Chidamide crystal form I and preparation method thereof

Abstract

The invention relates to the field of medicine crystal forms, in particular to a chidamide crystal form I and a preparation method thereof. The chidamide crystal form I has better stability, flowability and solubility, good bioavailability and lower hygroscopicity, has the advantage of patent medicine, and can be developed as a medicinal crystal form; the preparation method of the crystal form I is simple, good in repeatability, high in yield, easy to operate, green, environmentally friendly, small in needed solvent amount and beneficial to recycling, the reagent cost can be effectively reduced, and large-scale production is easy to achieve.

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 Aipusha) 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 systemic chemotherapy in the past; combined with aromatase inhibitors, it is used to treat hormone receptor-positive, human epidermal growth factor receptor-2-negative, postmenopausal, locally advanced or metastatic breast cancer patients who have relapsed or progressed after endocrine therapy. The structure of Chidamide is shown in the following formula (I):

[0003]

[0004] In the prior art, only CN103833626B discloses two crystal forms of cedabendine, which are crystal form A and crystal form B, but both crystal forms A and B have poor high temperature stability, high hygroscopicity, and low in vivo bioavailability. Example 2 of patent CN1284772C prepared cedabendine, but it was determined to be crystal form B after repeated determination, and the obtained solid contained 4.7% of non-target products, and the solvent content of tetrahydrofuran was 1.8%, which far exceeded the 0.072% residual solubility limit specified by ICH, and therefore was not suitable for drug manufacturing. Therefore, it is necessary to develop a pharmaceutically acceptable crystal form with excellent comprehensive performance in all aspects. Summary of the invention

[0005] In view of the above 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 and has good repeatability, high yield, easy operation, 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.

[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] The 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 crystalline form I and suspending them in solvent B;

[0017] (3) adding the solution of step (1) dropwise to the suspension of step (2), stirring and crystallizing 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 specific 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 1-10% by weight of the amount of the chidamide feed.

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

[0030] In some embodiments of the present invention, the stirring 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 the solid form of Chidamide to a certain temperature, maintaining it for a period of time, and then cooling it to room temperature to obtain the obtained product.

[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 crystal form I of the present invention and / or the Chidamide crystal 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 crystal form.

[0038] 2. Compared with the prior art 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 process of raw materials and preparations.

[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 vivo.

[0040] 4. The preparation method of the crystalline form I of the present invention is simple, has good repeatability, 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 crystalline form I of chidamide.

[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 of crystalline form of Chidamide Form I.

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

[0046] In order to make the present invention more easily understood, the present invention will be described in detail below in conjunction with embodiments. These embodiments are only for illustration and are not intended to limit the application scope of the present invention.

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

[0048] The "Cidabenamide 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 crystal form I of the present invention, the starting material, cedamide, needs to be dissolved, so the cedamide is not limited to the physical form, and may include crude cedamide, cedamide in an amorphous form, cedamide in any crystalline form, or a mixture of the above listed 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 determination was 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 the present invention are explained as follows:

[0053] XRD: X-ray powder diffraction

[0054] The X-ray powder diffraction (XRD) measurement of the present invention is collected using a Malvern Panalytical Empyrean X-ray powder diffractometer, and 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 meant 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" of a 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) of the present invention is carried out using a METTLER TOLEDO model TGA-2, with a heating rate of 10°C / min, a temperature range of 30-300°C, and a nitrogen purge rate of 20 mL / min during the test.

[0061] The error of TGA can be within about ±0.5 mass %. Figure 3 "shown" refers to the TGA spectrum and Figure 3 Substantially the same. 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 is used to detect the change of sample weight with humidity at 25°C. Specific parameters: equilibrate for 200 minutes at 25°C and 0% relative humidity, then perform a 10% relative humidity jump every 150 minutes. If the weight change is less than 0.01% within every 15 minutes, directly jump 10% relative humidity, and the relative humidity reaches 98%. After 150 minutes, perform a relative humidity jump in the opposite direction. The relative humidity changes 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 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 DMSO (dimethyl sulfoxide) at 25° C., 0.05 g of seed crystals of Form I were weighed and suspended in 30 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 0.86 g of chidamide Form I. It was determined that there was substantially no DMSO solvent residue.

[0066] The obtained Chidamide Form I was subjected to XRD analysis, DSC analysis and TGA analysis. The XRD spectrum 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 Figure 3 shown.

