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 application relates to the field of pharmaceutical crystal forms, in particular to a crystal form I of cedazanolamine and a preparation method thereof. BACKGROUND

[0002] Cedazanolamine (trade name: Esplon) is an HDAC inhibitor developed by Shenzhen Microchip Biotechnology Co., Ltd. for treating relapsed or refractory peripheral T-cell lymphoma (PTCL) patients who have received at least one systemic chemotherapy; combined with aromatase inhibitors for treating hormone receptor-positive, human epidermal growth factor receptor-2-negative, postmenopausal, endocrine therapy relapsed or advanced local advanced or metastatic breast cancer patients. The structure of cedazanolamine is shown in the following formula (I):

[0003]

[0004] The prior art only discloses two crystal forms of cedazanolamine, namely crystal form A and crystal form B in CN103833626B, but the high temperature stability of crystal form A and B is poor, and has high moisture absorption, and the in vivo bioavailability is also low. Patent CN1284772C example 2 prepared cedazanolamine, but its repeated determination is crystal form B, and the obtained solid contains 4.7% of non-target product, and the solvent content of tetrahydrofuran is 1.8%, far exceeding the ICH specified 0.072% residual solvent limit, so it is not suitable for pharmaceutical manufacturing. Therefore, it is necessary to develop a pharmaceutical crystal form with excellent comprehensive performance. SUMMARY

[0005] In view of the above problems existing in the prior art, the present application provides a crystal form I of cedazanolamine and a preparation method thereof; the crystal form I of cedazanolamine has better stability, hygroscopicity, solubility and bioavailability; the preparation method of the crystal form I is simple, reproducible, high-yield, easy to operate, green and environmentally friendly, requires small amount of solvent and is conducive to recycling and utilization, can effectively reduce the cost of reagents, and is easy to realize large-scale production.

[0006] The first aspect of the present application provides a crystal form I of cedazanolamine, which 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° in the X-ray powder diffraction pattern.

[0007] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline Form I has characteristic peaks at 2-theta 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 application, the X-ray powder diffraction pattern of the crystalline Form I has characteristic peaks at 2-theta 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 embodiments of the present application, the X-ray powder diffraction pattern of the crystalline Form I has characteristic peaks at 2-theta 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°. Figure 1

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

[0011] In some embodiments of the present application, the DSC pattern of the crystalline Form I has an endothermic peak at 238.53±5°C. Figure 2

[0012] In some embodiments of the present application, the TGA pattern of the crystalline Form I has a weight loss of about 0.55% at 30-120°C.

[0013] In some embodiments of the present application, the TGA pattern of the crystalline Form I has a weight loss of about 0.55% at 30-120°C. Figure 3

[0014] The second aspect of the present application provides a method for preparing the crystalline Form I of chidamide according to the first aspect, which comprises:

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

[0016] (2) suspending a proper amount of the crystal seeds of the crystalline Form I in solvent B;

[0017] (3) adding the solution of step (1) into the suspension of step (2) dropwise, and stirring to crystallize to obtain the crystalline Form I.​​​

[0018] In some embodiments of the present application, the temperature for dissolving in step (1) is room temperature.

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

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

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

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

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

[0024] In some embodiments of the present application, the solvent A is DMSO.

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

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

[0027] In some embodiments of the present application, the solvent B is ethanol.

[0028] In some embodiments of the present application, the amount of the seed crystal I is 1-10% of the weight of the chidamide to be fed.

[0029] In some embodiments of the present application, the amount of the seed crystal I is 5% of the weight of the chidamide to be fed.

[0030] In some embodiments of the present application, the stirring and crystallization in step (3) is performed for 1-4 h.

[0031] In some embodiments of the present application, the stirring and crystallization in step (3) is performed for 2 h.

[0032] The third aspect of the present application provides another method for preparing the chidamide crystal I of the first aspect, which comprises heating solid chidamide to a certain temperature for a certain period of time and then cooling to room temperature.

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

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

[0035] In some embodiments of the present application, the crystalline form I of secliduggine prepared by the third aspect of the present application can be used as a seed crystal for the preparation of the crystalline form I of the second aspect.

[0036] The beneficial effects of the present application are:

[0037] 1. The crystalline form I of secliduggine and the crystalline form I of secliduggine prepared by the preparation method of the present application have good physicochemical properties, especially good stability, solubility, lower hygroscopicity and more excellent bioavailability, and the solvent residue meets the requirements, and can be developed as a pharmaceutical crystalline form.

