103, such as 102.56.

[0028] In one embodiment, B is 1.2-1.3, such as 1.237.

[0029] In one embodiment, the mass ratio of the active ingredient to the pharmaceutical excipient is 1:(2-6), such as 1:4.

[0030] In one embodiment, the mass percentage of the filler in the composition is 10%-80%, such as 10%-40%, or 25.6%.

[0031] In one embodiment, the mass percentage of the diluent in the composition is 10%-90%, such as 40%-60%, or 51.2%.

[0032] In one embodiment, the mass percentage of the glidant in the composition is 0.1%-10%, such as 0.1%-1.5%, or 0.8%.

[0033] In one embodiment, the mass percentage of the disintegrant in the composition is 0.1%-10%, such as 1%-10%, or 2.4%.

[0034] In one embodiment, the composition is prepared by the following method: A mixture of the active ingredient (such as Resmetirom polymorph I), the filler, the diluent, a part of the glidant (such as 1 / 4 mass of all the glidant) and the disintegrant is tabletted, crushed, the remaining part of the glidant is added, and then tabletted to obtain the composition.

[0035] In one embodiment, the mass percentage of Resmetirom dihydrate in the active ingredient of the composition is the mass percentage of Resmetirom Polymorph I in the active ingredient.

[0036] The X-ray powder diffraction test is carried out on a conventional powder diffractometer in the art, such as a PANAlytical X-ray powder diffractometer, a Bruker D8 X-ray powder diffractometer, or a Rigaku X-ray powder diffractometer.

[0037] In one embodiment, the X-ray powder diffraction test is set with a tube voltage of 20 - 55 kV, such as 40 - 55 kV, or 40 kV for example.

[0038] In one embodiment, the X-ray powder diffraction test is set with a tube current of 20 - 55 mA, such as 40 - 55 mA, or 40 mA for example.

[0039] In one embodiment, the X-ray powder diffraction test is set with a step size of 0.001 - 0.02°, such as 0.001 - 0.01°, or 0.01° or 0.005° for example.

[0040] In one embodiment, the X-ray powder diffraction test is set with a scan time of 20 - 200 s per step, such as 50 - 200 s, or 50 s or 80 s for example.

[0041] In one embodiment, the detection method of Resmetirom Polymorph I comprises the following steps: performing X-ray powder diffraction on a composition containing Resmetirom Polymorph I;

[0042] The composition is composed of an active ingredient and the pharmaceutical excipient, and the active ingredient is composed of Resmetirom Polymorph I and Resmetirom dihydrate;

[0043] Calculate the mass content of Polymorph I according to the following formula:

[0044] wt% = A × (100 × (I AA ÷ (I AA + k × I DA ) - B;

[0045] where A is 102 - 103 and B is 1.2 - 1.3;

[0046] I AAThe sum of the peak areas in the X-ray powder diffraction pattern of Resmetirom polymorph I, expressed in 2θ angle, using Cu-Kα radiation, in the regions of 10.26 ± 0.2° to 10.62 ± 0.2° and 18.67 ± 0.2° to 18.88 ± 0.2°;

[0047] I DA The sum of the peak areas in the X-ray powder diffraction pattern of Resmetirom dihydrate, expressed in 2θ angle, using Cu-Kα radiation, in the regions of 5.36 ± 0.2° to 6.14 ± 0.2°, 9.03 ± 0.2° to 9.35 ± 0.2° and 11.75 ± 0.2° to 11.90 ± 0.2°;

[0048] k is I 0 AA / I 0 DA , where I 0 AA is the sum of the characteristic peak areas in the X-ray powder diffraction pattern of a composition with Resmetirom polymorph I as the active ingredient (i.e., the mass percentage of Resmetirom polymorph I in the active ingredient is 100%), I 0 DA is the sum of the characteristic peak areas in the X-ray powder diffraction pattern of a composition with Resmetirom dihydrate as the active ingredient (i.e., the mass percentage of Resmetirom dihydrate in the active ingredient is 100%);

[0049] wt% is the mass percentage of Resmetirom polymorph I in the active ingredient.

