Chidamide crystal form I and preparation method thereof

Abstract

The present invention relates to the field of drug crystal forms, and specifically relates to a crystal form I of chidamide and a preparation method thereof. The crystal form I of chidamide has good stability, fluidity, solubility, good bioavailability, and low hygroscopicity, possesses drug-forming advantages, and can be developed as a pharmaceutical crystal form. The preparation method of the crystal form I is simple, has good reproducibility, high yield, is easy to operate, is environmentally friendly, requires a small amount of solvent and is conducive to recycling, can effectively reduce reagent costs, and easily achieves large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of drug crystal forms, and in particular to a crystal form I of chidamide and a preparation method thereof. Background Art

[0002] Chidamide (trade name: Aipusa) is an HDAC inhibitor developed by Shenzhen Microchip Biotechnology Co., Ltd. for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) who have received at least one prior systemic chemotherapy. It is also used in combination with aromatase inhibitors to treat hormone receptor-positive, human epidermal growth factor receptor-2-negative, postmenopausal patients with locally advanced or metastatic breast cancer that has relapsed or progressed after endocrine therapy. The structure of Chidamide is shown in Formula (I):

[0003]

[0004] Only CN103833626B discloses two crystalline forms of chidamide, Form A and Form B. However, both Forms A and B exhibit poor high-temperature stability, high hygroscopicity, and low in vivo bioavailability. Example 2 of CN1284772C produced chidamide, but repeated analysis revealed Form B. The resulting solid contained 4.7% of undesired products and a tetrahydrofuran solvent content of 1.8%, far exceeding the ICH limit of 0.072% residual solubility, making it unsuitable for pharmaceutical manufacturing. Therefore, there is a need to develop a pharmaceutically acceptable crystalline form with excellent overall performance. Summary of the Invention

[0005] In response to the above-mentioned problems existing in the prior art, the present invention provides a crystalline form I of chidamide and a preparation method thereof; the crystalline form I of chidamide has better stability, hygroscopicity, solubility and bioavailability; the preparation method of the crystalline form I is simple, reproducible, high in yield, easy to operate, environmentally friendly, requires a small amount of solvent and is easy to recycle, can effectively reduce reagent costs, and easily achieves large-scale production.

[0006] In a first aspect, the present invention provides a crystalline form I of chidamide, whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.7±0.2°, 7.1±0.2°, 9.1±0.2°, 18.4±0.2°, 20.1±0.2° and 23.8±0.2°.

[0007] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ angles of 6.7±0.2°, 7.1±0.2°, 9.1±0.2°, 11.3±0.2°, 14.2±0.2°, 18.1±0.2°, 18.4±0.2°, 18.7±0.2°, 20.1±0.2°, 21.4±0.2°, 22.2±0.2°, 23.8±0.2° and 27.4±0.2°.

[0008] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ angles of 6.7±0.2°, 7.1±0.2°, 9.1±0.2°, 11.3±0.2°, 14.2±0.2°, 18.1±0.2°, 18.4±0.2°, 18.7±0.2°, 19.3±0.2°, 20.1±0.2°, 21.4±0.2°, 21.8±0.2°, 22.2±0.2°, 23.8±0.2°, 25.5±0.2°, 26.8±0.2°, 27.4±0.2°, 28.6±0.2° and 31.3±0.2°.

[0009] In some specific embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form I is substantially as follows: Figure 1 shown.

[0010] In some embodiments of the present invention, the DSC spectrum of the crystalline form I has an endothermic peak at 238.53±5°C.

[0011] In some specific embodiments of the present invention, the DSC spectrum of the crystalline form I is substantially as follows Figure 2 shown.

[0012] In some specific embodiments of the present invention, the TGA spectrum of the crystalline form I shows a weight loss of approximately 0.55% at 30-120°C.

[0013] In some specific embodiments of the present invention, the TGA spectrum of the crystalline form I is substantially as follows Figure 3 shown.

[0014] A second aspect of the present invention provides a method for preparing the Chidamide crystals I described in the first aspect, the method comprising:

[0015] (1) dissolving chidamide in solvent A;

[0016] (2) taking an appropriate amount of seed crystals of the Form I and suspending them in solvent B;

[0017] (3) The solution of step (1) is added dropwise to the suspension of step (2), stirred and crystallized to obtain Form I.

[0018] In some embodiments of the present invention, the dissolution temperature in step (1) is room temperature.

[0019] In some specific embodiments of the present invention, the mass volume ratio (g / mL) of chidamide to the solvent A is 1:(1-5).