[0038] 2. Compared with the crystalline form A and the crystalline form B of the prior art, the crystalline form I of the present application has more excellent solvent stability, thermal stability and lower hygroscopicity, and has better industrial availability in the process of bulk drug and preparation.

[0039] 3. Compared with the crystalline form A of the prior art, the crystalline form I of the present application also has more excellent pharmacokinetic parameters and better bioavailability in vivo.

[0040] 4. The preparation method of the crystalline form I of secliduggine of the present application is simple, reproducible, high-yield, easy to operate, green and environmentally friendly, requires small amount of solvent and is conducive to recycling and utilization, can effectively reduce the cost of reagents, and is easy to realize large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 The XRD pattern of the crystalline form I of secliduggine.

[0042] Figure 2 The DSC pattern of the crystalline form I of secliduggine.

[0043] Figure 3 The TGA pattern of the crystalline form I of secliduggine.

[0044] Figure 4 The long-term and accelerated stability test of the crystalline form I of secliduggine for 6 months.

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

[0046] In order to make the present application more easily understood, the present application will be described in detail below in conjunction with embodiments, which are only illustrative and not limited to the scope of the present application.

[0047] The "room temperature" as used herein refers to a temperature of 10-25°C.

[0048] The "crystalline form I of xidobamine" and "crystalline form I" as used herein can be used interchangeably without affecting the meaning thereof.

[0049] It is understood by those skilled in the art that, in the preparation of the crystalline form I of the present application, the xidobamine as a starting material needs to be dissolved, and therefore the xidobamine is not limited to a physical form, which can include xidobamine crude, xidobamine in amorphous form, xidobamine 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, the crystalline forms A and B are prepared according to the method disclosed in CN103833626B, and are determined by XRD and are consistent with the disclosure in CN103833626B.

[0051] In the preparation of the seed crystal of the crystalline form I herein, the starting material xidobamine is preferably crystalline form A or crystalline form B.

[0052] The explanations of the terms used in the present application are as follows:

[0053] XRD: X-ray powder diffraction

[0054] The X-ray powder diffraction (XRD) measurement as used herein is collected by 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 the present application, the error of the 2θ diffraction angle is ±0.20°. Herein, "the X-ray powder diffraction pattern is substantially as shown in Figure 1 ", means that the X-ray powder diffraction pattern and Figure 1 are substantially the same, and the term "substantially the same" in the X-ray powder diffraction pattern means that the representative peak position and intensity variation are taken into account.

[0057] DSC: differential scanning calorimetry The differential scanning calorimetry (DSC) measurement as used herein is collected by using a METTLER TOLEDO model DSC-1, with a temperature rate of 10°C / min, a temperature range of 25-250°C, and a nitrogen purging rate of 60 mL / min during the test.

[0058] As used herein, "a DSC pattern substantially as shown in Figure 2 As used herein, "a TGA pattern substantially as shown in Figure 2 As used herein, "a TGA pattern substantially as shown in

[0059] TGA: Thermogravimetric Analysis

[0060] The thermogravimetric analysis (TGA) determination described herein was performed using a METTLER TOLEDO model TGA-2 at 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 in TGA can be about ± 0.5 mass %. As used herein, "a TGA pattern substantially as shown in Figure 3 As used herein, "a TGA pattern substantially as shown in Figure 3 As used herein, "a TGA pattern substantially as shown in

[0062] DVS: Dynamic Vapor Sorption

[0063] The dynamic vapor sorption Q5000 (TA Instruments, USA) was used to measure the change in sample weight with humidity at 25 °C. The specific parameters were as follows: equilibration at 25 °C, 0% relative humidity for 200 min, then a 10% relative humidity jump every 150 min, if the weight change was less than 0.01% within 15 min, then directly jump to 10% relative humidity, the relative humidity reached 98%, and after 150 min, a reverse relative humidity jump was performed. 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%. The data analysis software was TA Universal Analysis (TA Instruments, USA).

[0064] Example 1: Preparation of crystalline form I of cedazanolamide

[0065] Cedazanolamide 1.0 g was weighed and dissolved in 3 mL of DMSO (dimethyl sulfoxide) at 25 °C with stirring, 0.05 g of crystal seed of form I was weighed and suspended in 30 mL of ethanol, the DMSO solution was slowly added to the ethanol suspension, and the mixture was stirred for 2 h to crystallize, filtered, and dried to obtain 0.86 g of cedazanolamide crystal form I. The determination showed that there was substantially no residual DMSO solvent.