[0050] The present invention provides a preparation method of the Resmetirom polymorph I, which comprises the following steps: crystallizing the Resmetirom dihydrate and an alcohol solvent mixture to obtain the Resmetirom polymorph I.

[0051] In the preparation method, the temperature of the mixture can be 40°C to the reflux temperature (for example, 60°C to reflux), for example, 60°C, or heated to reflux.

[0052] In the preparation method, the crystallization can be crystallization by cooling, for example, 0 - 30°C, for example, cooling to room temperature (room temperature is, for example, 20 - 25°C) to 10°C for crystallization, and preferably cooling to room temperature for crystallization.

[0053] In the preparation method, the alcohol solvent is an alcohol solvent miscible with water, for example, methanol, ethanol, n-propanol or isopropanol, for example, isopropanol.

[0054] In the preparation method, the mass-volume ratio of Resmetirom dihydrate to isopropyl alcohol can be 5:(10 - 100) g / mL, for example, 5 g / 50 mL or 5 g / 20 mL.

[0055] In one embodiment, the preparation method includes the following post-treatment steps: after crystallization, filtration, washing (e.g., washing with isopropyl alcohol), and drying to obtain the Resmetirom polymorph I.

[0056] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0057] The reagents and raw materials used in the present invention are all commercially available.

[0058] The positive and progressive effects of the present invention are as follows: The method for preparing polymorph I from the dihydrate crystal form provided by the present invention is simple in operation and not easy to form solvates. At the same time, the present invention also provides qualitative and quantitative methods for the dihydrate and polymorph I in the active pharmaceutical ingredient and preparation, with high precision, good stability, and fast and efficient. Description of the Drawings

[0059] Figure 1 XRPD pattern of the dihydrate crystal form obtained in Example 1.

[0060] Figure 2 TGA pattern of the dihydrate obtained in Example 1.

[0061] Figure 3 XRPD pattern of the polymorph I obtained in Example 2.

[0062] Figure 4 Comparison chart of Resmetirom polymorph I and Resmetirom dihydrate crystal form (API).

[0063] Figure 5 XRPD comparison chart of blank excipient, preparation of polymorph I and preparation of dihydrate crystal form.

[0064] Figure 6 Chart of crystal form content measurement results. Detailed Embodiments

[0065] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions in the following examples are carried out according to the conventional methods and conditions or selected according to the product specifications.

[0066] All the reagents used in the present invention are commercially available and can be used without further purification.

[0067] The detection methods used in the present invention are as follows:

[0068] 1. X-ray powder diffraction

[0069] Instrument: PANAlytical X'Pert Powder (Malvern Panalytical Ltd),

[0070] Target: Cu-Kα radiation,

[0071] Tube voltage: 40 kV,

[0072] Tube current: 40 mA.

[0073] Step size: 0.01°

[0074] Scanning time per step: 50 s

[0075] Sample amount: 40 mg ± 10%

[0076] 2. Differential scanning calorimetry

[0077] Instrument: TA Q2000 differential scanning calorimeter (TA, USA),

[0078] Temperature range: 30 - 300 °C,

[0079] Heating rate: 10 °C / min.

[0080] 3. Thermogravimetric analysis

[0081] Instrument: TA Q500 thermogravimetric analyzer (TA, USA),

[0082] Temperature range: 30 - 350 °C,

[0083] Heating rate: 10 °C / min.

[0084] 4. High performance liquid chromatography

[0085] Instrument: U3000 high performance liquid chromatograph (Thermo Fisher),

[0086] Chromatographic column: Water Sufire C18 (4.6 mm × 150 mm, 3.5 μm),

[0087] Detection wavelength: 220 nm,

[0088] Column temperature: 30 °C,

[0089] Mobile phase: water (0.08% TFA) / acetonitrile gradient elution

[0090] Flow rate: 1 mL / min.

[0091]

[0092] Example 1

[0093] Preparation of Resmetirom dihydrate

[0094] According to the method of Example 2 in Patent WO2021063367A1, 78.5 g of Resmetirom dihydrate was prepared.