[0020] In some specific embodiments of the present invention, the mass volume ratio (g / mL) of chidamide to the solvent A is 1:3.

[0021] In some specific embodiments of the present invention, the mass volume ratio (g / mL) of chidamide to the solvent B is 1:(10-50).

[0022] In some specific embodiments of the present invention, the mass volume ratio (g / mL) of chidamide to the solvent B is 1:30.

[0023] In some embodiments of the present invention, the solvent A is selected from one or more of DMF (N,N-dimethylformamide), NMP (N-methyl-2-pyrrolidone), and DMSO (dimethyl sulfoxide).

[0024] In some embodiments of the present invention, the solvent A is selected from DMSO.

[0025] In some embodiments of the present invention, the solvent B is an alcohol solvent.

[0026] In some specific embodiments of the present invention, the solvent B is selected from one or more of methanol, ethanol, isopropanol, etc.

[0027] In some embodiments of the present invention, the solvent B is selected from ethanol.

[0028] In some specific embodiments of the present invention, the amount of the seed crystal I is 1 to 10% by weight of the chidamide feed amount.

[0029] In some specific embodiments of the present invention, the amount of the seed crystal I is 5% by weight of the chidamide feed amount.

[0030] In some embodiments of the present invention, the stirring and crystallization time in step (3) is 1 to 4 hours.

[0031] In some embodiments of the present invention, the stirring crystallization time in step (3) is 2 hours.

[0032] The third aspect of the present invention provides another method for preparing the Chidamide crystals I described in the first aspect, the method comprising: heating solid Chidamide to a certain temperature, maintaining it for a period of time, and then cooling it to room temperature to obtain the Chidamide crystals I.

[0033] In some specific embodiments of the present invention, the heating temperature is 200°C-230°C, preferably 220°C.

[0034] In some specific embodiments of the present invention, the heating time is 10 min-60 min, preferably 30 min.

[0035] In some specific embodiments of the present invention, the crystalline form I of chidamide prepared in the third aspect of the present invention can be used as a seed crystal for the preparation of the crystalline form I described in the second aspect.

[0036] Beneficial effects of the present invention:

[0037] 1. The chidamide crystalline form I of the present invention and / or the chidamide crystalline form I prepared by the preparation method of the present invention has good physical and chemical properties, especially good stability, solubility, lower hygroscopicity and better bioavailability, and the solvent residue meets the requirements, and can be developed as a pharmaceutical crystalline form.

[0038] 2. Compared with the existing crystal forms A and B, the crystal form I of the present invention has better solvent stability, thermal stability and lower hygroscopicity, and has better industrial applicability in the raw material and preparation processes.

[0039] 3. Compared with the prior art crystal form A, the crystal form I of the present invention also has better pharmacokinetic parameters and better bioavailability in the body.

[0040] 4. The preparation method of the chidamide crystal form I of the present invention is simple, has good reproducibility, high yield, is easy to operate, is green and environmentally friendly, requires a small amount of solvent and is conducive to recycling, can effectively reduce reagent costs, and is easy to achieve large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is the XRD pattern of Chidamide Form I.

[0042] Figure 2 This is the DSC diagram of Chidamide Form I.

[0043] Figure 3 This is the TGA diagram of Chidamide Form I.

[0044] Figure 4 This is a comparison chart of the long-term and accelerated stability studies of 6 months for the crystalline form of Chidamide Form I.

[0045] Figure 5 1 is the average drug concentration-time curve of chidamide crystal form I and crystal form A. DETAILED DESCRIPTION

[0046] In order to make the present invention easier to understand, the present invention will be described in detail below with reference to embodiments. These embodiments are only for illustration and do not limit the scope of application of the present invention.

[0047] The "room temperature" mentioned in the present invention refers to a temperature of 10 to 25°C.

[0048] The "Cidamide Crystal Form I" and "Crystal Form I" described in the present invention can be used interchangeably without affecting their meanings.

[0049] Those skilled in the art will appreciate that in the preparation process of the crystalline form I of the present invention, the starting material, chidamide, needs to be dissolved. Therefore, the chidamide is not limited to physical forms and may include crude chidamide, chidamide in an amorphous form, chidamide in any crystalline form, or a mixture of the above physical forms. The starting material can be prepared according to any method disclosed in the prior art or commercially available.

[0050] Herein, crystal forms A and B were prepared according to the method disclosed in CN103833626B, and XRD analysis showed that they were consistent with that disclosed in patent CN103833626B.