[0066] The obtained crystalline form I of sedaquinamide was subjected to XRD analysis, DSC analysis and TGA analysis, the XRD pattern of the crystalline form I of sedaquinamide is shown in Figure 1 , the specific values of XRD characteristic peaks are shown in Table 1, the DSC pattern is shown in Figure 2 , and the TGA pattern is shown in Figure 3 .

[0067] Table 1: XRD pattern characteristic peak data of the crystalline form I of sedaquinamide

[0068]

[0069] Example 2: Preparation of seed crystal of the crystalline form I of sedaquinamide

[0070] Take 100 mg of sedaquinamide, heat to 220°C for 30 min, cool to room temperature to obtain the crystalline form I, and the XRD pattern is substantially consistent with Figure 1 .

[0071] Example 3: Preparation of seed crystal of the crystalline form I of sedaquinamide

[0072] Take 100 mg of sedaquinamide, heat to 200°C for 60 min, cool to room temperature to obtain the crystalline form I, and the XRD pattern is substantially consistent with Figure 1 .

[0073] Example 4: Preparation of seed crystal of the crystalline form I of sedaquinamide

[0074] Take 100 mg of sedaquinamide, heat to 230°C for 10 min, cool to room temperature to obtain the crystalline form I, and the XRD pattern is substantially consistent with Figure 1 .

[0075] Example 5: Preparation of the crystalline form I of sedaquinamide

[0076] Take 1.0 g of sedaquinamide, stir and dissolve in 1 mL of DMF (N,N-dimethylformamide) at 25°C, take 0.01 g of seed crystal of the crystalline form I and suspend in 10 mL of methanol, slowly drop the DMF solution into the methanol suspension, stir for 1 h to crystallize, filter and dry to obtain 0.79 g of the crystalline form I of sedaquinamide, and the XRD pattern is substantially consistent with Figure 1 .

[0077] Example 6: Preparation of the crystalline form I of sedaquinamide

[0078] Take 1.0 g of sedaquinamide, stir and dissolve in 5 mL of NMP (N-methyl-2-pyrrolidone) at 25°C, take 0.1 g of seed crystal of the crystalline form I and suspend in 50 mL of isopropanol, slowly drop the NMP solution into the isopropanol suspension, stir for 4 h to crystallize, filter and dry to obtain 0.85 g of the crystalline form I of sedaquinamide, and the XRD pattern is substantially consistent with Figure 1substantially the same.

[0079] Example 7: Preparation of crystalline form I of sedaabenamine

[0080] Sedaabenamine 10.0 g was weighed and dissolved by stirring in 30 mL of DMSO at 25°C, 0.5 g of crystal seeds of Form I were suspended in 300 mL of ethanol, and the DMSO solution was slowly added dropwise to the ethanol suspension, and crystals were precipitated by stirring for 2 h, filtered, and dried to obtain 8.75 g of Form I of sedaabenamine, and the XRD spectrum was substantially the same as that of Form I of sedaabenamine. Figure 1 substantially the same.

[0081] Test Example 1: Stability test of Form I of sedaabenamine

[0082] In order to investigate the storage stability of Form I of sedaabenamine prepared in Example 1 of the present application, the sample was placed under accelerated stability conditions of 25°C / RH 60% and 40°C / RH 75% for 3 months and 6 months to investigate the stability of the crystal form and purity, and the results are shown in Table 2 below, and the XRD spectrum is shown in Figure 4

[0083] Table 2: Stability test of Form I of sedaabenamine

[0084]

[0085] From Table 2 and Figure 4 it can be seen that Form I of sedaabenamine did not change in crystal form under the conditions investigated, and the purity remained substantially unchanged, and had good physical and chemical stability, which can ensure the quality to be stable and controllable under the conditions of pharmaceutical preparation and storage.

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

[0087] Form I of sedaabenamine prepared in Example 1 of the present application and Form A and Form B were suspended and stirred in different solvents, and the solid was filtered and characterized by XRD, and the results are shown in Table 3 below:

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

[0089]

[0090]

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

[0092] ​Test Example 3: Thermal stability test of crystalline form I of sedaabenamine and crystalline form A and form B of CN103833626B

[0093] Sedaabenamine crystalline form I and form A and form B were heated in a high temperature environment for a certain period of time, and then cooled and characterized by XRD. The results are shown in Table 4 below.