[0095] Its XRPD pattern has characteristic peaks at 2θ values of 5.9±0.2°, 9.5±0.2°, 11.8±0.2°, 12.6±0.2°, 13.2±0.2°, 14.6±0.2° and 25.4±0.2°, as Figure 1 shown. Its TGA pattern shows a weight loss of 7.54%, which is comparable to the theoretical value of 7.62%, as Figure 2 shown. Combining XRD, DSC, TGA and actual residual solvent and moisture determination, the molar ratio of Resmetirom to water in this crystal form is 1:2.

[0096] Example 2

[0097] Preparation of Crystal Form I

[0098] The dihydrate of Resmetirom (5 g) obtained in Example 1 and isopropyl alcohol (50 mL) were added to a 100 mL three-necked flask, heated to reflux, stirred for 1 h, cooled to room temperature, stirred for 1 h, filtered, washed with isopropyl alcohol (10 mL), and dried to obtain 4.14 g of a white solid. XRD showed it was Crystal Form I (i.e., Crystal Form I in WO2014043706A), and its XRPD pattern was as Figure 3 shown. Among them, the X-ray powder diffraction pattern of Crystal Form I using Cu-Kα radiation and expressed in 2θ angle has diffraction peaks at about 10.5°, 18.7°, 22.9°, 23.6°, 24.7°, 8.2°, 11.2°, 15.7°, 16.4°, 17.7°, 30.0° and 32.2°.

[0099] Example 3

[0100] Preparation of Crystal Form I

[0101] The dihydrate of Resmetirom (5 g) obtained in Example 1 and isopropyl alcohol (20 mL) were added to a 50 mL three-necked flask, heated to reflux, stirred for 1 h, cooled to room temperature, stirred for 1 h, filtered, washed with isopropyl alcohol (5 mL), and dried to obtain 4.19 g of a white solid. XRD showed it was Crystal Form I.

[0102] Example 4

[0103] Preparation of Crystal Form I

[0104] The dihydrate of Resmetirom (3 g) obtained in Example 1 and isopropyl alcohol (30 mL) were added to a 50 mL three-necked flask, stirred at 60 °C for 3 h, cooled to room temperature, stirred for 1 h, filtered, washed with isopropyl alcohol (5 mL), and dried to obtain 2.54 g of a white solid. XRD showed it to be Crystal Form I.

[0105] Effect Example 1

[0106] 1. Purity

[0107] (1) Method for measuring purity: Detection was carried out using a high-performance liquid chromatograph. The conditions and parameters for detection were as follows:

[0108] Instrument: U3000 high-performance liquid chromatograph (Thermo Fisher),

[0109] Chromatographic column: Water Sufire C18 (4.6 mm × 150 mm, 3.5 μm),

[0110] Detection wavelength: 220 nm,

[0111] Column temperature: 30 °C,

[0112] Mobile phase: Water (0.08% TFA) / acetonitrile gradient elution

[0113] Gradient:

[0114]

[0115]

[0116] Flow rate: 1 mL / min.

[0117] (2) The purity results of the examples are shown in Table 1.

[0118] 2. Yield

[0119] (1) Method for measuring yield:

[0120] Yield = (amount of target product produced / theoretical amount of target product produced) * 100%

[0121] (1) The yield results of the comparative examples and examples are shown in Table 1.

[0122] Table 1

[0123] Initial purity Chemical purity after crystallization Crystal form purity after crystallization Yield Example 1 95.5％ 100% dihydrate 85.7％ Example 2 95.5％ 99.1％ 100% crystal form I 89.6％ Example 3 95.5％ 99.2％ 100% crystal form I 90.7％ Example 4 95.5％ 99.2％ 100% crystal form I 91.7％

[0124] Note: The initial purity refers to the proportion of the peak area of Resmetirom in the HPLC of Resmetirom dihydrate.

[0125] The chemical purity after crystallization refers to the HPLC purity of Resmetirom in polymorph I. The polymorph purity after crystallization refers to the HPLC purity of polymorph I compared to the impurity polymorphs.