[0051] In the preparation process of the seed crystals of Form I described herein, the starting material chidamide is preferably Form A or Form B.

[0052] The terms used in this invention are explained as follows:

[0053] XRD: X-ray powder diffraction

[0054] The X-ray powder diffraction (XRD) measurement of the present invention is performed using a Malvern Panalytical Empyrean X-ray powder diffractometer. The specific parameters are as follows:

[0055]

[0056] In the X-ray powder diffraction pattern of this application, the error of the 2θ diffraction angle is ±0.20°. In this article, "X-ray powder diffraction pattern is substantially as Figure 1 "shown" refers to the X-ray powder diffraction pattern and Figure 1 Substantially the same. The term "substantially the same" with respect to X-ray powder diffraction patterns is intended to take into account variations in representative peak positions and intensities.

[0057] DSC: Differential Scanning Calorimetry Analysis The differential scanning calorimetry (DSC) measurement described in the present invention is performed using a METTLERTOLEDO model DSC-1 with a heating rate of 10°C / min, a temperature range of 25-250°C, and a nitrogen purge rate of 60 mL / min during the test.

[0058] In this article, “DSC spectra are basically Figure 2 "shown" refers to the DSC spectrum and Figure 2 Substantially the same, the term "substantially the same" with respect to the DSC spectrum means that representative characteristic peak positions will be taken into account, for example, those skilled in the art will understand that characteristic peak positions will show some variation, typically up to 5°C.

[0059] TGA: Thermogravimetric analysis

[0060] The thermogravimetric analysis (TGA) measurements described herein were performed using a METTLER TOLEDO model TGA-2 with a heating rate of 10°C / min over a temperature range of 30-300°C. The nitrogen purge rate during the test was 20 mL / min.

[0061] The error of TGA can be within about ±0.5 mass%. Figure 3 "shown" refers to the TGA spectrum and Figure 3 The term "substantially the same" with respect to TGA patterns means that such error variations are taken into account.

[0062] DVS: Dynamic Vapor Sorption Analyzer

[0063] The dynamic vapor sorption instrument Q5000 (TA Instruments, USA) described in this application was used to measure the change in sample weight with humidity at 25°C. Specific parameters: equilibration at 25°C and 0% relative humidity for 200 minutes, followed by 10% relative humidity jumps every 150 minutes. If the weight change was less than 0.01% within each 15-minute period, a 10% relative humidity jump was performed until the relative humidity reached 98%. After 150 minutes, the relative humidity jump was reversed. The relative humidity changes were as follows: 0% - 10% - 20% - 30% - 40% - 50% - 60% - 70% - 80% - 90% - 98% - 90% - 80% - 70% - 60% - 50% - 40% - 30% - 20% - 10% - 0%. Data analysis software was TA Universal Analysis (TA Instruments, USA).

[0064] Example 1: Preparation of Chidamide Crystal Form I

[0065] 1.0 g of chidamide was weighed and dissolved in 3 mL of dimethyl sulfoxide (DMSO) at 25°C with stirring. 0.05 g of Form I seed crystals was weighed and suspended in 30 mL of ethanol. The DMSO solution was slowly added dropwise to the ethanol suspension. The mixture was stirred for 2 h to allow crystallization, filtered, and dried to obtain 0.86 g of chidamide Form I. The DMSO solvent residue was essentially absent.

[0066] The obtained Chidamide Form I was subjected to XRD analysis, DSC analysis and TGA analysis. The XRD pattern of the Chidamide Form I is as follows: Figure 1 The specific values of XRD characteristic peaks are shown in Table 1, and the DSC spectrum is shown in Figure 2 As shown, the TGA spectrum is as Figure 3 shown.

[0067] Table 1 Characteristic peak data of XRD pattern of Chidamide Form I

[0068]

[0069] Example 2: Preparation of Chidamide Form I Seed Crystals

[0070] Weigh 100 mg of chidamide, heat to 220 ° C for 30 minutes, and cool to room temperature to obtain Form I. The XRD pattern is the same as Figure 1 Basically the same.

[0071] Example 3: Preparation of Chidamide Form I Seed Crystals

[0072] Weigh 100 mg of chidamide, heat to 200 ° C for 60 min, and cool to room temperature to obtain Form I. The XRD pattern is the same as Figure 1 Basically the same.

[0073] Example 4: Preparation of Chidamide Form I Seed Crystals

[0074] Weigh 100 mg of chidamide, heat to 230 ° C for 10 minutes, and cool to room temperature to obtain Form I. The XRD pattern is the same as Figure 1 Basically the same.