[0067] Table 1 Characteristic peak data of XRD pattern of cedabendamine crystal 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 min, and cool to room temperature to obtain Form I. The XRD pattern is similar to 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 min, and cool to room temperature to obtain Form I. The XRD spectrum is similar to Figure 1 Basically the same.

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

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

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

[0078] 1.0 g of cedaramide 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 cedaramide Form I. The XRD pattern was consistent with 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 consistent with 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 crystalline form I of chidamide 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 spectrum is 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 cedabenzamine Form I has not changed under the conditions studied, and the purity remains basically unchanged. It has good physical and chemical stability, and can ensure stable and controllable quality under the drug preparation process and storage conditions.

[0086] Test Example 2: Stability test of Chidamide Form I and CN103833626B Form A and Form B in different solvents

[0087] The chidamide crystal form I, crystal form A and crystal form B prepared in Example 1 of the present invention were suspended and stirred in different solvents, and the solids were filtered for XRD characterization. The results are shown in Table 3 below:

[0088] Table 3 Stability test of cedabenamide crystal form I, crystal form A and crystal form B in different solvents

[0089]

[0090]

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

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

[0093] Chidamide Form I, Form A and Form B were respectively placed in a high temperature environment and heated for a certain period of time, and then XRD characterization was performed after cooling. The results are shown in Table 4 below:

[0094] Table 4 Thermal stability test of cedabenamine crystal form I, crystal form A and crystal form B

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

[0096] The experimental results show that the crystalline form I of Chidamide has better high temperature stability than the crystalline form A and the crystalline form B. That is, the crystalline form I is a very stable crystal in a wider temperature range, and has better industrial applicability in the process of raw materials and preparations.

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

[0098] The hygroscopicity of the crystalline form I, crystalline form A and crystalline form B of Chidamide was investigated by DVS test, and the results are shown in Table 5 below:

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

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

[0101] The experimental results show that under 98% relative humidity conditions, 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 Study 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 characteristics and meets the requirements for the declaration of raw materials and preparations.

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

[0105] Animal experiments were conducted on the crystalline form I and the crystalline form A of Chidamide, and a certain amount of the test drug was accurately weighed, and a 0.5% methylcellulose solution was added and mixed to prepare a 0.5 mg / mL suspension for oral administration. Rats (n=2, half male and half female) were given a single oral dose of 1 mg / kg of the test product, and 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 after centrifugation. The concentration of the drug in the rat plasma samples was quantitatively detected by LC-MS / MS method, and the pharmacokinetic parameters were calculated according to the non-compartmental model method using WinNonlin software. Figure 5 The average drug concentration-time curve in plasma after a single oral administration in rats, the main pharmacokinetic parameters are shown in Table 6 below:

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

[0107]

[0108] The experimental results showed that the pharmacokinetics of cedabenamide crystal form I in male and female mice were significantly improved compared with crystal form A, especially in male mice, 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 implementations 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°, 18.4±0.2°, 20.1±0.2° and 23.8±0.2°.

2. The chidamide crystal form I according to claim 1, 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°, 20.1±0.2°, 21.4±0.2°, 22.2±0.2°, 23.8±0.2° and 27.4±0.2°; Preferably, 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°; More preferably, the X-ray powder diffraction pattern of the crystalline form I is substantially as shown in Figure 1.

3. The chidamide crystal form I according to any one of claims 1-2, characterized in that The DSC spectrum of the crystal form I has an endothermic peak at 238.53±5°C; Preferably, the DSC spectrum of the crystalline form I is substantially as shown in Figure 2.

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

5. A method for preparing the Chidamide crystal form I according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) dissolving chidamide in solvent A; (2) taking an appropriate amount of seed crystals of the crystalline 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.

6. The preparation method according to claim 5, characterized in that: The method comprises one or more of the following features: 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% of the weight of the chidamide feed; The stirring and crystallization time in step (3) is 1 to 4 hours.

7. The preparation method according to any one of claims 5 to 6, characterized in that: The method comprises 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 the chidamide feed; The stirring and crystallization time in step (3) is 2 hours.

8. A method for preparing the Chidamide crystalline form I according to any one of claims 1 to 4, comprising: After heating chidamide to a certain temperature, cooling to room temperature to obtain the crystal form I; Preferably, the heating temperature is 200°C-230°C; Preferably, the heating time is 10 min-60 min.

9. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 4 and a pharmaceutically acceptable additive.

10. Use of the crystal form according to any one of claims 1 to 4 and the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating diseases associated with cell differentiation and proliferation.

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