[0126] Thus, it can be seen that in alcohol solvents, it is convenient and fast to prepare drug polymorph I using Resmetirom dihydrate, which also illustrates the importance of quickly detecting the contents of Resmetirom dihydrate and Resmetirom polymorph I in the preparation.

[0127] Example 6

[0128] In this example, a Resmetirom preparation was prepared from the Resmetirom polymorph I obtained in Example 2, and its formulation composition is as follows:

[0129] Composition (500 tablets) Charge (g) Resmetirom crystal form I 50.0 Lactose 64.0 Microcrystalline cellulose 128.0 Magnesium stearate (added internally) 0.5g Croscarmellose sodium 6.0 Magnesium stearate (added externally) 1.5g Total 250

[0130] The preparation method is as follows:

[0131] Weigh Resmetirom polymorph I, lactose, microcrystalline cellulose, magnesium stearate (added internally), and croscarmellose sodium according to the prescription, mix them evenly and pass through a sieve. The sieved sample is compressed into flakes by a dry granulator, the flaky material is crushed and then passed through a sieve, magnesium stearate (added externally) is added, mixed evenly, and then tableted.

[0132] Example 7

[0133] In this example, a Resmetirom preparation was prepared from the Resmetirom dihydrate polymorph obtained in Example 1, and its formulation composition is as follows:

[0134] Composition (500 tablets) Charge (g) Resmetirom dihydrate crystal form 50.0 Lactose 64.0 Microcrystalline cellulose 128.0 Magnesium stearate (added internally) 0.5g Croscarmellose sodium 6.0 Magnesium stearate (added externally) 1.5g Total 250

[0135] The preparation method is as follows:

[0136] Weigh Resmetirom dihydrate, lactose, microcrystalline cellulose, magnesium stearate (added internally), and croscarmellose sodium according to the prescription, mix them evenly and pass through a sieve. The sieved sample is compressed into flakes by a dry granulator, the flaky material is crushed and then passed through a sieve, magnesium stearate (added externally) is added, mixed evenly, and then tableted.

[0137] Effect Example 2

[0138] 1. System suitability: The polymorph I of Resmetirom and the dihydrate polymorph of Resmetirom were taken from Example 2 and Example 1 respectively, and their characteristic peaks are as Figure 4As shown, the characteristic peaks of polymorph I are selected at 2θ of 8.2 ± 0.2° and 10.4 ± 0.2°, and the characteristic peaks of the dihydrate polymorph are at 2θ of 5.9 ± 0.2° and 14.6 ± 0.2°. Four quantitative curves were established respectively. With the content of polymorph I as the abscissa and the area of the characteristic peak of polymorph I / (the area of the characteristic peak of polymorph I + the area of the characteristic peak of the dihydrate polymorph) as the ordinate, the results are shown in the following table, and the correlation coefficients of the four curves can all reach above 0.99.

[0139]

[0140]

[0141] However, the above-mentioned diffraction peaks selected and the established quantitative relationships are not applicable to Resmetirom formulations. The excipients will interfere with the characteristic peaks of polymorph I of Resmetirom or its dihydrate, such as Figure 5 As shown, in the XRPD comparison of the Resmetirom dihydrate formulation prepared in Example 7 and the Resmetirom polymorph I formulation prepared in Example 6, there are a large number of interfering peaks. The characteristic peaks in the API are interfered by the excipients and cannot be directly applied to the formulation. Therefore, the characteristic peaks need to be reselected. The characteristic peaks of polymorph I are between 10.256° and 10.624° and between 18.666° and 18.883° for 2θ, and the characteristic peaks of the dihydrate polymorph are between 5.360° and 6.140°, between 9.029° and 9.350°, and between 11.747° and 11.898° for 2θ. To better avoid interference, the system suitability criterion is that the peak area at 11.747° - 11.898° is greater than 5 times the signal-to-noise ratio.