[0075] Example 5: Preparation of Chidamide Crystal Form I

[0076] 1.0 g of chidamide was weighed and dissolved in 1 mL of DMF (N,N-dimethylformamide) at 25 ° C. 0.01 g of seed crystals of Form I was weighed and suspended in 10 mL of methanol. The DMF solution was slowly added dropwise to the methanol suspension, stirred for 1 h to crystallize, filtered, and dried to obtain 0.79 g of chidamide Form I. The XRD pattern was the same as Figure 1 Basically the same.

[0077] Example 6: Preparation of Chidamide Crystal Form I

[0078] 1.0 g of chidamide was weighed and dissolved in 5 mL of NMP (N-methyl-2-pyrrolidone) at 25 ° C. 0.1 g of seed crystals of Form I was weighed and suspended in 50 mL of isopropanol. The NMP solution was slowly added dropwise to the isopropanol suspension, stirred for 4 h to crystallize, filtered, and dried to obtain 0.85 g of chidamide Form I. The XRD pattern was the same as Figure 1 Basically the same.

[0079] Example 7: Preparation of Chidamide Crystal Form I

[0080] 10.0 g of chidamide was weighed and dissolved in 30 mL of DMSO at 25 °C. 0.5 g of seed crystals of Form I was weighed and suspended in 300 mL of ethanol. The DMSO solution was slowly added dropwise to the ethanol suspension, stirred for 2 h to crystallize, filtered, and dried to obtain 8.75 g of chidamide Form I. The XRD pattern was the same as Figure 1 Basically the same.

[0081] Test Example 1: Stability Study of Chidamide Crystal Form I

[0082] In order to investigate the storage stability of the chidamide crystal form I prepared in Example 1 of the present invention, the sample was placed under accelerated stability conditions of 25°C / RH60% and 40°C / RH75% for 3 months and 6 months to investigate its crystal form and purity stability. The results are shown in Table 2 below. The XRD patterns are shown in Table 2 below. Figure 4 As shown:

[0083] Table 2 Stability test of Chidamide crystal form I

[0084]

[0085] From Table 2 and Figure 4 It can be seen that the crystal form of Chidamide Form I did not change under the conditions studied, and the purity remained basically unchanged. It has good physical and chemical stability, and can ensure stable and controllable quality during the drug preparation process and storage conditions.

[0086] Experimental Example 2: Stability Study of Chidamide Form I and CN103833626B Forms A and B in Different Solvents

[0087] Chidamide Form I, Form A, and Form B prepared in Example 1 of the present invention were suspended and stirred in different solvents, and the solids were filtered and characterized by XRD. The results are shown in Table 3 below:

[0088] Table 3 Stability test of Chidamide Form I, Form A and Form B in different solvents

[0089]

[0090]

[0091] The experimental results show that the crystalline form I of chidamide has good crystal stability in water at different temperatures, and has better crystal stability than the crystalline form A and the crystalline form B in ethanol solvent.

[0092] Test Example 3: Thermal Stability Study of Chidamide Form I and CN103833626B Forms A and B

[0093] Chidamide Form I, Form A, and Form B were heated at high temperature for a certain period of time, and then cooled and subjected to XRD characterization. The results are shown in Table 4 below:

[0094] Table 4 Thermal stability test of Chidamide Form I, Form A and Form B

[0095] Starting crystal form temperature time Determination of crystal form after cooling Form I 230℃ 1h Form I Form A 230℃ 1h Form I Form B 230℃ 1h Form I

[0096] Experimental results show that Form I of Chidamide exhibits superior high-temperature stability compared to Forms A and B. This means that Form I is a very stable crystal over a wider temperature range, offering greater industrial applicability in both API and formulation processes.

[0097] Test Example 4: Hygroscopicity Study of Chidamide Form I and CN103833626B Forms A and B

[0098] Chidamide Form I, Form A, and Form B were subjected to DVS tests to investigate their hygroscopicity. The results are shown in Table 5 below:

[0099] Table 5 Hygroscopicity test of Chidamide crystal form I, crystal form A and crystal form B

[0100] Investigate the crystal form relative humidity Moisture absorption and weight gain Form I 98％ 0.503％ Form A 98％ 1.108％ Form B 98％ 1.745％

[0101] The experimental results show that under conditions of 98% relative humidity, the hygroscopicity of Form A is more than twice that of Form I, and the hygroscopicity of Form B is more than three times that of Form I. It can be seen that Form I of chidamide has lower hygroscopicity than Form A and Form B, is less likely to absorb moisture, and is more conducive to the preparation and storage of pharmaceutical preparations.