[0094] Table 4 Thermal stability test of sidaabenamine crystalline form I and form A and form B

[0095] Starting crystalline form Temperature Time Determined crystalline form after cooling Crystalline Form I 230℃ 1h Crystalline Form I Crystalline Form A 230℃ 1h Crystalline Form I Crystalline Form B 230℃ 1h Crystalline Form I

[0096] The experimental results show that sidaabenamine crystalline form I has better high temperature stability than form A and form B. That is, crystalline form I is very stable at a wider temperature range, and has better industrial availability in the process of bulk drug and preparation.

[0097] Test Example 4: Hygroscopicity test of sidaabenamine crystalline form I and crystalline form A and form B of CN103833626B

[0098] Sedaabenamine crystalline form I and form A and form B were subjected to DVS test to investigate the hygroscopicity, and the results are shown in Table 5 below.

[0099] Table 5 Hygroscopicity test of sidaabenamine crystalline form I and form A and form B

[0100] Investigated crystalline form Relative humidity Hygroscopic weight gain Crystalline Form I 98％ 0.503％ Crystalline Form A 98％ 1.108％ Crystalline Form B 98％ 1.745％

[0101] The experimental results show that under the condition 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. Therefore, sidaabenamine crystalline form I has lower hygroscopicity than form A and form B, is less prone to moisture absorption, and is more conducive to the preparation and storage of pharmaceutical preparations.

[0102] Test Example 5: Solubility test of sidaabenamine crystalline form I

[0103] According to the current guidance principle of solubility test in Chinese Pharmacopoeia, the experiment was designed to test the solubility of form I in different solvent media. The experimental results show that form I has good solubility characteristics and meets the requirements of bulk drug and preparation declaration.

[0104] Test Example 6: Pharmacokinetics test of sidaabenamine crystalline form I and crystalline form A of CN103833626B

[0105] The chidamide Form I and Form A were respectively subjected to animal experiments, and a certain amount of test drug was accurately weighed, added into 0.5% methyl cellulose solution and mixed to obtain a suspension of 0.5 mg / mL for oral administration. Rats (n=2, half male and half female) were orally administered with 1 mg / kg of test product, and whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h before and after administration, and plasma was obtained after centrifugation. The concentration of the drug in the rat plasma sample was quantitatively detected by LC-MS / MS method, and the pharmacokinetic parameters were calculated by WinNonlin software according to the non-compartment model method. Figure 5 The average drug concentration-time curve in the plasma of rats after single oral administration is shown in Figure 2, and the main pharmacokinetic parameters are shown in Table 6.

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

[0107]

[0108] The test results show that the pharmacokinetics of chidamide Form I in male and female mice is significantly improved compared with Form A, especially in male mice, the AUC and Cmax of Form I are 2.5 times and 1.5 times higher than those of Form A, respectively. max Significant differences were obtained compared with Form A, and the pharmacokinetic properties were obviously better.

[0109] Those skilled in the art will appreciate that the scope of the present application is not limited to the various specific embodiments and examples described above, but that various modifications, substitutions, or re-combinations can be made without departing from the spirit of the present application, and all fall within the scope of the present application.

Claims

1. A crystalline form I of chidamide, characterized in that, The X-ray powder diffraction pattern of crystal 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 daidzein I crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form I shows 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 crystal 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 crystal form I is basically as shown in Figure 1.

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

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

5. A method for preparing styrene crystal form I as described in any one of claims 1-4, characterized in that, Includes the following steps: (1) Dissolve daidzein in solvent A; (2) Take an appropriate amount of the seed crystals of crystal form I and suspend them in solvent B; (3) Add the solution from step (1) dropwise to the suspension from step (2), stir to crystallize, and obtain the crystal form I.

6. The preparation method according to claim 5, characterized in that, The method includes one or more of the following features: In step (1), the dissolution temperature is room temperature; In step (1), the mass-to-volume ratio (g / mL) of daidzepine to solvent A is 1:(1-5); In step (1), the mass-to-volume ratio (g / mL) of daidzepine to solvent B is 1:(10-50); Solvent A is selected from one or more of DMF, NMP, and DMSO; Solvent B is selected from one or more of methanol, ethanol, and isopropanol; The amount of seed crystal I is 1 to 10% of the weight of the amount of dabenamine added; The stirring and crystallization time in step (3) is 1 to 4 hours.

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

8. A method for preparing styrazine crystal form I as described in any one of claims 1-4, comprising: Chidamide was heated to a certain temperature and then cooled to room temperature to obtain the crystal form I. Preferably, the heating temperature is 200℃-230℃; Preferably, the heating time is 10 min to 60 min.

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

10. The use of the crystal form according to any one of claims 1-4, 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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