[0142] 2. Detection method of powder X-ray diffraction:

[0143] Instrument: PANAlytical X'Pert Powder (Malvern Panalytical Ltd)

[0144] Target: Cu-Kα radiation

[0145] Tube voltage: 40 kV

[0146] Tube current: 40 mA

[0147] Step size: 0.01

[0148] Scanning time per step: 50 s

[0149] Sample amount: 40 mg ± 10%

[0150] 3. Sample preparation

[0151] Formulation: Referring to the specification of the marketed Resmetirom drug, which is 80 mg per tablet (0.4 g), the API (30 mg) was grouped into 0% (A0), 10% (A1), 20% (A2), 30% (A3), 50% (A4), 70% (A5), 80% (A6), 90% (A7), 100% (A8) after mixing with excipients (120 mg, and the formulation of the excipients was in accordance with Example 6 or 7). The percentage refers to the mass percentage of polymorph I in the API. After mixing evenly, it was sieved through a 100-mesh sieve.

[0152] Weighed with an analytical balance, and the results were repeated at least three times. After shaking and mixing evenly, it was measured with a powder diffractometer.

[0153] 4. Standard curve plotting

[0154] Due to the particularity of powder diffraction, especially the fact that the excipients in the formulation contain a large amount of amorphous substances, which seriously interfere with the quantitative results, the correlation coefficient of the content calibration curve is generally low in the actual process and it is difficult to achieve the high correlation of spectroscopic methods such as HPLC. In the present invention, through the calculation of variables and the addition of correction factors, the correlation coefficient can reach above 0.999.

[0155] As Figure 4 (API) and Figure 5 (formulation) showed that the present invention selected the characteristic peaks of polymorph I between 2θ of 10.256° - 10.624° and 18.666° - 18.883°, and the characteristic peaks of the dihydrate polymorph between 2θ of 5.360° - 6.140°, 9.029° - 9.350°, and 11.747° - 11.898°. Taking the content of polymorph I as the abscissa and the area of the characteristic peak of polymorph I / (the area of the characteristic peak of polymorph I + the area of the characteristic peak of the dihydrate polymorph) as the ordinate, a polymorph content calibration curve graph was made, and the graph was as Figure 6 shown, and the results are shown in Table 2.

[0156] Table 2

[0157]

[0158] The optimal content formula is:

[0159] Mass ratio of polymorph I (wt.-% of AA) = 102.56 × (100 × (I AA ÷ (I AA + k I DA )) - 1.2347; where the mass ratio of polymorph I refers to the mass ratio of polymorph I to the active ingredient.

[0160] Where I AA represents the sum of the peak areas in the XRPD diffraction pattern region of the selected polymorph I in Table 2 above, IDA The sum of the peak areas in the XRPD diffraction pattern region representing the selected dihydrate crystal form in Table 2 above, and k is a correction factor (I 0 AA / I 0 DA ).

[0161] Where I 0 AA is the sum of the peak areas (average of three times) of the characteristic peaks in the preparation of 100% crystal form I (composition containing only crystal form I), and I 0 DA is the sum of the peak areas (average of three times) of the characteristic peaks in the preparation of 100% dihydrate (composition containing only dihydrate).

[0162] 5. Method Validation

[0163] LOD = 3.3σ / s and LOQ = 10σ / s. LOD = 2.37%. LOQ = 7.18%

[0164] Accuracy Investigation:

[0165] The dihydrate crystal form and crystal form I were respectively formulated into mixed samples with 3%, 5%, 30% and 70% mass percentage of crystal form I in the API. The preparations were made according to Example 6 respectively. Three samples were prepared for each concentration. After pulverization, the peak intensities of the characteristic peaks in each sample were measured and calculated according to the law, substituted into the above linear equation, the contents of each crystal form were calculated, and the recovery rates of each sample were calculated. The specific values are shown in Table 3. The average recovery rate of crystal form I above 5% by this method is: 100.02%

[0166] Table 3 Recovery Rate (Preparation)

[0167]