[0102] Test Example 5: Solubility Investigation of Chidamide Crystal Form I

[0103] According to the solubility test guidelines of the current Chinese Pharmacopoeia, experiments were designed to test the solubility of Form I in different solvent media. The test results showed that Form I has good solubility properties and meets the requirements for API and preparation declaration.

[0104] Test Example 6: Pharmacokinetics of Chidamide Form I and CN103833626B Form A

[0105] Animal experiments were conducted with both Form I and Form A of chidamide. Accurately weighed amounts of the test drug were added to a 0.5% methylcellulose solution and mixed to create a 0.5 mg / mL suspension for oral administration. Rats (n=2, half male and half female) received a single oral dose of 1 mg / kg of the test product. Whole blood was collected before and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and plasma was obtained by centrifugation. LC-MS / MS was used to quantify drug concentrations in rat plasma samples, and pharmacokinetic parameters were calculated using WinNonlin software according to the non-compartmental model. Figure 5 The average drug concentration-time curve in rat plasma after a single oral dose, and the main pharmacokinetic parameters are shown in Table 6 below:

[0106] Table 6 Pharmacokinetic parameters of Chidamide Form I and Form A

[0107]

[0108] The experimental results showed that the pharmacokinetics of crystalline form I of chidamide in male and female rats were significantly improved compared with crystalline form A, especially in male rats, the AUC and C max Compared with crystal form A, significant differences were achieved and it has significantly better pharmacokinetic properties.

[0109] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementation modes and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. A crystalline form I of chidamide, characterized in that: The X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ angles of 6.7±0.2°, 7.1±0.2°, 9.1±0.2°, 11.3±0.2°, 14.2±0.2°, 18.1±0.2°, 18.4±0.2°, 18.7±0.2°, 19.3±0.2°, 20.1±0.2°, 21.4±0.2°, 21.8±0.2°, 22.2±0.2°, 23.8±0.2°, 25.5±0.2°, 26.8±0.2°, 27.4±0.2°, 28.6±0.2° and 31.3±0.2°.

2. The chidamide crystalline form I according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystalline form I is substantially as shown in FIG1 .

3. The chidamide crystalline form I according to any one of claims 1 to 2, characterized in that The DSC spectrum of the crystalline form I has an endothermic peak at 238.53±5°C.

4. The chidamide crystalline form I according to claim 3, characterized in that The DSC spectrum of the crystalline form I is basically shown in Figure 2.

5. The chidamide crystalline form I according to any one of claims 1-2, characterized in that The TGA spectrum of the crystalline form I is basically shown in Figure 3.

6. A method for preparing the Chidamide crystal form I according to claim 1 or 2, characterized in that: The following steps are involved: (1) dissolving chidamide in solvent A; (2) taking an appropriate amount of seed crystals of the Form I and suspending them in solvent B; (3) adding the solution of step (1) dropwise to the suspension of step (2), stirring and crystallizing to obtain the crystalline form I; in: In the step (1), the dissolution temperature is room temperature; In the step (1), the mass volume ratio (g / mL) of chidamide to the solvent A is 1:(1-5); In the step (1), the mass volume ratio (g / mL) of chidamide to the solvent B is 1:(10-50); The solvent A is selected from one or more of DMF, NMP, and DMSO; The solvent B is selected from one or more of methanol, ethanol, and isopropanol; The amount of the seed crystal I is 1 to 10% by weight of the amount of chidamide fed; The stirring and crystallization time in step (3) is 1 to 4 hours.

7. The preparation method according to claim 6, characterized in that The method includes one or more of the following features: In the step (1), the mass volume ratio (g / mL) of chidamide to the solvent A is 1:3; In the step (1), the mass volume ratio (g / mL) of chidamide to the solvent B is 1:30; The solvent A is selected from DMSO; The solvent B is selected from ethanol; The amount of the seed crystal I is 5% by weight of the amount of chidamide fed; The stirring and crystallization time in step (3) is 2 hours.

8. A method for preparing the chidamide crystalline form I according to claim 1 or 2, comprising: After heating chidamide to a certain temperature, cooling to room temperature to obtain the crystal form I; The heating temperature is 200°C-230°C; The heating time is 10 min-60 min.

9. A pharmaceutical composition comprising the crystal form according to claim 1 or 2 and a pharmaceutically acceptable additive.

10. Use of the crystal form according to claim 1 or 2 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating diseases related to cell differentiation and proliferation.

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