Claims

1. A method for detecting Resmetirom Form I, characterized in that: The method comprises the following steps: subjecting a composition comprising Resmetirom Form I to X-ray powder diffraction; The composition comprises an active ingredient and a pharmaceutical excipient, wherein the active ingredient comprises Resmetirom crystalline form I; The mass content of Form I was calculated according to the following formula: wt%=A×(100×(I AA ÷(I AA +k×I DA )-B; Among them, A is 100-104, B is 1.0-1.4; I AA The sum of the peak areas in the region of 10.26±0.2° to 10.62±0.2° and / or 18.67±0.2° to 18.88±0.2° of the X-ray powder diffraction pattern of Resmetirom Form I using Cu-Kα radiation and expressed in 2θ angles; I DA X-ray powder diffraction pattern of Resmetirom dihydrate using Cu-Kα radiation, expressed in 2θ angles, in the region of 5.36±0.2° to 6.14±0.2°, or the sum of the peak areas in the regions of 5.36±0.2° to 6.14±0.2°, 9.03±0.2° to 9.35±0.2° and 11.75±0.2° to 11.90±0.2°; k is I 0 AA / I 0 DA , where I 0 AA The sum of the areas of the characteristic peaks of the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation for the composition whose active ingredient is Resmetirom crystalline form I, 0 DA The sum of the areas of characteristic peaks of the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation for a composition whose active ingredient is Resmetirom dihydrate; wt% is the mass percentage of Resmetirom Form I in the active ingredient.

2. The method for detecting Resmetirom Form I according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The active ingredient further comprises Resmetirom dihydrate; preferably, the composition consists of the active ingredient and the pharmaceutical excipient, wherein the active ingredient consists of the Resmetirom crystalline form I and the Resmetirom dihydrate; (2) The X-ray powder diffraction pattern of Resmetirom dihydrate using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 5.9±0.2°, 9.5±0.2°, 11.8±0.2°, 12.6±0.2°, 13.2±0.2°, 14.6±0.2° and 25.4±0.2°; (3) the X-ray powder diffraction pattern of Resmetirom Form I using Cu-Kα radiation and expressed in 2θ angles has diffraction peaks at 10.5±0.2°, 18.7±0.2°, 22.9±0.2°, 23.6±0.2° and 24.7±0.2°. Preferably, the X-ray powder diffraction pattern of Resmetirom Form I using Cu-Kα radiation and expressed in 2θ angles further has diffraction peaks at 8.2±0.2°, 11.2±0.2°, 15.7±0.2°, 16.4±0.2°, 17.7±0.2°, 30.0±0.2° and 32.2±0.2°; (4) The mass percentage of Resmetirom Form I to the active ingredient is 3% to 100%, such as 5%, 20%, 30% or 70%; (5) A is 102-103, for example, 102.56; (6) B is 1.2-1.3, for example 1.

237.

3. The method for detecting Resmetirom Form I according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The thermogravimetric analysis curve of Resmetirom dihydrate shows a weight loss of 7.54% from 25±3°C to 150±3°C; preferably, the thermogravimetric analysis curve of Resmetirom dihydrate is substantially as shown in FIG2 ; (2) the X-ray powder diffraction pattern of Resmetirom dihydrate using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in Figure 1; (3) The pharmaceutical excipients include one or more of a filler, a disintegrant, a diluent and a glidant; preferably, the filler is, for example, lactose, the diluent is, for example, microcrystalline cellulose, the glidant is, for example, magnesium stearate, and the disintegrant is, for example, cross-linked carboxymethyl cellulose sodium; (4) The mass ratio of the active ingredient to the pharmaceutical excipient is 1:(2-6), for example 1:

4.

4. The method for detecting Resmetirom Form I according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The filler accounts for 10% to 80% by weight of the composition, for example, 10% to 40%, preferably 25.6% by weight; (2) the mass percentage of the diluent in the composition is 10%-90%, for example 40%-60%, preferably 51.2%; (3) The mass percentage of the glidant in the composition is 0.1%-10%, for example 0.1%-1.5%, preferably 0.8%; (4) The disintegrant accounts for 0.1%-10% by weight of the composition, for example 1%-10%, preferably 2.4% by weight; Preferably, the composition is prepared by the following method: tableting a mixture of the active ingredient, the filler, the diluent, a part of the glidant and the disintegrant, crushing, adding the remaining part of the glidant, tableting, and obtaining the composition.

5. The method for detecting Resmetirom Form I according to claim 1, characterized in that: The mass percentage of Resmetirom dihydrate in the active ingredient of the composition is 1-the mass percentage of Resmetirom crystalline form I in the active ingredient.

6. The method for detecting Resmetirom Form I according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The X-ray powder diffraction test is performed on a PANAlytical X-ray powder diffractometer, a Bruker D8 X-ray powder diffractometer or a Rigaku X-ray powder diffractometer; (2) The X-ray powder diffraction test is set to a tube voltage of 20-55 kV, such as 40-55 kV, preferably 40 kV; (3) The X-ray powder diffraction test sets the tube current to 20-55 mA, such as 40-55 mA, preferably 40 mA; (4) The X-ray powder diffraction test is set to a step size of 0.001-0.02°, such as 0.001-0.01°, preferably 0.01° or 0.005°; (5) The X-ray powder diffraction test is performed with a scanning time of 20-200 s per step, such as 50-200 s, preferably 50 s or 80 s.

7. A method for detecting Resmetirom Form I according to any one of claims 1 to 4, characterized in that: The method for detecting Resmetirom Form I comprises the following steps: subjecting a composition comprising Resmetirom Form I to X-ray powder diffraction; The composition is composed of an active ingredient and the pharmaceutical excipient, wherein the active ingredient is composed of the Resmetirom crystalline form I and the Resmetirom dihydrate; The mass content of Form I was calculated according to the following formula: wt%=A×(100×(I AA ÷(I AA +k×I DA )-B; Among them, A is 102-103, B is 1.2-1.3; I AA The sum of the peak areas in the region of 10.26±0.2° to 10.62±0.2° and 18.67±0.2° to 18.88±0.2° of the X-ray powder diffraction pattern of Resmetirom Form I using Cu-Kα radiation and expressed in 2θ angles; I DA The sum of the peak areas in the regions of 5.36±0.2° to 6.14±0.2°, 9.03±0.2° to 9.35±0.2° and 11.75±0.2° to 11.90±0.2° of the X-ray powder diffraction pattern of Resmetirom dihydrate using Cu-Kα radiation expressed in 2θ angles; k is I 0 AA / I 0 DA , where I 0 AA The sum of the areas of the characteristic peaks in the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation for a composition whose active ingredient is Resmetirom crystalline form I, 0 DA The sum of the areas of characteristic peaks in the X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation for a composition in which the active ingredient is Resmetirom dihydrate; wt% is the mass percentage of Resmetirom Form I in the active ingredient.

8. A method for preparing Resmetirom Form I, characterized in that: The method comprises the following steps: crystallizing a mixture of Resmetirom dihydrate and an alcohol solvent to obtain the Resmetirom crystal form I.

9. The method for preparing Resmetirom Form I according to claim 8, characterized in that: It meets one or more of the following conditions: (1) The Resmetirom Form I is as described in claim 2; (2) The Resmetirom dihydrate is as described in claim 2 or 3; (3) In the preparation method, the mixture temperature is 40°C to reflux temperature, for example, 60°C or heated to reflux; (4) In the preparation method, the crystallization is crystallization by cooling, for example, 0-30°C, for example, crystallization by cooling to room temperature to 10°C, preferably crystallization by cooling to room temperature; (5) In the preparation method, the alcohol solvent is methanol, ethanol, n-propanol or isopropanol, such as isopropanol; (6) In the preparation method, the mass volume ratio of Resmetirom dihydrate to isopropanol is 5:(10-100) g / mL, for example 5 g / 50 mL or 5 g / 20 mL.

10. The method for preparing Resmetirom Form I according to claim 8, characterized in that: The preparation method comprises the following post-treatment steps: after crystallization, filtering, washing and drying to obtain the Resmetirom Form I, wherein the washing is performed, for example, with isopropanol.

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